Embryology - User contributions [en-gb]

User:Z3372824

2015-10-30T02:38:52Z

Z3372824:

==Lab Attendance==

--[[User:Z3372824|Z3372824]] ([[User talk:Z3372824|talk]]) 13:46, 7 August 2015 (AEST)

--[[User:Z3372824|Z3372824]] ([[User talk:Z3372824|talk]]) 13:38, 14 August 2015 (AEST)

--[[User:Z3372824|Z3372824]] ([[User talk:Z3372824|talk]]) 15:14, 21 August 2015 (AEST)

--[[User:Z3372824|Z3372824]] ([[User talk:Z3372824|talk]]) 12:12, 28 August 2015 (AEST)

--[[User:Z3372824|Z3372824]] ([[User talk:Z3372824|talk]]) 12:14, 4 September 2015 (AEST)

--[[User:Z3372824|Z3372824]] ([[User talk:Z3372824|talk]]) 12:57, 25 September 2015 (AEST)

--[[User:Z3372824|Z3372824]] ([[User talk:Z3372824|talk]]) 12:48, 9 October 2015 (AEDT)

--[[User:Z3372824|Z3372824]] ([[User talk:Z3372824|talk]]) 13:37, 16 October 2015 (AEDT)

--[[User:Z3372824|Z3372824]] ([[User talk:Z3372824|talk]]) 13:07, 23 October 2015 (AEDT)

--[[User:Z3372824|Z3372824]] ([[User talk:Z3372824|talk]]) 13:38, 30 October 2015 (AEDT)

----

{{StudentPage2015}}

[[Test student 2015]]

==Week 1 Assessment==

1) PMID 18603501

Increased Progesterone/Estradiol Ration on the Day of hCG Administration Adversely Affects Success of In Vitro Fertilisation-Embryo Transfer in Patients Stimulated with Gonadotropin-releasing Hormone Agonist and Recombinant Follicle-stimulating Hormone

This study examines the influence of premature luteinisation, with respect to ovarian response, during IVF. This was done using gonadotropin-releasing hormone agonist (GnRHa) and recombinant follicle-stimulating hormone (rFSH).The study defined premature luteinisation as a ratio between progesterone and estradiol of greater than one, the day hCG was administered. The experimental group of prematurely luteinised was then compared to the non-prematurely luteinised groups.

The study was performed on 311 infertile couples, in which a total of 339 cycles of ovarian hyperstimulation with GnRHa and rFSH. The females studied were aged from 20 to 40 years, and did not undergo cycles incorporating hMG, nor did they receive oocyte donations. The patients underwent ovarian stimulation, a long stimulation protocol of GnRHa therapy, rFSH administration as well as transvaginal oocyte retrieval, respectively. hCG was administered after adequate follicular maturation and oocytes were obtained 35-37 hours after hCG administration using transvaginal aspiration with ultrasound assistance. The follicular fluids and follicular washes were examined using a dissecting stereomicroscope that was incubated at 37 degrees with 5%CO2. Sperm insemination procedures were also performed, after which the oocytes were inseminated with spermatozoa. The oocytes were removed after 2 hour exposures to the spermatozoa and cultured in fresh IVF medium. The control group underwent ICSI procedures, while the experimental group underwent IVF procedures. The oocytes were then cultured and assessed for pronuclei presence 16-18 hours incubation in order to determine fertilisation (presence of 2 pronuclei). Embryos were then cultured and classified, as were the blastocysts.

The study found 137 out of the 339 cycles to have premature luteinisation. Poor ovarian response was more common in the experimental group. It was also found the the experimental group had a higher progesterone level and lower E2 level on the hCG administration day. However the mean luteinising hormone on day 6 of stimulation was similar in both control and study groups but higher in the control group on hCG administeration day. The experimental group demonstrated a lower number of oocytes obtained, and lower number of mature oocytes recovered. It should be noted that fertilisation rates were similar in both groups. Embryo number was lower for the experimental group compared to the control group. 130 gestational sacs were demonstrated after a transfer of 577 embryos in the control group while 76 gestational sacs were demonstrated out of 339 embryo transfers in the study group. The non-prematurely luteinised group and prematurely luteinised group had similar implantation rates. It was also found that 48.5% of the non-prematurely luteinised group achieved clinical pregnancies while 36.6% of the prematurely luteinised group achieved clinical pregnancies.

<pubmed>18603501</pubmed>

2) PMID 21793811

Impact of endometriosis on in vitro fertilization and embryo transfer cycles in young women; a stage-dependent interference

Due to the significantly higher prevalence of endometriosis in infertile women as compared to the general population, a causal relationship between endometriosis and infertility has been postulated. In vitro fertilisation and embryo transfer (IVF-ET) has been considered a suitable treatment for patients with a history of endometriosis. This study examines the effect of endometriosis on IVF-ET cycles on women younger than 35 years of age and who have had surgical treatment for endometriosis without clinical recurrence signs. The endometriosis group was compared to another group of patients also undergoing IVF-ET, but with tubal infertility without clinical signs of endometriosis. The results were analysed according to the different stages of endometriosis as classified by the American Society for Reproductive Medicine.

The experimental group consisted of 148 patients whereas the control group (tubal infertility patients) consisted of 72 patients. All groups consisted of patients that were less than 35 years of age and did not have clinical indication for any other cause of infertility. The experimental group underwent 164 IVF-ET cycles while the control group underwent 80 IVF-ET cycles. Patients received a long-acting down-regulation drug regime, a daily subcutaneous FSH dose, as well as gonadotropin doses which were decided individually according to age, basal FSH, ovarian volume and ovarian response. After two or more follicles reached maximal diameter of 17-18mm, hCG was administered and oocytes were obtained 36 hours later using vaginal ultrasonography, to then be fertilised on the same day. Embryo transfers were made two to three days after oocyte retrieval. Natural progesterone in oil was then administered. Plasma beta-hCG values were used to assess pregnancy. Clinical pregnancy was determined when at least one gestational sac was found with a fetal pole and heart activity through ultrasond.

It was found that the experimental group had significantly lower numbers of follicles on the hCG day, oocytes obtained and transferred when compared to the control group, despite receiving a higher FSH dose. However no significant differences were found regardingt cycle cancellation rate, peak E2 levels of the length of the stimulation phase. 11.6% of clinical pregnancies per started cucle were observed in the experimental group as compared to 22.5% in the control group. However, this value wa not significant when the clinical pregnancy rate was considered per oocyte retrieval or per embryo transfer. It was also found that patients at stage I-II of endomtriosis had a significantly lower rate of fertilisation when compared to the control group patients. Patients at stage III-IV of endometriosis had a large reduction in pregnancy rate than the control group, however the fertilisation rate was comparable. Patients at stage III-IV had lower peak E2 concentrations, less follicles on the hCG day, fewer oocytes at retrieval and lower implantation rates. Furthermore, poor ovarion responses in 15 out of 109 cycles resulted in discontinuation of the cycle in patients at stage III-IV of the endometriosis group, compared to 2 of 55 in the stage I-II group and 3 of 80 in the control group.

<pubmed>21793811</pubmed>

--[[User:Z8600021|Mark Hill]] ([[User talk:Z8600021|talk]]) 14:08, 16 September 2015 (AEST) These are good summaries of the se 2 articles. You should make an effort to clearly identify what you have written as opposed to quoting directly from the paper.(5/5)

==Week 2 Assessment==

[[File:Epigenetic factors Influencing Human Development.jpg|300px]]

PMID 26216216

--[[User:Z8600021|Mark Hill]] ([[User talk:Z8600021|talk]]) 14:12, 16 September 2015 (AEST) Image uploaded and named correctly. Image summary includes information, reference, copyright and student image template. (5/5)

==Week 3 Assessment==

PMID 26074966
<pubmed>26074966</pubmed>

PMID 20416867
<pubmed>20416867</pubmed>

PMID 23873146
<pubmed>23873146</pubmed>

The three key pathways by which the incidence of OHSS has been curtailed involve identifying risk factors to predict OHSS development, modifying treatment regimes on the basis of the identified risk factors and intervention to prevent progression to OHSS once the patient has undergone Controlled Ovarian Stimulation.

1) Risk factors

Primary: Preexisting factors likely to exacerbate the ovarian stimulation response. Include: young age, low body weight, history of elevated response to gonadotropins, Polycystic Ovary Syndrome (PCOS), isolated PCOS characteristic or a previous history of OHSS. Anti-Mullerian Hormone markers (AMH) are a newly developed predictive tool with a sensitivity of 90.5% and specificity of 81.3%. Ultrasonographic markers including antral follicle count
PMID 26074966

Secondary:

2) Prevention

Primary:
a) Gonadotropins: reduce duration, reduce dose, avoid GnRH Agonists PMID 23873146

b) Use Metformin Therapy

c) Target Unifollicular Ovulation

d) Avoid hCG

e) In Vitro Maturation

Secondary:
a) Reduce hCG dose

b) Coasting

c) Cryopreservation of Embryos

d) Cancel Cycle

e) Use alternative Agents

PMID 20416867

--[[User:Z8600021|Mark Hill]] ([[User talk:Z8600021|talk]]) 14:12, 16 September 2015 (AEST) These are relevant to your group project. Hopefully these will be useful in the final project page. (5/5)

==Week 4 Assessment==
===Fertilisation Quiz===

<quiz display=simple>

{Which of the following statements is incorrect in regards to the acrosome:
|type="()"}
-The acrosome reaction allows for the exposure of the inner-acrosomal membrane
-Only acrosome reacted spermatozoa fuse with the oocyte
-The acrosome within the spermatozoa is derived from the golgi apparatus
+Zona Pellucida Binding Protein 1 is synthesised by the oocyte
-The enzymatic contents of the acrosome degrade the zona pellucida
||This is correct, the [[Z#zona pellucida binding protein 1|zona pellucida binding protein 1]] is in fact a spermatozoa protein located on the acrosome surface, and binds to the zona pellucida of the oocyte during fertilisation.

{Which of the following statements about the zona pellucida is incorrect:
|type="()"}
-It is an insoluble extracellular matrix
-It expresses several glycoproteins
-It surrounds the blastocyst
-It surrounds the developing oocyte
+It prevents sperm binding
||Yes, the [[Z#zona pellucida|zona pellucida]] is a specialised extracellular matrix which surrounds the developing oocyte. It expresses several glycoproteins including ZP1, ZP2, ZP3 and ZP4, all of which play an important role in fertilisation. The zona pellucida facilitates sperm binding as the ZP2 binds the spermatozoa before fertilisation. Following fertilisation, the zona pellucida continues to surround the blastocyst during the first week of development, before being broken down through uterine and blastula secretions.

{Fertilisation does not:
|type="()"}
+result in the formation of the first polar body after the second meiotic division
-often occurs in the first 1/3 of the oviduct
-involve spermatozoa and oocyte fusion
-require the exocytosis of cortical granules in the cortical reaction
- require the exocytosis of acrosomal enzymes during the acrosome reaction
||Yes, [[F#fertilization|fertilization]] results in the formation of the second polar body after the second meiotic division. The first polar body forms during the first meiotic division.

</quiz>

--[[User:Z8600021|Mark Hill]] ([[User talk:Z8600021|talk]]) 14:20, 16 September 2015 (AEST) Three negative questions. Q1 An interesting range of options. I suggest that your question might be more instructive. The incorrect option (zona pellucida binding protein 1) is a bit of a give away as why would the oocyte make this protein? A student using simple logic (rather than knowledge) may get this right. Q2 A little simplistic, as we spent some time on ZP sperm binding. Q3 has too simple options and is not well structured. (7/10)

[[ANAT2341 Student 2015 Quiz Questions]]
==Week 5 Assessment==

What is the difference between gastroschisis and omphalocele?

Gastroschisis and Omphalocele are both congenital abdominal wall defects. Omphalocele is a condition involving the umbilical ring whereby the internal organs, typically consisting of the small intestine, colon, liver and spleen, are disemboweled in a sac made of peritoneum, Wharton's jelly and amnion. Gastroschisis is an anterior abdominal wall defect often located to the right of the umbilical cord, where like Omphalocele, there is a protrusion of the bowel. However, in Gastroschisis there is no sac covering the herniation. As such, both conditions defer with respect to location and presence of a sac. Omphalocele is caused by an abnormality in the embryo before week 9 of gestation whereby the bowel loops are malrotated or non rotated and do not return to the abdominal cavity. There are several competing theories as to the cause of Gastroschisis. A leading hypothesis suggests that Gastroschisis results from the inability of the vitelline structures and yolk sac to be incorporated into the body stalk.

Gastroschisis and Omphalocele represent the two most common abdominal wall defects. Gastroschisis is more common of the two and occurs at a rate of one per 600 live births. Omphalocele occurs in about one in 3000 to 10000 live births. Whilst the incidence of Omphalocele is stable, the incidence of Gastroschisis appears to be increasing. It is suspected that this may be due to better technology and screening methods. The male to female ratio of Omphalocele is 1:1.5 while the male to female ratio of Gastroschisis is equivalent. The maternal age of mothers who give birth to a child suffering from Omphalocele is typically 30 years of age. A mother who gives birth to a child from Gastroschisis is typically 22 years of age.

A key difference between Gastroschisis and Omphalocele is that congenital Omphaloceles are frequently associated with other abnormalities while Gastroschisis is not. In Omphalocele, chromosomal defects are found in 30-40% of cases while multiple associated anomalies including chromosomal changes are observed in 67-80% of cases. It is rare for associated anomalies to occur with Gastroschisis. These include: intestinal atresia which is found in 10% of cases, as well as cardiac, renal, musculoskeletal and central nervous system anomalies.

PMID 25459013

<pubmed>25459013</pubmed>

PMID 26229394

<pubmed>26229394</pubmed>

--[[User:Z8600021|Mark Hill]] ([[User talk:Z8600021|talk]]) 14:20, 16 September 2015 (AEST) These are good summaries. (5/5)

==Week 7 Assessment==

PMID 26395490

<pubmed>26395490</pubmed>

1. Although it is currently thought that thyroid C cells originate from cephalic neural crest cells, growing evidence suggests that the embryonic origin may in fact be from Sox17+ anterior endoderm. This study traced Wtn1 expressing cells to determine neural crest origin. Wtn1 expression occurs in the dorsal neural tube and is necessary for neural crest cell expansion. Foregut endoderm origin was established from tracing Sox17 expression, as it is known that transient expression of Sox17 occurs during formation of endoderm. Through fate mapping, the study in mice found that thyroid C cells derived from Sox17+ anterior endoderm, rather than Wtn1 expressing neural crest progeny. However, Wtn1 neural crest cells play a role in the development of thyroid connective tissue. Through lineage tracing, it was also found that in thyroid C cell precursors, the transcription factors Foxa1 and Foxa2 are differentially expressed. These transcription factors are commonly expressed in endoderm organs, and were also found in the thyroid bud and pharyngeal pouch, from which the ultimobranchial bodies that give rise to the thyroid emerge. Within embryonic thyroid C cells, the two transcription factors are coexpressed.

2.Tooth Development consists of ectoderm, mesoderm and neural crest ectomesenchyme involvement. The Ameloblasts produce enamel. Odontoblasts derive from neural crest mesenchyme and form predentin which calcifies to form dentin. The periodontal ligament secures the tooth in the bone socket, acts as a shock absorber, transmits chew forces from bone to tooth and relays sensory information.

==Peer Reviews==

'''Group 1'''

This Group Project has a lot of potential. Information is presented in an engaging way through an introductory video documenting a case, timeline providing retrospective insight as well as diagrams detailing the complex processes in a concise manner. I also found some subsections interesting and relevant, including the discussion on ethics, Current research areas, as well as the glossary which provides a quick reference.

Although I understand you intend to elaborate more on certain areas including current research, the project does seem a little thin in regards to text. There are many papers that are linked with no explanation. For example, with regards to the table under prohibitions, I am confused as to what exactly those countries prohibit (all genetic modification? mitochondrial techniques only?) and also whether there is any more nuance to the discussion (do they ban different things?). Of course, one could click through the links under each country, but i think some text before the table itself would only add to your project and bring more context to the table itself. Diagrams themselves can also be referred to in the text (as you would find in a textbook), to add context and create a more cohesive wikipedia page (e.g. for Pronuclear transfer). In terms of the information provided, a little deeper exploration or discussion about certain issues including the reasoning behind ethics arguments may be relevant. If the articles listed under the headings are anything to go by, it seems you intend to do this.

Finally, some proofreading will be very beneficial in polishing up the wikipedia page. There are some sentences like "And it effectiveness in doing so. And the processes that occur in the oocyte when this method is used" under Human Embryo Model, which may well do with some editing. I would like to add that the referencing has been fantastic and consistent. Good Luck!

'''Group 3'''

I found this Wikipedia page particularly interesting. A wide assortment of visual media including histological slides, ultrasound images, geographical maps, tables, flow diagrams and hand-drawn images, all add a richness and balance to the text. This page does well to direct the reader's attention with highlighted text as well, to make for an aesthetically pleasing article. In particular, i found the hand-drawn diagram particularly intelligent and impressive.

In terms of text, i think this article is of adequate complexity and provides educational value to its intended audience of fellow university students. However, more diagrams to accompany the pathophysiological mechanisms and simplify the process may be of benefit. The text under 'Causes' is informative, but there is an imbalance of information for the various subsections within that heading. I assume, you intend to elaborate on those subsections that seem a little thin. It may be more effective to break up the 'genetic factors' section to a simple list of genetic influences, with details of studies relevant to that factor alongside it. This way, you don't have to read through several paragraphs to get to a particular gene/information point. Also, some arrows pointing to the actual cysts explicitly in the histological slide may be useful, as already done in the Ultrasound slide.

Finally, although the Wikipedia page is organised logically and contains particularly relevant sections, it may do with some more. As an age old issue, I'm interested in the epidemiology of PCOS and a bit about its history (or where/when we know what we do about it). Other than that, the page looks pretty good and reads well too.

'''Group 4'''

This Group Project is impressively detailed and provides a comprehensive view of male infertility detailing the normal process as well as the various disorder types and causes. The wikipedia page flows logically, provides excellent summaries and may well be an excellent educational resource. The video chosen is fantastic and tables have been used well to present information quickly.

I find that the Introduction is clear and concise. However, i feel it may be improved further by an introductory visual. Other than that, the page has many relevant diagrams and images. In terms of the 'development of gonadotropin preparations', it does seem a little out of place as it isn't particularly referred to in the text. I understand timelines add a richness to the text and can give perspective, but i feel that it may be of more relevance if given regarding male infertility treatments as a whole, rather than gonadotropin preparations. Of course, you can always have both.

Other than that, I am quite impressed with this wikipedia page. It is referenced well and information is backed with reference to the findings of various studies. A final tip may be to add a simple glossary for ease of reference as opposed to having to scroll back up to the section (e.g. varicocele) to remind oneself of the meaning. However, it should be commended that jargon was defined well throughout the article.

'''Group 5'''

This Group Project covers a wide breadth of topics in a very easy to understand manner. The types of chemotherapy treatments or drugs for example, were very easy to read and understand. The various tables and histological slides employed also make for an interesting and easy to digest wikipedia article. The visual aids detailing the IVF process was also well appreciated and balanced well with the text.

However, I feel that in general there should be more visual media to accompany the text. An issue of a current image I have (patient undergoing chemotherapy) is that I don't think it adds much to the wikipedia page and is not informative. Furthermore, I was hoping there would be an introduction to the wikipedia page that would explicitly detail what it aims to cover. This would provide more structure and give a logical flow to the wikipedia page. Another way to improve the logical flow, is to subdivide sections into male and female (e.g. surgeries and drugs, the transition from surgeries for males to drugs for female infertility was abrupt and disorienting). The top half of the page may be made less verbose through the use of more jargon e.g. in the Radiation section "cells can't grow and divide" etc. Naturally, a glossary is also a convenient reference point that may be included.

Also, there is an imbalance in detail with more input within cancer cells section than other sections more directly relevant in ART including IVF. However, I do understand this Group Project is still a work in progress. Overall, there is a lot of potential in the wikipedia page.

'''Group 6'''

This wikipedia article is impressively organised and easy to follow. It is sufficiently detailed, and despite being content heavy it has a good layout as it is well spaced out. This article is well referenced as well, a testament to the work that has been put in.

I understand that the advantages and disadvantages are listed as bullet points. Have you thought of organising it in a table? It may be a way to include a 'visual aid' in order to reach a balance in terms of visual/text content. Generally, more diagrams will only improve this article. Cohesion between the visual and written text may be increased by referrals to the diagrams/images throughout e.g. human blastocyst biopsy as opposed to a caption only. Also, having a section directly comparing the genetic techniques/purpose/effectivity/results in a table may be interesting.

Overall, wonderful work. In my opinion this is definitely a frontrunner and particularly difficult to critique.

==Week 10 Assessment==

[https://embryology.med.unsw.edu.au/embryology/Slides/Embryo_Stages/Stage22/08-eye/Stage22-08-eye.html?zoom=6&lat=-3223.5&lon=3922&layers=B Stage 22 Eye]

Hyaloid artery supplies the developing lens and is surrounded by the vitreous. Developing lens consists of lens fibers which derive from surface ectoderm.

[[Vision - Lens Development]] --Development Overview

==References==

PMID 26244658
look at this <ref><pubmed>26244658</pubmed>

here's the list
<references/>

2015 Group Project 2

2015-10-23T17:07:37Z

Z3372824: /* Secondary Prevention */

{{ANAT2341Project2015header}}

==<span style="font-size:120%">'''Ovarian Hyper-stimulation Syndrome (OHSS)'''</span>==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

Ovarian Hyper stimulation Syndrome (OHSS) is an iatrogenic complication of '''Assisted Reproduction Technology''' (ART), in which women take medications to stimulate oocyte growth. It is generally identified by cystic enlargements of the ovaries and fluid accumulation in the peritoneal cavity due to the increased capillary permeability and ovarian neoangiogenesis <ref name="PMID22065820"><pubmed>22065820</pubmed></ref>. It is an occurrence which is dependent on the controlled stimulation of the ovaries in preparation for IVF i.e. administration of human Chorionic Gonadotropin (hCG).

OHSS was first described in 1943 as ''“syndrome d’hyperluteinisation massive des ovaries”''. It was during this time that gonadotropins were prepared from animals such as sheep to bring on ovulation in women. The first recorded death as a result of OHSS occurred in 1951 and was due to renal failure as a result of oligouria, a complication of the syndrome <ref name="OHSS"> Marie M. Budev, DO, MPH; Alejandro C. Arroliga, MD; Tommaso Falcone, MD, [ http://utilis.net/Morning%20Topics/REI/Ovarian%20Hyperstimulation.pdf ], 'Ovarian Hyperstimulation Syndrome'</ref> <ref name="PMID12638783"><pubmed>12638783</pubmed></ref>.

<span style="color:#FA58D0">'''This wikipage aims to provide clear information on various areas surrounding OHSS such as diagnosis, prevention and complications and will look into the genetics behind the disorder and the various animals models used to research it'''.</span>

<html5media height="350" width="450">https://www.youtube.com/watch?v=aXmjJw234a4</html5media>

'''Overview of Ovarian Hyperstimulation Syndrome''' <ref> Howcast (2013, August 27) Ovarian Hyperstimulation Syndrome | Infertility. Retrieved from https://www.youtube.com/watch?v=aXmjJw234a4</ref>

</div>

==Epidemiology==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

Ovarian Hyper-Stimulation Syndrome (OHSS) rarely occurs sporadically, and if it does, it is usually the result of an underlying genetic problem. The majority of OHSS is due to the ovaries being stimulated to mature and release an abundance of oocytes, in response to hormones Human Chorionic Gonadotropin (hCG) and Follicle Stimulating hormone (FSH), during IVF. Rarely, Clomifene Citrate therapy can cause OHSS.<ref name="WikiOHSS"> Wikipedia, [ https://en.wikipedia.org/wiki/Ovarian_hyperstimulation_syndrome ], 'Ovarian Hyperstimulation Syndrome'</ref>

OHSS only affects '''0.5-5%''' of women undergoing Ovarian Hyper-stimulation, but despite its small prevalence, it is a potentially fatal outcome of a non-vital procedure and remains a prevalent problem for fertility specialists <ref name="PMID12498425"><pubmed>12498425</pubmed></ref> <ref name="PMID12638783"><pubmed>12638783</pubmed></ref>. Age has been cited as a factor affecting those with OHSS, with younger women more at risk. Additionally, women with allergies were seen to have a higher incidence of OHSS. It is important to note that at this point in time, there is no positive correlation between gonadotropin dose and OHSS.

Of the 0.5-5% of women affected with OHSS mentioned above, 2% of those women will require hospitalisation. As of 2011, it has been reported that the incidence of OHSS was '''increasing''', resulting in approximately 3 deaths per 100,000 women undergoing ovarian stimulation per year <ref name="PMID21828116"><pubmed>21828116</pubmed></ref>. This is particularly worrying as in 2008, in the United States alone, there were around 150,000 IVF cycles undertaken.

{|
|-bgcolor="F8E0F1"
|
'''With the field of Assisted Reproductive Technologies expanding and more women partaking in IVF treatments, the threat of women developing OHSS is an ongoing and increasing one''' <ref name="PMID21828116" />.
|}
{| class="wikitable mw-collapsible mw-collapsed"
! colspan=4|Characteristics of women with OHSS by complication group <ref name="PMID19591989"><pubmed>19591989</pubmed></ref>
|-
! scope="col" width="100px" height="60px" style="text-align:center| '''Characteristic'''
! scope="col" width="100px" height="60px" style="text-align:center| '''No Complications
(N = 212,041)'''
! scope="col" width="100px" height="60px" style="text-align:center| '''Moderate OHSS
(N = 1,523)'''
! scope="col" width="100px" height="60px" style="text-align:center| '''Severe OHSS
(N = 655)'''
|-
|style="text-align:center; background: #FF99FF;"| '''Maternal Age (Mean ± SD)'''
|style="text-align:center; background: #F6CEEC;"| 35.6 ± 4.6
|style="text-align:center; background: #F6CEEC;"| 33.0 ± 4.3
|style="text-align:center; background: #F6CEEC;"| 33.1 ± 4.4
|-
|style="text-align:center; background: #FF99FF;"| '''Maternal Age (%)'''
|-
|style="text-align:left; background: #F6CEEC;"| <30 years
|style="text-align:center; background: #F6CEEC;"| 10 %
|style="text-align:center; background: #F6CEEC;"| 21.1 %
|style="text-align:center; background: #F6CEEC;"| 20.6 %
|-
|style="text-align:left; background: #F6CEEC;"| 30-34 years
|style="text-align:center; background: #F6CEEC;"| 30.4 %
|style="text-align:center; background: #F6CEEC;"| 43.2 %
|style="text-align:center; background: #F6CEEC;"| 40.5 %
|-
|style="text-align:left; background: #F6CEEC;"| 35-39 years
|style="text-align:center; background: #F6CEEC;"| 37.8 %
|style="text-align:center; background: #F6CEEC;"| 27.2 %
|style="text-align:center; background: #F6CEEC;"| 32.5 %
|-
|style="text-align:left; background: #F6CEEC;"| >40 years
|style="text-align:center; background: #F6CEEC;"| 21.8 %
|style="text-align:center; background: #F6CEEC;"| 8.4 %
|style="text-align:center; background: #F6CEEC;"| 6.4 %
|-
|style="text-align:center; background: #FF99FF;"| '''Nulligravida (%)'''
|style="text-align:center; background: #F6CEEC;"| 45.8 %
|style="text-align:center; background: #F6CEEC;"| 51.5 %
|style="text-align:center; background: #F6CEEC;"| 51.8 %
|-
|style="text-align:center; background: #FF99FF;"| '''Infertility Diagnosis (%)'''
|-
|style="text-align:left; background: #F6CEEC;"| Male factor
|style="text-align:center; background: #F6CEEC;"| 37.7 %
|style="text-align:center; background: #F6CEEC;"| 41.0 %
|style="text-align:center; background: #F6CEEC;"| 33.4 %
|-
|style="text-align:left; background: #F6CEEC;"| Endometriosis
|style="text-align:center; background: #F6CEEC;"| 13.5 %
|style="text-align:center; background: #F6CEEC;"| 13.5 %
|style="text-align:center; background: #F6CEEC;"| 10.7 %
|-
|style="text-align:left; background: #F6CEEC;"| Ovulation Disorders
|style="text-align:center; background: #F6CEEC;"| 14.0 %
|style="text-align:center; background: #F6CEEC;"| 29.5 %
|style="text-align:center; background: #F6CEEC;"| 22.4 %
|-
|style="text-align:left; background: #F6CEEC;"| Diminished ovarian reserve
|style="text-align:center; background: #F6CEEC;"| 16.9 %
|style="text-align:center; background: #F6CEEC;"| 3.2 %
|style="text-align:center; background: #F6CEEC;"| 2.4 %
|-
|style="text-align:left; background: #F6CEEC;"| Tubal factors
|style="text-align:center; background: #F6CEEC;"| 20.4 %
|style="text-align:center; background: #F6CEEC;"| 22.6 %
|style="text-align:center; background: #F6CEEC;"| 22.3 %
|-
|style="text-align:left; background: #F6CEEC;"| Uterine factors
|style="text-align:center; background: #F6CEEC;"| 5.1 %
|style="text-align:center; background: #F6CEEC;"| 4.3 %
|style="text-align:center; background: #F6CEEC;"| 3.1 %
|-
|style="text-align:left; background: #F6CEEC;"| Other factors
|style="text-align:center; background: #F6CEEC;"| 13.9 %
|style="text-align:center; background: #F6CEEC;"| 13.1 %
|style="text-align:center; background: #F6CEEC;"| 10.4 %
|-
|style="text-align:left; background: #F6CEEC;"| Unexplained factor
|style="text-align:center; background: #F6CEEC;"| 12.7 %
|style="text-align:center; background: #F6CEEC;"| 11.8 %
|style="text-align:center; background: #F6CEEC;"| 18.6 %
|-
|}
</div>

==Causative Agents==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

[[File:Follicular Development.jpeg|right|thumbnail|500px|Infertility treatments aim to facilitate follicular development and induce ovulation to improve chances of fertilisation <ref name="PMID24717179"><pubmed>24717179</pubmed></ref>]]

Normally a woman produces one egg per month from the ovaries, which travel down the Fallopian tube to be fertilized or be released from the body. In cases where women have difficulty falling pregnant, they are given medication which help them to produce and release eggs (as shown in the diagram to the right), further increasing their chances of fertilization and pregnancy <ref><pubmed>19573285</pubmed></ref>. Ovarian Hyper stimulation Syndrome generally occurs during infertility treatments when the ovaries are overstimulated by the fertility medication which causes the ovaries to swell and leak fluids into the belly and abdomen. The prevalence of OHSS onset is linked with excessive number of follicle development in response to the administration of injectable Follicle Stimulating Hormones (FSH) followed by the '''Human Chorionic Gonadotrophins''' (hCG) which triggers the release of the oocytes <ref><pubmed>26190539</pubmed></ref>.

'''Follicle Stimulating Hormones''' (FSH) <ref name="PMID9020850"><pubmed>9020850</pubmed></ref> are glycoprotein hormones that are produced and secreted from the Anterior Pituitary gland into the bloodstream, which regulate the developmental, growth, maturation and the reproductive processes within the body. In females, the Follicle Stimulating Hormones initiates the stages of growth and development of immature ovarian follicles within the ovaries before the release of an egg from a follicle at ovulation. When FSH is administered to a patient who is suffering from infertility, the increase FSH levels affect the rate of development and production, in turn increasing the amount of follicles which are ready to be released during ovulation.

</div>

==Symptoms==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

OHSS is classified based on a criteria from mild, moderate and severe <ref name="WikiOHSS" />:

'''Mild Symptoms'''- abdominal bloating, minimal weight gain, nausea, diarrhoea and a feeling of fullness.

'''Moderate Symptoms'''- Substantial weight gain (on average 2 or more pounds a day), increased abdominal girth, darkend urine and excessive thirst in addition to the mild symptoms.

'''Severe Symptoms'''- In addition to the symptoms associated with Mild and Moderate OHSS, in severe OHSS, you see shortness of breath, calf and chest pains and pleural effusion.

===<span style="font-size:100%">Classifications of Ovarian Hyper-stimulation Syndrome:</span> <ref name="PMID22065820"><pubmed>22065820</pubmed></ref>===

{| class="wikitable" style="text-align:center
|-
! scope="col" width="70px"| '''Classification'''
! scope="col" width="650px"| '''Symptoms'''
|-
|style="text-align:center; background: #F6CEEC;"| '''Mild'''
|style="height: 60px; background: #F6CEEC;"| '''Grade 1''' - Abdominal distention and discomfort
'''Grade 2''' - Abdominal distention, discomfort with nausea, vomiting and/or diarrhea and ovarian enlargement from 5~12cm
|-
|style="text-align:center; background: #F8E0F1;"| '''Moderate'''
|style="height: 60px; background: #F8E0F1;"| '''Grade 3''' - All features of Mild OHSS with ultrasonographic evidence of ascites
|-
|style="text-align:center; background: #F6CEEC;"| '''Severe'''
|style="height: 60px; background: #F6CEEC;"| '''Grade 4''' - All features of Moderate OHSS with the addition of clinical evidence of ascites and breathing difficulties present
'''Grade 5''' - All of the above symptoms along with a change in the blood volume, increased blood viscosity due to coagulation and diminished renal function
|}

</div>

==Diagnosis==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

Whilst symptoms of OHSS can occur as soon as 24 hours post hCG administration, they are usually seen in women 7-10 days post administration. Initially women with OHSS will present with abdominal bloating, as a result of fluid in the peritoneal cavity and an increase in ovary size. When women present with severe OHSS they are often dehydrated, due to increased vascular permeability, and have hemoconcentration. The above results in a decrease in intravascular volume, leading to '''oligouria''' <ref name="PMID22416285" />.

===History===

Initially a thorough history of the patient is taken during which the clinician looks for evidence of ovarian stimulation, followed by ovulation. During this history taking, the clinician will inquire into any weight gain noticed, urine output, and the woman's ability to maintain oral hydration. A key diagnostic tool for clinicians regarding women who are taking gonadotropins is to identify if they are at an increased risk of developing OHSS. Some risk factors include woman aged less than 30, women who have polycystic ovaries, woman with a previous history of OHSS and women who have had greater than 20 oocytes retrieved <ref name="PMID22416285" />.

===Physical Exam===
[[File:Vaginal_Ultrasonography_in_Sagittal_Plane.jpg|right|thumbnail|600px|Vaginal Ultrasonography in Sagittal plane <ref name="Wikiversity Journal of Medicine"> Häggström, Mikael. "Medical gallery of Mikael Häggström 2014". Wikiversity Journal of Medicine 1 (2). DOI:10.15347/wjm/2014.008. ISSN 20018762</ref>]]
After a history of the patient is taken, the next step is to perform a physical exam on the patient. Women who present with abdominal bloating will produce a shifting dullness upon abdominal percussion. Additionally the clinician will test the woman's vital signs, measure her abdominal girth, weight and will look for evidence of ascites or increase in calf size (usually unilateral)<ref name="PMID22416285" />.

===Investigations===

If the clinician further suspects a women of having OHSS, various investigations can be done such as an ultrasound.The intraperitoneal fluid is best imaged via vaginal ultrasound due to the enlarged ovaries making it difficult to image the pelvis using transabdominal ultrasound. The clinician can also order laboratory testing to look for urine specific gravity and and complete blood count to look for hemoconcentration with a hematocrit. Additionally, liver function tests can be ordered to look for elevated function. The clinician will also look for evidence of elevated D-dimers and fibrinogen and decreased levels of anti-thrombin 3 <ref name="SAHealth"> Government of South Australia Health [ http://www.sahealth.sa.gov.au/wps/wcm/connect/9b61ed004ee5348da663afd150ce4f37/Ovarian-hyperstimulation-syndrome-WCHN-PPG-17072012.pdf?MOD=AJPERES&CACHEID=9b61ed004ee5348da663afd150ce4f37 ], 'South Australian Paediatric Clinical Guidelines OHSS'</ref>.

====Ultrasound====

Typical appearances of the ultrasound include <ref name="Ultrasound"> Radiopaedia [ http://radiopaedia.org/articles/ovarian-hyperstimulation-syndrome-1 ], 'Ovarian Hyperstimulation Syndrome'</ref>:

*Bilaterally and symmetrically enlarged ovaries (>12cm)
* "Spoke-Wheel appearance" - presence of multiple cysts of varying size
*May also see ascites (fluid)

===Severity===

Once a clinician has deduced a women is suffering from OHSS, the severity of their condition needs to be established as either mild, moderate or severe. This is done by referring to the criteria under the sub-heading [[Symptoms]].The subsequent course of treatment for the woman will be based upon this evaluation.

{|
|-bgcolor="F6CEEC"
|
'''Further investigations''' can be done including a Chest X-ray to check for pleural effusions and oedema and USS with Doppler's to check for ascites or possible ovary torsion. <ref name="PMID22416285"><pubmed>22416285</pubmed></ref>
|}

===Differential Diagnosis===

Conditions presenting with similar symptoms or ultrasound images include <ref name="Ultrasound" />:

*Polycystic Ovaries (PO)
:: The difference is that with PO is that the cycts are typically smaller than OHSS cysts and there is no evidence of ascited or pleural effusion
*Mucinous Ovarian Malignancy
:: A type of Ovarian Epithelial tumour
*Ectopic Pregnancy <ref name="Casereport"> Australian Medical Student Journal [ http://www.amsj.org/wpcontent/uploads/files/articles/amsj_v2_i1/AMSJ_v2_i1_pg58-60.pdf ], 'Ovarian hyperstimulation syndrome'</ref>
::A pregnancy in which the foetus develops outside of the uterus e.g. in the fallopian tube

</div>

==Pathophysiology==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

The definition of Ovarian Stimulation is enlarged ovaries with many luteinized cysts, that can present with secondary complications. What distinguishes Ovarian Stimulation from OHSS is the presence of vascular hyper-permeability that results in fluids being redirected elsewhere in the body.

The key process to OHSS appears to be caused by '''Vascular Endothelial Growth Factor''' (VEGF), that is released along with other cytokines, estrogen and progesterone, due to the ovary undergoing luteinization as a result of stimulation by hCG. VEGF increases vascular permeability and as a result the capillaries become more "leaky" to the fluids in them. These fluids can then escape the capillaries and accumulate in the pleural and abdominal cavities as ascites. The woman then becomes hypovolemic and is at an increased risk of circulatory, renal and respiratory issues such as arterial thromboembolism due to the thickening of the blood. Note, the blood is thickened as fluid is leaving the capillaries, leaving behind red blood cells and other cellular components of the blood <ref name="WikiOHSS" />.

The increase in expression of VEGF and VEGF Receptor 2 (VEGFR2) is attributed to the greatly increased amount of their mRNA present in the body after stimulation with hCG <ref name="PMID21082502"><pubmed>21082502</pubmed></ref>. VEGF interacts with VEGF2 and VEGF Receptor 1 (VEGFR1) to create a strong angiogenic effect. Both VEGFR2 and VEGFR1 belong to a family of receptors called tyrosine kinases. VEGF2 is involved in the regulation of angiogenesis and vascular permeability whilst VEGF1 has a slightly contradictory role in that is is involved in the maintenance of the tight junctions between endothelial cells in blood vessels. A study by Gómez ''et. al.'' <ref name="PMID21082502" /> showed that women experiencing OHSS had substantially higher plasma levels of VEGF and lower levels of VEGFR1.

[[File:Pathogenesis_of_OHSS.png|600px|centre|thumb|Pathogenesis of OHSS <ref name="PMID20416867"><pubmed>20416867</pubmed></ref>]]

</div>

==Complications==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

Ovarian torsion or rupture, renal insufficiency and thrombophlebitis can all complicate OHSS. If a pregnancy occurs, symptoms may persist longer than the usual 1 to 2 weeks and become more severe, however, even with severe OHSS, they do not extend past the first trimester <ref name="WikiOHSS" />. [[File:Polycystic Ovaries.jpeg|right|thumbnail|360px|Comparison of Normal and Polycystic Ovary]]

<span style="color:#FA58D0"> '''1-2% of women who undergo ovarian stimulation develop a severe form of OHSS''' </span>. Complications from severe OHSS include:

*Fluid collection in the abdomen
*Electrolyte disturbances (sodium and potassium)
*Kidney failure
*Ovary twisting
*Rupture of a cyst in an ovary
*Breathing problems
*Blood clots in large vessels (most commonly the legs)
*Pregnancy loss from miscarriage or termination
*Rarely, death

A study by Nouri ''et. al.'' <ref name="PMID24996451"><pubmed>24996451</pubmed></ref> found that women with '''Polycystic Ovarian Syndrome''' (PCOS) and those that were induced with hCG experienced longer recovery times from severe OHSS than women who were not pregnant. They looked at a cohort of women hospitalised for the first time with severe OHSS and subject them to the same treatments. Based on a defined criteria, they established the recovery time of these women and compared the times between those that were pregnant to those that were not pregnant. They also found that whether a woman had PCOS or ovulation induction did not affect her risk of developing OHSS if she was not pregnant. It is only a risk factor for pregnant women.

===Thromboembolic events===

A frequent and deadly complication of OHSS are thromboembolic events due to increased blood clotting. This increase in blood clotting has been attributed to a variety of complications such as hemoconcentration (which thickens the blood), hypovolemia and an increase in the permeability of blood vessels as a result of increased vasoactive substances in the body of ovarian origin. Thromboembolic events include venous thromboses often in the upper extremities and arterial thromboses such as those in the cerebrovascular region. These events can lead to amputations of extremities, brain damage, miscarriage and death. To avoid this, anti-coagulants are given to pateitns with OHSS and they are fitted with compression stockings (see [[Treatment]]) <ref name="PMID23378404"><pubmed>23378404</pubmed></ref>.

{|
|-bgcolor="F8E0F1"
|
The risk of a woman developing OHSS is higher if she is having a '''twin pregnancy''', as she is exposed to higher concentration of hCG. <ref name="PMID9756273"><pubmed>9756273</pubmed></ref>
|}

</div>

==Treatment==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

'''General treatment
'''
*''Acetaminophen'' with or without a narcotic agent- used to treat abdominal discomfort
*Women are encouraged to drink 2-3 litres of water a day to prevent hemoconcentration
*Women are advised to avoid sexual intercourse and vigorous exercise at the risk of torsion or rupture of the ovaries
*NSAID's with anti-platelet properties should NOT be used as they may effect renal function in a women with OHSS
*Patients with significantly painful ascites or breathing problems may undergo ''Paracentesis'' (drainage of the ascites)
*''Culdocentesis'' (extraction of fluid from recto-uterine pouch) can be done to decrease the likelihood of a woman with moderate OHSS progressing to severe OHSS.<ref name="PMID22416285" />

===Mild to Moderate OHSS===

Mild OHSS can often resolve on its own, however, moderate OHSS may include treatments such as<ref name="WikiOHSS" />:

*Anti-nausea medication and prescription painkillers
*Regular physical examinations and ultrasounds
*Daily weigh-ins and waist measurements
*Measuring the amount of urine produced each day
*Frequent blood tests for monitoring dehydration and electrolyte imbalance
*Maintaining a high balance of fluids
*Drainage of excess abdominal fluid by inserting a needle in the abdominal cavity
*Wearing support stockings which help prevent blood clots/thrombosis

===Severe OHSS===

[[File:Abdominal Paracentesis.png|thumb|right|350px|Paracentesis is a common procedure done on women who have OHSS as it is used to drain the ascites in their abdomen. In this image you can see the puncture of the peritoneal cavity with a needle that then drains the fluid externally. <ref name="Wikiversity Journal of Medicine"> Blausen.com staff. "Blausen gallery 2014". Wikiversity Journal of Medicine. DOI:10.15347/wjm/2014.010. ISSN 20018762 </ref>]]

Severe OHSS requires hospital care in order for constant monitoring and treatment such as <ref name="WikiOHSS" />:

*Intravenous fluids with a crystalloid solution (100-150mL/hr)
*Intravenous Albumin is administered is IV fluids are insufficient (15-20mL/hr of 25% albumin for 4 hrs)
*In addition to Acetaminophen, ''Opioid analgesics'' can be administered for pain relief
*''Antiemetics'' can be used to subside nauseas and/or vomiting
*Woman administered to hospital of OHSS are considered at high risk of thromboembolic complications and are given low molecular weight ''heparin'', an anti-coagulant
*''Cabergoline''- lessens OHSS symptoms
*''GnRH agonist''- suppresses ovarian activity
**If at risk of OHSS, alternates include using a GnRH agonist instead of hCG however its effects on pregnancy rates are questionable. Using a GnRH agonist to replace the use of hCG for final oocyte stimulation will see a 6% decrease in delivery rate.
*Daily monitoring of creatine, urea, creatine clearance C-reactive protein (to rule out infection) are all required in combination with weekly tests such as liver and renal function tests and chest x-rays (to check for pleural effusion) <ref name="PMID12638783" />.

If there are serious complications then additional treatments are required:

*Surgery for a ruptured ovarian cyst
*Intensive care for the liver or lung complications

====Paracentesis====

For women with severe/grade 3 OHSS, paracentesis, the removal of fluid from the body using an aspiration needle, can be undertaken. It is a diagnostic and a therapeutic method that can be done trans-abdominally and trans-vaginally. It is used to relieve symptoms, improve haemodynamics e.g. Urinary output, and shorten the women's hospital stay. Complications of paracentesis include bleeding, infection and organ injury, however are note common <ref name="Paracentesis"> S. Monica Soni, HMS 3, Gillian Lieberman, MD [ http://eradiology.bidmc.harvard.edu/LearningLab/genito/Soni.pdf ], 'Ovarian Hyperstimulation Syndrome'</ref>.

{|
|-bgcolor="F8E0F1"
|
The most important aspect of treatment for any women with OHSS is close and constant '''monitoring''' with her healthcare professional. Counselling may also be provided to women and their partners or families in order to provide them with the best possible knowledge base to manage and treat their OHSS. It is important to note that there is '''no one cure or treatment''' for OHSS. Treatment involves managing and eliminating the symptoms until such time as the syndrome resolves itself <ref name="WikiOHSS" />.
|}

</div>

==Prevention==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

There are three key avenues through which the incidence of OHSS may be prevented. These include identifying risk factors to predict OHSS development, modifying treatment regimes on the basis of the identified risk factors and intervention to prevent progression to OHSS once the patient has undergone '''Controlled Ovarian Stimulation''' (COS).

=== Risk factors===

'''Primary risk factors'''

Pre-existing factors likely to exacerbate the ovarian stimulation response. Primary risk factors include <ref name="PMID26074966"><pubmed>26074966</pubmed></ref>:

*Young age
*Low body weight
*History of elevated response to gonadotropins
*Polycystic Ovary Syndrome (PCOS)
*Isolated PCOS characteristic
*Previous history of OHSS.
*High pretreatment basal Anti-Mullerian Hormone (AMH) concentration
*Large Antral Follicle Count (AFC)

'''Secondary risk factors'''

Secondary risk factors involve the monitoring of ovarian response parameters once COS has been initiated. These parameters are monitored for <ref name="PMID19007627"><pubmed>19007627</pubmed></ref>:

*rapidly rising E2 levels
*E2 concentration larger than 2500 pg/mL
*large number of developing follicles (10-14mm) on the day hCG is administered
*large number of oocytes retrieved

These factors in combination, act as a predictive tool to assess the likelihood of severe OHSS development, with a 83% sensitivity and 84% specificity. <ref name="PMID19007627"/>

=== Primary Prevention===
[[File:Severe OHSS Prevention.jpeg|right|thumbnail|400px|GnRH antagonists, embryo cryopreservation and cycle cancellation are key strategies in preventing OHSS progression in high-risk patients <ref name="PMID22938051"><pubmed>22938051</pubmed></ref>]]

Primary Prevention involves the modification of treatment regimens on the basis of OHSS risk classifications, in order to prevent OHSS occurrence.

'''Ovulation Induction'''

Unifollicular Ovulation Induction through Ovulation Induction (OI) is a primary means of avoiding OHSS in women with Polycystic Ovarian Syndrome, who are at an increased risk. In order to promote unifollicular development, the ovaries are stimulated with a low starting dose of FSH (75 IU).<ref name="PMID20416867"><pubmed>20416867</pubmed></ref> Studies suggests that a minimum gonadotropin dose lowers OHSS risk and thus a step-up regimen is utilised to achieve an ovarian response, whereby the FSH dosage is increased every 7 days until follicular development of greater than 10mm is noted.<ref name="PMID26074966" /> Alternatively, a step-down regimen may be followed, whereby a high initial FSH dosage is lowered according to the ovarian response. Another method to increase FSH levels during OI, is through '''Aromatase Inhibitors''' which promote folliculogenesis by increasing pituitary secretion of FSH, and downregulate oestrogen production through a negative feedback loop. However, Aromatase Inhibitors have not been shown to reduce OHSS incidence in comparison to other methods of OI.<ref name="PMID26074966" /> During OI, a key objective is to prevent early cycle cancellation due to premature luteinisation from pituitary secretion of LH. In order to downregulate LH secretion, '''Gonadotropin-releasing hormone agonists''' (GnRHa) are administered in addition to gonadotropins. Alternatively, '''GnRH antagonists''', which have a rapid onset of action, may be administered to downregulate endogenous LH secretion, with relative success as depicted in the diagram to the right.<ref name="PMID20416867" /> Comparative studies have shown that the GnRH antagonist protocol has a greater effect in lowering the incidence of mild to severe OHSS. However due to the rare nature of OHSS, and insufficient sample sizes, the difference was not found to be significant. <ref name="PMID21082508"><pubmed>21082508</pubmed></ref>. Generally, the duration of exposure to gonadotropins and subsequent risk of OHSS may be minimised through mild stimulation protocols which administer FSH only in the mid to late follicular phase.<ref name="PMID20416867" />

'''Adjuvant Metformin Therapy'''

Adjuvant Metformin Therapy has been found to lower the risk of OHSS by 63%.<ref name="PMID25406011"><pubmed>25406011</pubmed></ref> It involves the administration of metformin at a daily dosage of 1000 to 2000mg, 2 months prior to Controlled Ovarian Stimulation <ref name="PMID26074966"/>. Metformin lowers the elevated insulin levels in PCOS which consequently reduce intraovarian androgen levels. This leads to a reduced sensitivity and expression of granulosa cell-follicle stimulating hormone receptors which result in a less exaggerated response to gonadotropins. Furthermore, it is suggested that Metformin prevents OHSS by controlling vascular permeability through the inhibition of various vasoactive molecules, including VEGF.

'''Avoiding hCG during Luteal Phase Support

Following Controlled Ovarian Stimulation, the steroid levels of E2 and P4 are reduced during the luteal phase due to the negative feedback on the pituitary. This leads to low endogenous LH levels, which consequently reduce endometrial receptivity as well as the luteal phase duration itself. As a result, implantation and pregnancy rates are reduced and early pregnancy loss rates are increased.<ref name="PMID20416867" /> Luteal Phase Support (LPS) serves to combat these adverse events with the use of hCG. However, hCG has been found to increase the risk of OHSS. Alternatively, the use of progesterone has been found to not only halve the risk of OHSS, but also induce similar improvements in pregnancy and miscarriage rates as hCG.<ref name="PMID26148507"><pubmed>26148507</pubmed></ref>

===Secondary Prevention===
[[File:Cryopreservation of Porcine Embryos.jpeg|right|thumbnail|300px|Cryopreservation in the swine model: a) mature oocyte b) day 1 embryo c) day 4 embryo d) blastocyst from cryopreserved day 1 embryo with an intact zona pellucida excluding the lipid droplet. Scale bars=20μm <ref name="PMID26309801"><pubmed>26309801</pubmed></ref>]]
Secondary Prevention aims to prevent progression to OHSS once COS has been initiated and the patient has been found to mount an exaggerated response. <ref name="PMID20416867" />

'''Coasting'''

Coasting is a first-line secondary preventative strategy. It consists of the withdrawal of gonadotrophins when a critical number of follicles and/or E2 concentration is reached. hCG is administered once the E2 concentration reduces to a safe level, before the process of oocyte retrieval commences. This preventative strategy is conducted for a period of less than 3 days in order to avoid compromising IVF outcomes.<ref name="PMID26074966"/>

'''Cryopreservation'''

Cryopreservation of embryos after oocyte retrieval is another avenue which may avert OHSS progression. The cryopreserved embryos are only reimplanted once the patient's hormone serum levels have normalised. Using oocyte vitrification, crystal formation within embryo tissue is avoided and so cryopreserved embryos have been found to produce better pregnancy rates with a 32% increase, than fresh embryo transfer.<ref name="PMID26074966"/> Recent studies suggest cryopreservation itself does not reduce OHSS rates, but must be followed by a GnRHa trigger to avert OHSS.<ref name="PMID24753847"><pubmed>24753847></ref>

'''Cycle cancellation'''

Cycle cancellation is a guaranteed method to prevent early OHSS whereby hCG is withheld. This is a last resort strategy as it carries the risk of significant psychological distress and financial loss for the patient. <ref name="PMID20416867"/>

</div>

==Effect on the Newborn==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

</div>
Women who develop OHSS while undergoing Assisted Reproductive Technologies (ART) treatment are not only more likely to achieve a pregnancy, but have a live birth as the pregnancy outcome. This live birth is also more likely to be a multiple birth of two, three or more children. <ref name="PMID19591989"><pubmed>19591989</pubmed></ref> It has been postulated that a multi-fetal pregnancy leads to a more rapid increase in hCG levels, resulting in an increased risk of OHSS. However, the causal nature between multi-fetal pregnancy and OHSS development is disputed and further research is required to distinguish correlation from causation. <ref name="PMID19573292"><pubmed>19573292</pubmed></ref>

OHSS development is also associated with an increased risk of adverse outcomes including '''stillbirth, premature birth and low birth weight'''.<ref name="PMID19591989" /> Although the cause for the increased risk in adverse pregnancy outcomes is unknown, it is suggested that as the incidence of OHSS is reduced through various prevention strategies, the risk of such outcomes may be also be reduced.

'''<span style="color:#FA58D0"> [http://pregnancyperfect.com/emilyley/ The following link is to a podcast of a woman describing her pregnancy in which she underwent IVF, had OHSS and gave birth to healthy twins]<ref name="Emily"> Pregnancy Perfect[ http://pregnancyperfect.com/emilyley/ ], 'TWINS, IVF, OHSS AND C-SECTION WITH EMILY LEY'</ref> </span>'''

==Genetics==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

Despite OHSS typically being of iatrogenic origin as a result of ovarian stimulation with gonadotropins, research has been conducted into the potential genetics behind OHSS as many sporadic and familial cases have been observed. '''Mutations''' in the receptor for hormones such as Follicle Simulating Hormone (FSH), Lutenizing Hormone (LH) and hCG have all been targets of OHSS genetics research. Interestingly, they too also arise from a common ancestral gene.

===Follicle Stimulating Hormome===

Dr. Botros Rizk, of the University of South Alabama College of Medicine <ref name="PMID19573286"><pubmed>19573286</pubmed></ref>, has written extensively regarding the genetics behind OHSS. In particular, he talks about '''FSH receptors''' (FSHR) and their role in the syndrome. He hypothesises that mutations in these receptors could be activating or inactivating, leading to an increased risk of developing OHSS or sterility respectively. Currently, 744 single nucleotide polymorphisms (a type of mutation) have been found in the gene encoding the FSHR, 8 of which are located in its exons (coding regions of the gene). How the ovary responds is resultant on the FSHR genotype. For example, Ser680Asn, a polymorphism in the FSHR gene has been shown to aid in predicting the severity of a woman's OHSS. Ordinarily FSH stimulates the growth of ovarian follicles, however, when mutated, it is stimulated by the hCG resulting in excessive follicle development.

Spontaneous OHSS, OHSS that arises and cannot be attributed to any form of ovarian stimulation or Assisted Reproductive Technology, has been linked to activating mutations in the FSHR <ref name="PMID23499866"><pubmed>23499866</pubmed></ref>. This familial disorder is an autosomal dominant one. In most cases the FSHR can be stimulated by the presence of Thyroid Stimulating Hormone (TSH) or hCG, in the absence of FSH (the ligand for FSHR).

[[File:FSHR Gene.jpg|centre|thumbnail|700px|This image depicts the location of the FSHR Gene on chromosome 2. It is located on the short arm between positions 21 and 16. Changed to the FSHR gene has been linked to OHSS. <ref name="Genetcis"> Genetics Home Reference [http://ghr.nlm.nih.gov/gene/FSHR'</ref>]]

===Lutenizing Hormome===

The '''Lutenizing Hormone Receptor''' (LHR) gene in humans is comprised of 11 exons. Animal studies have shown that many primates exhibit a similar gene which is comprised of only 10 exons, however a gene lacking the 10th exon has been identified and termed the type 2 LHR. Expression of the type 2 LHR has been seen in humans. The type 2 LHR, compared to the wild-type LHR appears to be repaired with regard to its function. Defects in the type 2 LHR include a decrease in efficiency of transport to the plasma membrane and irregularities in signal transduction. Inactivating mutations in the LHR have been seen to cause infertility in women as well as amenorrhoea. Activating LHR gene mutations are asymptomatic and are not associated with OHSS in women.

===Bone Morphogenic Protein===

An imporant growth factor, derived from oocytes called '''BMP-15''' (Bone Morphogenic Protein 15) is vital for female fertility. It belongs to the family of growth factors, Transforming Growth Factor β (TGF-β) and is heavily involved in folliculogenesis. It has been found that mutations in the BMP-15 gene caused infertility in female sheep. Conversely, it has also been indicated in enhanced fertility when BMP-15 is present is high amounts in follicular fluid <ref name="PMID19573286" />.

A case study done by Hanevik ''et. al.'' in 2013 <ref name="PMID21565556"><pubmed>21565556</pubmed></ref> found that a Single Nuclear Polymorphism (SNP) in the BMP-15 gene is responsible for a high response to ovarian hyper-stimulation. The aim of the study was to test the effect the SNP had on BMP-15 with regard to high and low responders buy taking blood from 53 high responders, 38 low responders and 100 non-responders (controls) and analysing 5 noted SNP's. Results from their study showed a correlation between a high response to ovarian hyper-stimulation and the BMP-15 9G allele. The article does state however, that further research is required into the molecular effects of SNP's on the function of BMP-15.

===Vascular Endothelial Growth Factor===

'''Vascular endothelial growth factor''' (VEGF) has been indicated as one of the key agents causing vascular permeability and subsequent ascites in OHSS. The gene, which is located on chromosome 12, is made up of 8 exons (coding regions), of which exons 6 and 7 do not always appear due to the exons being spliced out.The splicing of this gene allows for various isoforms of the gene to exist of which VEGF 121 and 165 appear to play a role in angiogenesis. There are two VEGF Receptors, VEGFR-1 and VEGFR-2 that belong to the tyrosine kinase family of receptors (for more information on VEGF see [[Pathophysiology]]). Because of its distinct role in OHSS, it has been targeted as an area for research for potential treatments. The idea is that if the genetic expression of VEGF and its receptors can be controlled, OHSS can be avoided or treated.<ref name="PMID19573286" />

A different study by Hanevik ''et. al.'' , <ref name="PMID22587628"><pubmed>22587628</pubmed></ref> done in 2012 involved analysing blood samples from 53 women with OHSS and 100 women without it (controls) and analysing 6 SNP's in the VEGFR2 gene to find any genetic variations. They found a correlation between women with the VEGF +405cc genotype and the development of OHSS indicating women that undergo controlled ovarian hyper-stimulation and posses his genotype, are at an increased risk of developing OHSS.

</div>

== Current Research on Animal Models==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

{|
|-bgcolor="FFF5FF"
|<span style="font-size:120%">'''Inhibition of Cyclooxygenase-2 (COX-2) by Meloxican decreasing the incidence of OHSS in Rat Model'''</span> <ref name="PMID18166186"><pubmed>18166186</pubmed></ref>

Reasearch was carried out to investigate the effects of selective inhibition of the enzyme COX-2 on the Ovarian Hyperstimulation Syndrome (OHSS) using Female Wistar rates as the subjects. The research aimed to find results by measuring the number of antral and luteinized follicles, ovarian weight, vascualr endothelial growth factors and COX-2 immunohistochemistry. The rats being tested were all 22 days old and were divided into four equal groups;

'''Group 1 (Control group)''' was subject to a 0.1 ml of Intraperitoneal Saline from days 22 ~ 26

'''Group 2 (Mildly-stimulated group)''' subject to 10IU of pregnant mare serum gonadotrophin (PMSG) on day 24 and then 10IU of Human Chorionic Gonadotrophin (hCG) on day 26

'''Group 3 (OHSS positive group)''' was subject to 10IU of PMSG from days 22 ~ 26 and then administered 30IU of hCG on day 26 to induce OHSS

'''Group 4 (OHSS positive variant group)''' received 15mg/ml of Meloxicam 2 hours prior to administration of 10IU PMSG from days 22 ~ 26

Results showed there was no difference in ovarian weight in samples from Group 1 and Group 2, however Group 3 showed signs of significant ovarian weight increase which in group 4 was suppressed by the introduction of Meloxicam. No differences were observed in the number of antral follicles amongst the four test groups. Results from Group 2 and Group 3 showed that the granulosa cells of preovulatory follicles and the stromal cells were highly VEGF immunoreactive, however the Meloxicam treated Group 4 showed less immunoreactivity than Group 2 and Group 3 which indicated the correlation between Meloxicam and the diminished VEGF expression. Group 3 presented an increased COS-2 immunoreactivity which was highly diminished than in Group 4.

The research concluded that in a rat model, the enzyme Meloxicam has a beneficial effect on OHSS by reducing the increase of ovarian weight and the expression of VEGF associated with OHSS, the effects of which may be mediated by the inhibitory capacity of COX-2 on Meloxicam
|}

{|
|-bgcolor="FFF5FF"
|<span style="font-size:120%">'''Inhibition of Ovarian VEGF secretion by activation of Dopamine Receptor 2'''</span> <ref name="PMID25217874"><pubmed>25217874</pubmed></ref>

This research was carried out to investigate a possibility in whether a Dopamine Receptor 2 agonist '''(D2-ag)''' can assist in the prevention of Ovarian Hyperstimulation Syndrome, using rat models, by decreasing the ovarian vascular endothelial growth factor '''(VEGF)''' production. Using Immature Wistar rats (22 days old) as their animal model, the rats were initially stimulated with Gonadotrophins to mimic the onset and effects of OHSS and then subjected to treatment with a D2-agonist and/or a D2-antagonist (D2-ant). The vascular permeability was measured at the endpoint after day 26 by measuring the peritoneal extravasion of a previously injected dye and ovaries from all subjects were collected to assess the effects of D2-ag and D2-ant on the production of Ovarian VEGF. The expression of VEGF mRNA was measured by quantitative real time PCR and the levels of VEGF proteins were measured by Western Blots.

Results showed that the D2-ag caused a large reduction in the vascular permeability which was in turn associated with the great decreased in VEGF protein production in the OHSS rat ovaries, whereas the introduction of D2-ant showed opposite results with a increase in the vascular permeability leading to the increase of VEGF protein production in the ovaries. Ovarian VEGF mRNA levels were found to be unaffected by the introduction of these drugs in OHSS rat subjects. Conclusions were drawn on the fact that Dopamine Receptor 2 agonists prevent the increase of vascular permeability in subjects with OHSS by decreasing the ovarian production of VEGF and also that due to the dose-dependent inhibitory effect of the D2-ag on ovarian VEGF, current OHSS therapies used in humans can benefit by increasing the intraovarian concentration of D2-ag.
|}

</div>

==Glossary==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

'''Aromatase Inhibitor''' - A drug that inhibits enzyme aromatase, which in turn suppresses estrogen synthesis.

'''Ascites''' - An accumulation of fluid in the peritoneal cavity with resultant abdominal swelling.

'''Cabergoline''' - A dopamine receptor agonist used to treat hormone imbalance.

'''Controlled Ovarian Stimulation''' - female infertility treatment using medications to stimulate the ovaries to develop follicles.

'''Cryopreservation''' - Cooling and storing biological material at extremely low temperatures.

'''E2''' - Estradiol - Potent estrogen sex hormone.

'''FSH''' - Follicle Stimulating Hormone

'''Gonadotropin''' - Any hormone that has a stimulating effect on the gonads.

'''GnRH agonist''' - Gonadotropin Releasing Hormone - A class of compounds that mimic the effect of the natural Gonadotropin Releasing Hormone.

'''GnRH antagonist''' - Gonadotropin Releasing Hormone - A class of compounds that are similar in terms of the structure of natural Gonadotropin Releasing Hormone but has a antagonistic effect.

'''hCG'''- Human Chorionic Gonadotropin

'''Hemoconcentration''' - An increase in the concentration of circulating red blood cells in response to a decrease in blood plasma volume.

'''Hypovolemic''' - A decrease in circulating blood volume.

'''Iatrogenic''' - Illness caused as a result of a medical examination or treatment.

'''Intravenous fluids''' - Is the infusion of liquid substances directly into a vein.

'''IVF''' - In-vitro Fertilization

'''LH''' - Luteinizing Hormone

'''Metformin''' - A biguanide, antidiabetic drug used as an adjuvant to modify the effect of other agents.

'''NSAID''' - Non-steroidal Anti-Inflammatory Drug e.g. Ibuprofen

'''Oocyte vitrification''' - technique for cryopreservation of oocytes.

'''OHSS''' - Ovarian Hyper-stimulation Syndrome

'''Oliguria'''- Decreased urine output/small amounts of urine produced.

'''P4''' - Progesterone - endogenous progestogen sex hormone.

'''PCOS''' - Polycystic Ovarian Syndrome. An endrocrine system disorder whereby the ovaries are enlarged with small collections of fluid.

</div>

==References==

2015 Group Project 2

2015-10-23T17:06:38Z

Z3372824: /* Secondary Prevention */

{{ANAT2341Project2015header}}

==<span style="font-size:120%">'''Ovarian Hyper-stimulation Syndrome (OHSS)'''</span>==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

Ovarian Hyper stimulation Syndrome (OHSS) is an iatrogenic complication of '''Assisted Reproduction Technology''' (ART), in which women take medications to stimulate oocyte growth. It is generally identified by cystic enlargements of the ovaries and fluid accumulation in the peritoneal cavity due to the increased capillary permeability and ovarian neoangiogenesis <ref name="PMID22065820"><pubmed>22065820</pubmed></ref>. It is an occurrence which is dependent on the controlled stimulation of the ovaries in preparation for IVF i.e. administration of human Chorionic Gonadotropin (hCG).

OHSS was first described in 1943 as ''“syndrome d’hyperluteinisation massive des ovaries”''. It was during this time that gonadotropins were prepared from animals such as sheep to bring on ovulation in women. The first recorded death as a result of OHSS occurred in 1951 and was due to renal failure as a result of oligouria, a complication of the syndrome <ref name="OHSS"> Marie M. Budev, DO, MPH; Alejandro C. Arroliga, MD; Tommaso Falcone, MD, [ http://utilis.net/Morning%20Topics/REI/Ovarian%20Hyperstimulation.pdf ], 'Ovarian Hyperstimulation Syndrome'</ref> <ref name="PMID12638783"><pubmed>12638783</pubmed></ref>.

<span style="color:#FA58D0">'''This wikipage aims to provide clear information on various areas surrounding OHSS such as diagnosis, prevention and complications and will look into the genetics behind the disorder and the various animals models used to research it'''.</span>

<html5media height="350" width="450">https://www.youtube.com/watch?v=aXmjJw234a4</html5media>

'''Overview of Ovarian Hyperstimulation Syndrome''' <ref> Howcast (2013, August 27) Ovarian Hyperstimulation Syndrome | Infertility. Retrieved from https://www.youtube.com/watch?v=aXmjJw234a4</ref>

</div>

==Epidemiology==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

Ovarian Hyper-Stimulation Syndrome (OHSS) rarely occurs sporadically, and if it does, it is usually the result of an underlying genetic problem. The majority of OHSS is due to the ovaries being stimulated to mature and release an abundance of oocytes, in response to hormones Human Chorionic Gonadotropin (hCG) and Follicle Stimulating hormone (FSH), during IVF. Rarely, Clomifene Citrate therapy can cause OHSS.<ref name="WikiOHSS"> Wikipedia, [ https://en.wikipedia.org/wiki/Ovarian_hyperstimulation_syndrome ], 'Ovarian Hyperstimulation Syndrome'</ref>

OHSS only affects '''0.5-5%''' of women undergoing Ovarian Hyper-stimulation, but despite its small prevalence, it is a potentially fatal outcome of a non-vital procedure and remains a prevalent problem for fertility specialists <ref name="PMID12498425"><pubmed>12498425</pubmed></ref> <ref name="PMID12638783"><pubmed>12638783</pubmed></ref>. Age has been cited as a factor affecting those with OHSS, with younger women more at risk. Additionally, women with allergies were seen to have a higher incidence of OHSS. It is important to note that at this point in time, there is no positive correlation between gonadotropin dose and OHSS.

Of the 0.5-5% of women affected with OHSS mentioned above, 2% of those women will require hospitalisation. As of 2011, it has been reported that the incidence of OHSS was '''increasing''', resulting in approximately 3 deaths per 100,000 women undergoing ovarian stimulation per year <ref name="PMID21828116"><pubmed>21828116</pubmed></ref>. This is particularly worrying as in 2008, in the United States alone, there were around 150,000 IVF cycles undertaken.

{|
|-bgcolor="F8E0F1"
|
'''With the field of Assisted Reproductive Technologies expanding and more women partaking in IVF treatments, the threat of women developing OHSS is an ongoing and increasing one''' <ref name="PMID21828116" />.
|}
{| class="wikitable mw-collapsible mw-collapsed"
! colspan=4|Characteristics of women with OHSS by complication group <ref name="PMID19591989"><pubmed>19591989</pubmed></ref>
|-
! scope="col" width="100px" height="60px" style="text-align:center| '''Characteristic'''
! scope="col" width="100px" height="60px" style="text-align:center| '''No Complications
(N = 212,041)'''
! scope="col" width="100px" height="60px" style="text-align:center| '''Moderate OHSS
(N = 1,523)'''
! scope="col" width="100px" height="60px" style="text-align:center| '''Severe OHSS
(N = 655)'''
|-
|style="text-align:center; background: #FF99FF;"| '''Maternal Age (Mean ± SD)'''
|style="text-align:center; background: #F6CEEC;"| 35.6 ± 4.6
|style="text-align:center; background: #F6CEEC;"| 33.0 ± 4.3
|style="text-align:center; background: #F6CEEC;"| 33.1 ± 4.4
|-
|style="text-align:center; background: #FF99FF;"| '''Maternal Age (%)'''
|-
|style="text-align:left; background: #F6CEEC;"| <30 years
|style="text-align:center; background: #F6CEEC;"| 10 %
|style="text-align:center; background: #F6CEEC;"| 21.1 %
|style="text-align:center; background: #F6CEEC;"| 20.6 %
|-
|style="text-align:left; background: #F6CEEC;"| 30-34 years
|style="text-align:center; background: #F6CEEC;"| 30.4 %
|style="text-align:center; background: #F6CEEC;"| 43.2 %
|style="text-align:center; background: #F6CEEC;"| 40.5 %
|-
|style="text-align:left; background: #F6CEEC;"| 35-39 years
|style="text-align:center; background: #F6CEEC;"| 37.8 %
|style="text-align:center; background: #F6CEEC;"| 27.2 %
|style="text-align:center; background: #F6CEEC;"| 32.5 %
|-
|style="text-align:left; background: #F6CEEC;"| >40 years
|style="text-align:center; background: #F6CEEC;"| 21.8 %
|style="text-align:center; background: #F6CEEC;"| 8.4 %
|style="text-align:center; background: #F6CEEC;"| 6.4 %
|-
|style="text-align:center; background: #FF99FF;"| '''Nulligravida (%)'''
|style="text-align:center; background: #F6CEEC;"| 45.8 %
|style="text-align:center; background: #F6CEEC;"| 51.5 %
|style="text-align:center; background: #F6CEEC;"| 51.8 %
|-
|style="text-align:center; background: #FF99FF;"| '''Infertility Diagnosis (%)'''
|-
|style="text-align:left; background: #F6CEEC;"| Male factor
|style="text-align:center; background: #F6CEEC;"| 37.7 %
|style="text-align:center; background: #F6CEEC;"| 41.0 %
|style="text-align:center; background: #F6CEEC;"| 33.4 %
|-
|style="text-align:left; background: #F6CEEC;"| Endometriosis
|style="text-align:center; background: #F6CEEC;"| 13.5 %
|style="text-align:center; background: #F6CEEC;"| 13.5 %
|style="text-align:center; background: #F6CEEC;"| 10.7 %
|-
|style="text-align:left; background: #F6CEEC;"| Ovulation Disorders
|style="text-align:center; background: #F6CEEC;"| 14.0 %
|style="text-align:center; background: #F6CEEC;"| 29.5 %
|style="text-align:center; background: #F6CEEC;"| 22.4 %
|-
|style="text-align:left; background: #F6CEEC;"| Diminished ovarian reserve
|style="text-align:center; background: #F6CEEC;"| 16.9 %
|style="text-align:center; background: #F6CEEC;"| 3.2 %
|style="text-align:center; background: #F6CEEC;"| 2.4 %
|-
|style="text-align:left; background: #F6CEEC;"| Tubal factors
|style="text-align:center; background: #F6CEEC;"| 20.4 %
|style="text-align:center; background: #F6CEEC;"| 22.6 %
|style="text-align:center; background: #F6CEEC;"| 22.3 %
|-
|style="text-align:left; background: #F6CEEC;"| Uterine factors
|style="text-align:center; background: #F6CEEC;"| 5.1 %
|style="text-align:center; background: #F6CEEC;"| 4.3 %
|style="text-align:center; background: #F6CEEC;"| 3.1 %
|-
|style="text-align:left; background: #F6CEEC;"| Other factors
|style="text-align:center; background: #F6CEEC;"| 13.9 %
|style="text-align:center; background: #F6CEEC;"| 13.1 %
|style="text-align:center; background: #F6CEEC;"| 10.4 %
|-
|style="text-align:left; background: #F6CEEC;"| Unexplained factor
|style="text-align:center; background: #F6CEEC;"| 12.7 %
|style="text-align:center; background: #F6CEEC;"| 11.8 %
|style="text-align:center; background: #F6CEEC;"| 18.6 %
|-
|}
</div>

==Causative Agents==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

[[File:Follicular Development.jpeg|right|thumbnail|500px|Infertility treatments aim to facilitate follicular development and induce ovulation to improve chances of fertilisation <ref name="PMID24717179"><pubmed>24717179</pubmed></ref>]]

Normally a woman produces one egg per month from the ovaries, which travel down the Fallopian tube to be fertilized or be released from the body. In cases where women have difficulty falling pregnant, they are given medication which help them to produce and release eggs (as shown in the diagram to the right), further increasing their chances of fertilization and pregnancy <ref><pubmed>19573285</pubmed></ref>. Ovarian Hyper stimulation Syndrome generally occurs during infertility treatments when the ovaries are overstimulated by the fertility medication which causes the ovaries to swell and leak fluids into the belly and abdomen. The prevalence of OHSS onset is linked with excessive number of follicle development in response to the administration of injectable Follicle Stimulating Hormones (FSH) followed by the '''Human Chorionic Gonadotrophins''' (hCG) which triggers the release of the oocytes <ref><pubmed>26190539</pubmed></ref>.

'''Follicle Stimulating Hormones''' (FSH) <ref name="PMID9020850"><pubmed>9020850</pubmed></ref> are glycoprotein hormones that are produced and secreted from the Anterior Pituitary gland into the bloodstream, which regulate the developmental, growth, maturation and the reproductive processes within the body. In females, the Follicle Stimulating Hormones initiates the stages of growth and development of immature ovarian follicles within the ovaries before the release of an egg from a follicle at ovulation. When FSH is administered to a patient who is suffering from infertility, the increase FSH levels affect the rate of development and production, in turn increasing the amount of follicles which are ready to be released during ovulation.

</div>

==Symptoms==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

OHSS is classified based on a criteria from mild, moderate and severe <ref name="WikiOHSS" />:

'''Mild Symptoms'''- abdominal bloating, minimal weight gain, nausea, diarrhoea and a feeling of fullness.

'''Moderate Symptoms'''- Substantial weight gain (on average 2 or more pounds a day), increased abdominal girth, darkend urine and excessive thirst in addition to the mild symptoms.

'''Severe Symptoms'''- In addition to the symptoms associated with Mild and Moderate OHSS, in severe OHSS, you see shortness of breath, calf and chest pains and pleural effusion.

===<span style="font-size:100%">Classifications of Ovarian Hyper-stimulation Syndrome:</span> <ref name="PMID22065820"><pubmed>22065820</pubmed></ref>===

{| class="wikitable" style="text-align:center
|-
! scope="col" width="70px"| '''Classification'''
! scope="col" width="650px"| '''Symptoms'''
|-
|style="text-align:center; background: #F6CEEC;"| '''Mild'''
|style="height: 60px; background: #F6CEEC;"| '''Grade 1''' - Abdominal distention and discomfort
'''Grade 2''' - Abdominal distention, discomfort with nausea, vomiting and/or diarrhea and ovarian enlargement from 5~12cm
|-
|style="text-align:center; background: #F8E0F1;"| '''Moderate'''
|style="height: 60px; background: #F8E0F1;"| '''Grade 3''' - All features of Mild OHSS with ultrasonographic evidence of ascites
|-
|style="text-align:center; background: #F6CEEC;"| '''Severe'''
|style="height: 60px; background: #F6CEEC;"| '''Grade 4''' - All features of Moderate OHSS with the addition of clinical evidence of ascites and breathing difficulties present
'''Grade 5''' - All of the above symptoms along with a change in the blood volume, increased blood viscosity due to coagulation and diminished renal function
|}

</div>

==Diagnosis==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

Whilst symptoms of OHSS can occur as soon as 24 hours post hCG administration, they are usually seen in women 7-10 days post administration. Initially women with OHSS will present with abdominal bloating, as a result of fluid in the peritoneal cavity and an increase in ovary size. When women present with severe OHSS they are often dehydrated, due to increased vascular permeability, and have hemoconcentration. The above results in a decrease in intravascular volume, leading to '''oligouria''' <ref name="PMID22416285" />.

===History===

Initially a thorough history of the patient is taken during which the clinician looks for evidence of ovarian stimulation, followed by ovulation. During this history taking, the clinician will inquire into any weight gain noticed, urine output, and the woman's ability to maintain oral hydration. A key diagnostic tool for clinicians regarding women who are taking gonadotropins is to identify if they are at an increased risk of developing OHSS. Some risk factors include woman aged less than 30, women who have polycystic ovaries, woman with a previous history of OHSS and women who have had greater than 20 oocytes retrieved <ref name="PMID22416285" />.

===Physical Exam===
[[File:Vaginal_Ultrasonography_in_Sagittal_Plane.jpg|right|thumbnail|600px|Vaginal Ultrasonography in Sagittal plane <ref name="Wikiversity Journal of Medicine"> Häggström, Mikael. "Medical gallery of Mikael Häggström 2014". Wikiversity Journal of Medicine 1 (2). DOI:10.15347/wjm/2014.008. ISSN 20018762</ref>]]
After a history of the patient is taken, the next step is to perform a physical exam on the patient. Women who present with abdominal bloating will produce a shifting dullness upon abdominal percussion. Additionally the clinician will test the woman's vital signs, measure her abdominal girth, weight and will look for evidence of ascites or increase in calf size (usually unilateral)<ref name="PMID22416285" />.

===Investigations===

If the clinician further suspects a women of having OHSS, various investigations can be done such as an ultrasound.The intraperitoneal fluid is best imaged via vaginal ultrasound due to the enlarged ovaries making it difficult to image the pelvis using transabdominal ultrasound. The clinician can also order laboratory testing to look for urine specific gravity and and complete blood count to look for hemoconcentration with a hematocrit. Additionally, liver function tests can be ordered to look for elevated function. The clinician will also look for evidence of elevated D-dimers and fibrinogen and decreased levels of anti-thrombin 3 <ref name="SAHealth"> Government of South Australia Health [ http://www.sahealth.sa.gov.au/wps/wcm/connect/9b61ed004ee5348da663afd150ce4f37/Ovarian-hyperstimulation-syndrome-WCHN-PPG-17072012.pdf?MOD=AJPERES&CACHEID=9b61ed004ee5348da663afd150ce4f37 ], 'South Australian Paediatric Clinical Guidelines OHSS'</ref>.

====Ultrasound====

Typical appearances of the ultrasound include <ref name="Ultrasound"> Radiopaedia [ http://radiopaedia.org/articles/ovarian-hyperstimulation-syndrome-1 ], 'Ovarian Hyperstimulation Syndrome'</ref>:

*Bilaterally and symmetrically enlarged ovaries (>12cm)
* "Spoke-Wheel appearance" - presence of multiple cysts of varying size
*May also see ascites (fluid)

===Severity===

Once a clinician has deduced a women is suffering from OHSS, the severity of their condition needs to be established as either mild, moderate or severe. This is done by referring to the criteria under the sub-heading [[Symptoms]].The subsequent course of treatment for the woman will be based upon this evaluation.

{|
|-bgcolor="F6CEEC"
|
'''Further investigations''' can be done including a Chest X-ray to check for pleural effusions and oedema and USS with Doppler's to check for ascites or possible ovary torsion. <ref name="PMID22416285"><pubmed>22416285</pubmed></ref>
|}

===Differential Diagnosis===

Conditions presenting with similar symptoms or ultrasound images include <ref name="Ultrasound" />:

*Polycystic Ovaries (PO)
:: The difference is that with PO is that the cycts are typically smaller than OHSS cysts and there is no evidence of ascited or pleural effusion
*Mucinous Ovarian Malignancy
:: A type of Ovarian Epithelial tumour
*Ectopic Pregnancy <ref name="Casereport"> Australian Medical Student Journal [ http://www.amsj.org/wpcontent/uploads/files/articles/amsj_v2_i1/AMSJ_v2_i1_pg58-60.pdf ], 'Ovarian hyperstimulation syndrome'</ref>
::A pregnancy in which the foetus develops outside of the uterus e.g. in the fallopian tube

</div>

==Pathophysiology==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

The definition of Ovarian Stimulation is enlarged ovaries with many luteinized cysts, that can present with secondary complications. What distinguishes Ovarian Stimulation from OHSS is the presence of vascular hyper-permeability that results in fluids being redirected elsewhere in the body.

The key process to OHSS appears to be caused by '''Vascular Endothelial Growth Factor''' (VEGF), that is released along with other cytokines, estrogen and progesterone, due to the ovary undergoing luteinization as a result of stimulation by hCG. VEGF increases vascular permeability and as a result the capillaries become more "leaky" to the fluids in them. These fluids can then escape the capillaries and accumulate in the pleural and abdominal cavities as ascites. The woman then becomes hypovolemic and is at an increased risk of circulatory, renal and respiratory issues such as arterial thromboembolism due to the thickening of the blood. Note, the blood is thickened as fluid is leaving the capillaries, leaving behind red blood cells and other cellular components of the blood <ref name="WikiOHSS" />.

The increase in expression of VEGF and VEGF Receptor 2 (VEGFR2) is attributed to the greatly increased amount of their mRNA present in the body after stimulation with hCG <ref name="PMID21082502"><pubmed>21082502</pubmed></ref>. VEGF interacts with VEGF2 and VEGF Receptor 1 (VEGFR1) to create a strong angiogenic effect. Both VEGFR2 and VEGFR1 belong to a family of receptors called tyrosine kinases. VEGF2 is involved in the regulation of angiogenesis and vascular permeability whilst VEGF1 has a slightly contradictory role in that is is involved in the maintenance of the tight junctions between endothelial cells in blood vessels. A study by Gómez ''et. al.'' <ref name="PMID21082502" /> showed that women experiencing OHSS had substantially higher plasma levels of VEGF and lower levels of VEGFR1.

[[File:Pathogenesis_of_OHSS.png|600px|centre|thumb|Pathogenesis of OHSS <ref name="PMID20416867"><pubmed>20416867</pubmed></ref>]]

</div>

==Complications==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

Ovarian torsion or rupture, renal insufficiency and thrombophlebitis can all complicate OHSS. If a pregnancy occurs, symptoms may persist longer than the usual 1 to 2 weeks and become more severe, however, even with severe OHSS, they do not extend past the first trimester <ref name="WikiOHSS" />. [[File:Polycystic Ovaries.jpeg|right|thumbnail|360px|Comparison of Normal and Polycystic Ovary]]

<span style="color:#FA58D0"> '''1-2% of women who undergo ovarian stimulation develop a severe form of OHSS''' </span>. Complications from severe OHSS include:

*Fluid collection in the abdomen
*Electrolyte disturbances (sodium and potassium)
*Kidney failure
*Ovary twisting
*Rupture of a cyst in an ovary
*Breathing problems
*Blood clots in large vessels (most commonly the legs)
*Pregnancy loss from miscarriage or termination
*Rarely, death

A study by Nouri ''et. al.'' <ref name="PMID24996451"><pubmed>24996451</pubmed></ref> found that women with '''Polycystic Ovarian Syndrome''' (PCOS) and those that were induced with hCG experienced longer recovery times from severe OHSS than women who were not pregnant. They looked at a cohort of women hospitalised for the first time with severe OHSS and subject them to the same treatments. Based on a defined criteria, they established the recovery time of these women and compared the times between those that were pregnant to those that were not pregnant. They also found that whether a woman had PCOS or ovulation induction did not affect her risk of developing OHSS if she was not pregnant. It is only a risk factor for pregnant women.

===Thromboembolic events===

A frequent and deadly complication of OHSS are thromboembolic events due to increased blood clotting. This increase in blood clotting has been attributed to a variety of complications such as hemoconcentration (which thickens the blood), hypovolemia and an increase in the permeability of blood vessels as a result of increased vasoactive substances in the body of ovarian origin. Thromboembolic events include venous thromboses often in the upper extremities and arterial thromboses such as those in the cerebrovascular region. These events can lead to amputations of extremities, brain damage, miscarriage and death. To avoid this, anti-coagulants are given to pateitns with OHSS and they are fitted with compression stockings (see [[Treatment]]) <ref name="PMID23378404"><pubmed>23378404</pubmed></ref>.

{|
|-bgcolor="F8E0F1"
|
The risk of a woman developing OHSS is higher if she is having a '''twin pregnancy''', as she is exposed to higher concentration of hCG. <ref name="PMID9756273"><pubmed>9756273</pubmed></ref>
|}

</div>

==Treatment==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

'''General treatment
'''
*''Acetaminophen'' with or without a narcotic agent- used to treat abdominal discomfort
*Women are encouraged to drink 2-3 litres of water a day to prevent hemoconcentration
*Women are advised to avoid sexual intercourse and vigorous exercise at the risk of torsion or rupture of the ovaries
*NSAID's with anti-platelet properties should NOT be used as they may effect renal function in a women with OHSS
*Patients with significantly painful ascites or breathing problems may undergo ''Paracentesis'' (drainage of the ascites)
*''Culdocentesis'' (extraction of fluid from recto-uterine pouch) can be done to decrease the likelihood of a woman with moderate OHSS progressing to severe OHSS.<ref name="PMID22416285" />

===Mild to Moderate OHSS===

Mild OHSS can often resolve on its own, however, moderate OHSS may include treatments such as<ref name="WikiOHSS" />:

*Anti-nausea medication and prescription painkillers
*Regular physical examinations and ultrasounds
*Daily weigh-ins and waist measurements
*Measuring the amount of urine produced each day
*Frequent blood tests for monitoring dehydration and electrolyte imbalance
*Maintaining a high balance of fluids
*Drainage of excess abdominal fluid by inserting a needle in the abdominal cavity
*Wearing support stockings which help prevent blood clots/thrombosis

===Severe OHSS===

[[File:Abdominal Paracentesis.png|thumb|right|350px|Paracentesis is a common procedure done on women who have OHSS as it is used to drain the ascites in their abdomen. In this image you can see the puncture of the peritoneal cavity with a needle that then drains the fluid externally. <ref name="Wikiversity Journal of Medicine"> Blausen.com staff. "Blausen gallery 2014". Wikiversity Journal of Medicine. DOI:10.15347/wjm/2014.010. ISSN 20018762 </ref>]]

Severe OHSS requires hospital care in order for constant monitoring and treatment such as <ref name="WikiOHSS" />:

*Intravenous fluids with a crystalloid solution (100-150mL/hr)
*Intravenous Albumin is administered is IV fluids are insufficient (15-20mL/hr of 25% albumin for 4 hrs)
*In addition to Acetaminophen, ''Opioid analgesics'' can be administered for pain relief
*''Antiemetics'' can be used to subside nauseas and/or vomiting
*Woman administered to hospital of OHSS are considered at high risk of thromboembolic complications and are given low molecular weight ''heparin'', an anti-coagulant
*''Cabergoline''- lessens OHSS symptoms
*''GnRH agonist''- suppresses ovarian activity
**If at risk of OHSS, alternates include using a GnRH agonist instead of hCG however its effects on pregnancy rates are questionable. Using a GnRH agonist to replace the use of hCG for final oocyte stimulation will see a 6% decrease in delivery rate.
*Daily monitoring of creatine, urea, creatine clearance C-reactive protein (to rule out infection) are all required in combination with weekly tests such as liver and renal function tests and chest x-rays (to check for pleural effusion) <ref name="PMID12638783" />.

If there are serious complications then additional treatments are required:

*Surgery for a ruptured ovarian cyst
*Intensive care for the liver or lung complications

====Paracentesis====

For women with severe/grade 3 OHSS, paracentesis, the removal of fluid from the body using an aspiration needle, can be undertaken. It is a diagnostic and a therapeutic method that can be done trans-abdominally and trans-vaginally. It is used to relieve symptoms, improve haemodynamics e.g. Urinary output, and shorten the women's hospital stay. Complications of paracentesis include bleeding, infection and organ injury, however are note common <ref name="Paracentesis"> S. Monica Soni, HMS 3, Gillian Lieberman, MD [ http://eradiology.bidmc.harvard.edu/LearningLab/genito/Soni.pdf ], 'Ovarian Hyperstimulation Syndrome'</ref>.

{|
|-bgcolor="F8E0F1"
|
The most important aspect of treatment for any women with OHSS is close and constant '''monitoring''' with her healthcare professional. Counselling may also be provided to women and their partners or families in order to provide them with the best possible knowledge base to manage and treat their OHSS. It is important to note that there is '''no one cure or treatment''' for OHSS. Treatment involves managing and eliminating the symptoms until such time as the syndrome resolves itself <ref name="WikiOHSS" />.
|}

</div>

==Prevention==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

There are three key avenues through which the incidence of OHSS may be prevented. These include identifying risk factors to predict OHSS development, modifying treatment regimes on the basis of the identified risk factors and intervention to prevent progression to OHSS once the patient has undergone '''Controlled Ovarian Stimulation''' (COS).

=== Risk factors===

'''Primary risk factors'''

Pre-existing factors likely to exacerbate the ovarian stimulation response. Primary risk factors include <ref name="PMID26074966"><pubmed>26074966</pubmed></ref>:

*Young age
*Low body weight
*History of elevated response to gonadotropins
*Polycystic Ovary Syndrome (PCOS)
*Isolated PCOS characteristic
*Previous history of OHSS.
*High pretreatment basal Anti-Mullerian Hormone (AMH) concentration
*Large Antral Follicle Count (AFC)

'''Secondary risk factors'''

Secondary risk factors involve the monitoring of ovarian response parameters once COS has been initiated. These parameters are monitored for <ref name="PMID19007627"><pubmed>19007627</pubmed></ref>:

*rapidly rising E2 levels
*E2 concentration larger than 2500 pg/mL
*large number of developing follicles (10-14mm) on the day hCG is administered
*large number of oocytes retrieved

These factors in combination, act as a predictive tool to assess the likelihood of severe OHSS development, with a 83% sensitivity and 84% specificity. <ref name="PMID19007627"/>

=== Primary Prevention===
[[File:Severe OHSS Prevention.jpeg|right|thumbnail|400px|GnRH antagonists, embryo cryopreservation and cycle cancellation are key strategies in preventing OHSS progression in high-risk patients <ref name="PMID22938051"><pubmed>22938051</pubmed></ref>]]

Primary Prevention involves the modification of treatment regimens on the basis of OHSS risk classifications, in order to prevent OHSS occurrence.

'''Ovulation Induction'''

Unifollicular Ovulation Induction through Ovulation Induction (OI) is a primary means of avoiding OHSS in women with Polycystic Ovarian Syndrome, who are at an increased risk. In order to promote unifollicular development, the ovaries are stimulated with a low starting dose of FSH (75 IU).<ref name="PMID20416867"><pubmed>20416867</pubmed></ref> Studies suggests that a minimum gonadotropin dose lowers OHSS risk and thus a step-up regimen is utilised to achieve an ovarian response, whereby the FSH dosage is increased every 7 days until follicular development of greater than 10mm is noted.<ref name="PMID26074966" /> Alternatively, a step-down regimen may be followed, whereby a high initial FSH dosage is lowered according to the ovarian response. Another method to increase FSH levels during OI, is through '''Aromatase Inhibitors''' which promote folliculogenesis by increasing pituitary secretion of FSH, and downregulate oestrogen production through a negative feedback loop. However, Aromatase Inhibitors have not been shown to reduce OHSS incidence in comparison to other methods of OI.<ref name="PMID26074966" /> During OI, a key objective is to prevent early cycle cancellation due to premature luteinisation from pituitary secretion of LH. In order to downregulate LH secretion, '''Gonadotropin-releasing hormone agonists''' (GnRHa) are administered in addition to gonadotropins. Alternatively, '''GnRH antagonists''', which have a rapid onset of action, may be administered to downregulate endogenous LH secretion, with relative success as depicted in the diagram to the right.<ref name="PMID20416867" /> Comparative studies have shown that the GnRH antagonist protocol has a greater effect in lowering the incidence of mild to severe OHSS. However due to the rare nature of OHSS, and insufficient sample sizes, the difference was not found to be significant. <ref name="PMID21082508"><pubmed>21082508</pubmed></ref>. Generally, the duration of exposure to gonadotropins and subsequent risk of OHSS may be minimised through mild stimulation protocols which administer FSH only in the mid to late follicular phase.<ref name="PMID20416867" />

'''Adjuvant Metformin Therapy'''

Adjuvant Metformin Therapy has been found to lower the risk of OHSS by 63%.<ref name="PMID25406011"><pubmed>25406011</pubmed></ref> It involves the administration of metformin at a daily dosage of 1000 to 2000mg, 2 months prior to Controlled Ovarian Stimulation <ref name="PMID26074966"/>. Metformin lowers the elevated insulin levels in PCOS which consequently reduce intraovarian androgen levels. This leads to a reduced sensitivity and expression of granulosa cell-follicle stimulating hormone receptors which result in a less exaggerated response to gonadotropins. Furthermore, it is suggested that Metformin prevents OHSS by controlling vascular permeability through the inhibition of various vasoactive molecules, including VEGF.

'''Avoiding hCG during Luteal Phase Support

Following Controlled Ovarian Stimulation, the steroid levels of E2 and P4 are reduced during the luteal phase due to the negative feedback on the pituitary. This leads to low endogenous LH levels, which consequently reduce endometrial receptivity as well as the luteal phase duration itself. As a result, implantation and pregnancy rates are reduced and early pregnancy loss rates are increased.<ref name="PMID20416867" /> Luteal Phase Support (LPS) serves to combat these adverse events with the use of hCG. However, hCG has been found to increase the risk of OHSS. Alternatively, the use of progesterone has been found to not only halve the risk of OHSS, but also induce similar improvements in pregnancy and miscarriage rates as hCG.<ref name="PMID26148507"><pubmed>26148507</pubmed></ref>

===Secondary Prevention===

Secondary Prevention aims to prevent progression to OHSS once COS has been initiated and the patient has been found to mount an exaggerated response. <ref name="PMID20416867" />
[[File:Cryopreservation of Porcine Embryos.jpeg|right|thumbnail|300px|Cryopreservation in the swine model: a) mature oocyte b) day 1 embryo c) day 4 embryo d) blastocyst from cryopreserved day 1 embryo with an intact zona pellucida excluding the lipid droplet. Scale bars=20μm <ref name="PMID26309801"><pubmed>26309801</pubmed></ref>]]
'''Coasting'''

Coasting is a first-line secondary preventative strategy. It consists of the withdrawal of gonadotrophins when a critical number of follicles and/or E2 concentration is reached. hCG is administered once the E2 concentration reduces to a safe level, before the process of oocyte retrieval commences. This preventative strategy is conducted for a period of less than 3 days in order to avoid compromising IVF outcomes.<ref name="PMID26074966"/>

'''Cryopreservation'''

Cryopreservation of embryos after oocyte retrieval is another avenue which may avert OHSS progression. The cryopreserved embryos are only reimplanted once the patient's hormone serum levels have normalised. Using oocyte vitrification, crystal formation within embryo tissue is avoided and so cryopreserved embryos have been found to produce better pregnancy rates with a 32% increase, than fresh embryo transfer.<ref name="PMID26074966"/> Recent studies suggest cryopreservation itself does not reduce OHSS rates, but must be followed by a GnRHa trigger to avert OHSS.<ref name="PMID24753847"><pubmed>24753847></ref>

'''Cycle cancellation'''

Cycle cancellation is a guaranteed method to prevent early OHSS whereby hCG is withheld. This is a last resort strategy as it carries the risk of significant psychological distress and financial loss for the patient. <ref name="PMID20416867"/>

</div>

==Effect on the Newborn==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

</div>
Women who develop OHSS while undergoing Assisted Reproductive Technologies (ART) treatment are not only more likely to achieve a pregnancy, but have a live birth as the pregnancy outcome. This live birth is also more likely to be a multiple birth of two, three or more children. <ref name="PMID19591989"><pubmed>19591989</pubmed></ref> It has been postulated that a multi-fetal pregnancy leads to a more rapid increase in hCG levels, resulting in an increased risk of OHSS. However, the causal nature between multi-fetal pregnancy and OHSS development is disputed and further research is required to distinguish correlation from causation. <ref name="PMID19573292"><pubmed>19573292</pubmed></ref>

OHSS development is also associated with an increased risk of adverse outcomes including '''stillbirth, premature birth and low birth weight'''.<ref name="PMID19591989" /> Although the cause for the increased risk in adverse pregnancy outcomes is unknown, it is suggested that as the incidence of OHSS is reduced through various prevention strategies, the risk of such outcomes may be also be reduced.

'''<span style="color:#FA58D0"> [http://pregnancyperfect.com/emilyley/ The following link is to a podcast of a woman describing her pregnancy in which she underwent IVF, had OHSS and gave birth to healthy twins]<ref name="Emily"> Pregnancy Perfect[ http://pregnancyperfect.com/emilyley/ ], 'TWINS, IVF, OHSS AND C-SECTION WITH EMILY LEY'</ref> </span>'''

==Genetics==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

Despite OHSS typically being of iatrogenic origin as a result of ovarian stimulation with gonadotropins, research has been conducted into the potential genetics behind OHSS as many sporadic and familial cases have been observed. '''Mutations''' in the receptor for hormones such as Follicle Simulating Hormone (FSH), Lutenizing Hormone (LH) and hCG have all been targets of OHSS genetics research. Interestingly, they too also arise from a common ancestral gene.

===Follicle Stimulating Hormome===

Dr. Botros Rizk, of the University of South Alabama College of Medicine <ref name="PMID19573286"><pubmed>19573286</pubmed></ref>, has written extensively regarding the genetics behind OHSS. In particular, he talks about '''FSH receptors''' (FSHR) and their role in the syndrome. He hypothesises that mutations in these receptors could be activating or inactivating, leading to an increased risk of developing OHSS or sterility respectively. Currently, 744 single nucleotide polymorphisms (a type of mutation) have been found in the gene encoding the FSHR, 8 of which are located in its exons (coding regions of the gene). How the ovary responds is resultant on the FSHR genotype. For example, Ser680Asn, a polymorphism in the FSHR gene has been shown to aid in predicting the severity of a woman's OHSS. Ordinarily FSH stimulates the growth of ovarian follicles, however, when mutated, it is stimulated by the hCG resulting in excessive follicle development.

Spontaneous OHSS, OHSS that arises and cannot be attributed to any form of ovarian stimulation or Assisted Reproductive Technology, has been linked to activating mutations in the FSHR <ref name="PMID23499866"><pubmed>23499866</pubmed></ref>. This familial disorder is an autosomal dominant one. In most cases the FSHR can be stimulated by the presence of Thyroid Stimulating Hormone (TSH) or hCG, in the absence of FSH (the ligand for FSHR).

[[File:FSHR Gene.jpg|centre|thumbnail|700px|This image depicts the location of the FSHR Gene on chromosome 2. It is located on the short arm between positions 21 and 16. Changed to the FSHR gene has been linked to OHSS. <ref name="Genetcis"> Genetics Home Reference [http://ghr.nlm.nih.gov/gene/FSHR'</ref>]]

===Lutenizing Hormome===

The '''Lutenizing Hormone Receptor''' (LHR) gene in humans is comprised of 11 exons. Animal studies have shown that many primates exhibit a similar gene which is comprised of only 10 exons, however a gene lacking the 10th exon has been identified and termed the type 2 LHR. Expression of the type 2 LHR has been seen in humans. The type 2 LHR, compared to the wild-type LHR appears to be repaired with regard to its function. Defects in the type 2 LHR include a decrease in efficiency of transport to the plasma membrane and irregularities in signal transduction. Inactivating mutations in the LHR have been seen to cause infertility in women as well as amenorrhoea. Activating LHR gene mutations are asymptomatic and are not associated with OHSS in women.

===Bone Morphogenic Protein===

An imporant growth factor, derived from oocytes called '''BMP-15''' (Bone Morphogenic Protein 15) is vital for female fertility. It belongs to the family of growth factors, Transforming Growth Factor β (TGF-β) and is heavily involved in folliculogenesis. It has been found that mutations in the BMP-15 gene caused infertility in female sheep. Conversely, it has also been indicated in enhanced fertility when BMP-15 is present is high amounts in follicular fluid <ref name="PMID19573286" />.

A case study done by Hanevik ''et. al.'' in 2013 <ref name="PMID21565556"><pubmed>21565556</pubmed></ref> found that a Single Nuclear Polymorphism (SNP) in the BMP-15 gene is responsible for a high response to ovarian hyper-stimulation. The aim of the study was to test the effect the SNP had on BMP-15 with regard to high and low responders buy taking blood from 53 high responders, 38 low responders and 100 non-responders (controls) and analysing 5 noted SNP's. Results from their study showed a correlation between a high response to ovarian hyper-stimulation and the BMP-15 9G allele. The article does state however, that further research is required into the molecular effects of SNP's on the function of BMP-15.

===Vascular Endothelial Growth Factor===

'''Vascular endothelial growth factor''' (VEGF) has been indicated as one of the key agents causing vascular permeability and subsequent ascites in OHSS. The gene, which is located on chromosome 12, is made up of 8 exons (coding regions), of which exons 6 and 7 do not always appear due to the exons being spliced out.The splicing of this gene allows for various isoforms of the gene to exist of which VEGF 121 and 165 appear to play a role in angiogenesis. There are two VEGF Receptors, VEGFR-1 and VEGFR-2 that belong to the tyrosine kinase family of receptors (for more information on VEGF see [[Pathophysiology]]). Because of its distinct role in OHSS, it has been targeted as an area for research for potential treatments. The idea is that if the genetic expression of VEGF and its receptors can be controlled, OHSS can be avoided or treated.<ref name="PMID19573286" />

A different study by Hanevik ''et. al.'' , <ref name="PMID22587628"><pubmed>22587628</pubmed></ref> done in 2012 involved analysing blood samples from 53 women with OHSS and 100 women without it (controls) and analysing 6 SNP's in the VEGFR2 gene to find any genetic variations. They found a correlation between women with the VEGF +405cc genotype and the development of OHSS indicating women that undergo controlled ovarian hyper-stimulation and posses his genotype, are at an increased risk of developing OHSS.

</div>

== Current Research on Animal Models==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

{|
|-bgcolor="FFF5FF"
|<span style="font-size:120%">'''Inhibition of Cyclooxygenase-2 (COX-2) by Meloxican decreasing the incidence of OHSS in Rat Model'''</span> <ref name="PMID18166186"><pubmed>18166186</pubmed></ref>

Reasearch was carried out to investigate the effects of selective inhibition of the enzyme COX-2 on the Ovarian Hyperstimulation Syndrome (OHSS) using Female Wistar rates as the subjects. The research aimed to find results by measuring the number of antral and luteinized follicles, ovarian weight, vascualr endothelial growth factors and COX-2 immunohistochemistry. The rats being tested were all 22 days old and were divided into four equal groups;

'''Group 1 (Control group)''' was subject to a 0.1 ml of Intraperitoneal Saline from days 22 ~ 26

'''Group 2 (Mildly-stimulated group)''' subject to 10IU of pregnant mare serum gonadotrophin (PMSG) on day 24 and then 10IU of Human Chorionic Gonadotrophin (hCG) on day 26

'''Group 3 (OHSS positive group)''' was subject to 10IU of PMSG from days 22 ~ 26 and then administered 30IU of hCG on day 26 to induce OHSS

'''Group 4 (OHSS positive variant group)''' received 15mg/ml of Meloxicam 2 hours prior to administration of 10IU PMSG from days 22 ~ 26

Results showed there was no difference in ovarian weight in samples from Group 1 and Group 2, however Group 3 showed signs of significant ovarian weight increase which in group 4 was suppressed by the introduction of Meloxicam. No differences were observed in the number of antral follicles amongst the four test groups. Results from Group 2 and Group 3 showed that the granulosa cells of preovulatory follicles and the stromal cells were highly VEGF immunoreactive, however the Meloxicam treated Group 4 showed less immunoreactivity than Group 2 and Group 3 which indicated the correlation between Meloxicam and the diminished VEGF expression. Group 3 presented an increased COS-2 immunoreactivity which was highly diminished than in Group 4.

The research concluded that in a rat model, the enzyme Meloxicam has a beneficial effect on OHSS by reducing the increase of ovarian weight and the expression of VEGF associated with OHSS, the effects of which may be mediated by the inhibitory capacity of COX-2 on Meloxicam
|}

{|
|-bgcolor="FFF5FF"
|<span style="font-size:120%">'''Inhibition of Ovarian VEGF secretion by activation of Dopamine Receptor 2'''</span> <ref name="PMID25217874"><pubmed>25217874</pubmed></ref>

This research was carried out to investigate a possibility in whether a Dopamine Receptor 2 agonist '''(D2-ag)''' can assist in the prevention of Ovarian Hyperstimulation Syndrome, using rat models, by decreasing the ovarian vascular endothelial growth factor '''(VEGF)''' production. Using Immature Wistar rats (22 days old) as their animal model, the rats were initially stimulated with Gonadotrophins to mimic the onset and effects of OHSS and then subjected to treatment with a D2-agonist and/or a D2-antagonist (D2-ant). The vascular permeability was measured at the endpoint after day 26 by measuring the peritoneal extravasion of a previously injected dye and ovaries from all subjects were collected to assess the effects of D2-ag and D2-ant on the production of Ovarian VEGF. The expression of VEGF mRNA was measured by quantitative real time PCR and the levels of VEGF proteins were measured by Western Blots.

Results showed that the D2-ag caused a large reduction in the vascular permeability which was in turn associated with the great decreased in VEGF protein production in the OHSS rat ovaries, whereas the introduction of D2-ant showed opposite results with a increase in the vascular permeability leading to the increase of VEGF protein production in the ovaries. Ovarian VEGF mRNA levels were found to be unaffected by the introduction of these drugs in OHSS rat subjects. Conclusions were drawn on the fact that Dopamine Receptor 2 agonists prevent the increase of vascular permeability in subjects with OHSS by decreasing the ovarian production of VEGF and also that due to the dose-dependent inhibitory effect of the D2-ag on ovarian VEGF, current OHSS therapies used in humans can benefit by increasing the intraovarian concentration of D2-ag.
|}

</div>

==Glossary==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

'''Aromatase Inhibitor''' - A drug that inhibits enzyme aromatase, which in turn suppresses estrogen synthesis.

'''Ascites''' - An accumulation of fluid in the peritoneal cavity with resultant abdominal swelling.

'''Cabergoline''' - A dopamine receptor agonist used to treat hormone imbalance.

'''Controlled Ovarian Stimulation''' - female infertility treatment using medications to stimulate the ovaries to develop follicles.

'''Cryopreservation''' - Cooling and storing biological material at extremely low temperatures.

'''E2''' - Estradiol - Potent estrogen sex hormone.

'''FSH''' - Follicle Stimulating Hormone

'''Gonadotropin''' - Any hormone that has a stimulating effect on the gonads.

'''GnRH agonist''' - Gonadotropin Releasing Hormone - A class of compounds that mimic the effect of the natural Gonadotropin Releasing Hormone.

'''GnRH antagonist''' - Gonadotropin Releasing Hormone - A class of compounds that are similar in terms of the structure of natural Gonadotropin Releasing Hormone but has a antagonistic effect.

'''hCG'''- Human Chorionic Gonadotropin

'''Hemoconcentration''' - An increase in the concentration of circulating red blood cells in response to a decrease in blood plasma volume.

'''Hypovolemic''' - A decrease in circulating blood volume.

'''Iatrogenic''' - Illness caused as a result of a medical examination or treatment.

'''Intravenous fluids''' - Is the infusion of liquid substances directly into a vein.

'''IVF''' - In-vitro Fertilization

'''LH''' - Luteinizing Hormone

'''Metformin''' - A biguanide, antidiabetic drug used as an adjuvant to modify the effect of other agents.

'''NSAID''' - Non-steroidal Anti-Inflammatory Drug e.g. Ibuprofen

'''Oocyte vitrification''' - technique for cryopreservation of oocytes.

'''OHSS''' - Ovarian Hyper-stimulation Syndrome

'''Oliguria'''- Decreased urine output/small amounts of urine produced.

'''P4''' - Progesterone - endogenous progestogen sex hormone.

'''PCOS''' - Polycystic Ovarian Syndrome. An endrocrine system disorder whereby the ovaries are enlarged with small collections of fluid.

</div>

==References==

2015 Group Project 2

2015-10-23T16:44:47Z

Z3372824: /* Secondary Prevention */

{{ANAT2341Project2015header}}

==<span style="font-size:120%">'''Ovarian Hyper-stimulation Syndrome (OHSS)'''</span>==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

Ovarian Hyper stimulation Syndrome (OHSS) is an iatrogenic complication of '''Assisted Reproduction Technology''' (ART), in which women take medications to stimulate oocyte growth. It is generally identified by cystic enlargements of the ovaries and fluid accumulation in the peritoneal cavity due to the increased capillary permeability and ovarian neoangiogenesis <ref name="PMID22065820"><pubmed>22065820</pubmed></ref>. It is an occurrence which is dependent on the controlled stimulation of the ovaries in preparation for IVF i.e. administration of human Chorionic Gonadotropin (hCG).

OHSS was first described in 1943 as ''“syndrome d’hyperluteinisation massive des ovaries”''. It was during this time that gonadotropins were prepared from animals such as sheep to bring on ovulation in women. The first recorded death as a result of OHSS occurred in 1951 and was due to renal failure as a result of oligouria, a complication of the syndrome <ref name="OHSS"> Marie M. Budev, DO, MPH; Alejandro C. Arroliga, MD; Tommaso Falcone, MD, [ http://utilis.net/Morning%20Topics/REI/Ovarian%20Hyperstimulation.pdf ], 'Ovarian Hyperstimulation Syndrome'</ref> <ref name="PMID12638783"><pubmed>12638783</pubmed></ref>.

<span style="color:#FA58D0">'''This wikipage aims to provide clear information on various areas surrounding OHSS such as diagnosis, prevention and complications and will look into the genetics behind the disorder and the various animals models used to research it'''.</span>

<html5media height="350" width="450">https://www.youtube.com/watch?v=aXmjJw234a4</html5media>

'''Overview of Ovarian Hyperstimulation Syndrome''' <ref> Howcast (2013, August 27) Ovarian Hyperstimulation Syndrome | Infertility. Retrieved from https://www.youtube.com/watch?v=aXmjJw234a4</ref>

</div>

==Epidemiology==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

Ovarian Hyper-Stimulation Syndrome (OHSS) rarely occurs sporadically, and if it does, it is usually the result of an underlying genetic problem. The majority of OHSS is due to the ovaries being stimulated to mature and release an abundance of oocytes, in response to hormones Human Chorionic Gonadotropin (hCG) and Follicle Stimulating hormone (FSH), during IVF. Rarely, Clomifene Citrate therapy can cause OHSS.<ref name="WikiOHSS"> Wikipedia, [ https://en.wikipedia.org/wiki/Ovarian_hyperstimulation_syndrome ], 'Ovarian Hyperstimulation Syndrome'</ref>

OHSS only affects '''0.5-5%''' of women undergoing Ovarian Hyper-stimulation, but despite its small prevalence, it is a potentially fatal outcome of a non-vital procedure and remains a prevalent problem for fertility specialists <ref name="PMID12498425"><pubmed>12498425</pubmed></ref> <ref name="PMID12638783"><pubmed>12638783</pubmed></ref>. Age has been cited as a factor affecting those with OHSS, with younger women more at risk. Additionally, women with allergies were seen to have a higher incidence of OHSS. It is important to note that at this point in time, there is no positive correlation between gonadotropin dose and OHSS.

Of the 0.5-5% of women affected with OHSS mentioned above, 2% of those women will require hospitalisation. As of 2011, it has been reported that the incidence of OHSS was '''increasing''', resulting in approximately 3 deaths per 100,000 women undergoing ovarian stimulation per year <ref name="PMID21828116"><pubmed>21828116</pubmed></ref>. This is particularly worrying as in 2008, in the United States alone, there were around 150,000 IVF cycles undertaken.

{|
|-bgcolor="F8E0F1"
|
'''With the field of Assisted Reproductive Technologies expanding and more women partaking in IVF treatments, the threat of women developing OHSS is an ongoing and increasing one''' <ref name="PMID21828116" />.
|}
{| class="wikitable mw-collapsible mw-collapsed"
! colspan=4|Characteristics of women with OHSS by complication group <ref name="PMID19591989"><pubmed>19591989</pubmed></ref>
|-
! scope="col" width="100px" height="60px" style="text-align:center| '''Characteristic'''
! scope="col" width="100px" height="60px" style="text-align:center| '''No Complications
(N = 212,041)'''
! scope="col" width="100px" height="60px" style="text-align:center| '''Moderate OHSS
(N = 1,523)'''
! scope="col" width="100px" height="60px" style="text-align:center| '''Severe OHSS
(N = 655)'''
|-
|style="text-align:center; background: #FF99FF;"| '''Maternal Age (Mean ± SD)'''
|style="text-align:center; background: #F6CEEC;"| 35.6 ± 4.6
|style="text-align:center; background: #F6CEEC;"| 33.0 ± 4.3
|style="text-align:center; background: #F6CEEC;"| 33.1 ± 4.4
|-
|style="text-align:center; background: #FF99FF;"| '''Maternal Age (%)'''
|-
|style="text-align:left; background: #F6CEEC;"| <30 years
|style="text-align:center; background: #F6CEEC;"| 10 %
|style="text-align:center; background: #F6CEEC;"| 21.1 %
|style="text-align:center; background: #F6CEEC;"| 20.6 %
|-
|style="text-align:left; background: #F6CEEC;"| 30-34 years
|style="text-align:center; background: #F6CEEC;"| 30.4 %
|style="text-align:center; background: #F6CEEC;"| 43.2 %
|style="text-align:center; background: #F6CEEC;"| 40.5 %
|-
|style="text-align:left; background: #F6CEEC;"| 35-39 years
|style="text-align:center; background: #F6CEEC;"| 37.8 %
|style="text-align:center; background: #F6CEEC;"| 27.2 %
|style="text-align:center; background: #F6CEEC;"| 32.5 %
|-
|style="text-align:left; background: #F6CEEC;"| >40 years
|style="text-align:center; background: #F6CEEC;"| 21.8 %
|style="text-align:center; background: #F6CEEC;"| 8.4 %
|style="text-align:center; background: #F6CEEC;"| 6.4 %
|-
|style="text-align:center; background: #FF99FF;"| '''Nulligravida (%)'''
|style="text-align:center; background: #F6CEEC;"| 45.8 %
|style="text-align:center; background: #F6CEEC;"| 51.5 %
|style="text-align:center; background: #F6CEEC;"| 51.8 %
|-
|style="text-align:center; background: #FF99FF;"| '''Infertility Diagnosis (%)'''
|-
|style="text-align:left; background: #F6CEEC;"| Male factor
|style="text-align:center; background: #F6CEEC;"| 37.7 %
|style="text-align:center; background: #F6CEEC;"| 41.0 %
|style="text-align:center; background: #F6CEEC;"| 33.4 %
|-
|style="text-align:left; background: #F6CEEC;"| Endometriosis
|style="text-align:center; background: #F6CEEC;"| 13.5 %
|style="text-align:center; background: #F6CEEC;"| 13.5 %
|style="text-align:center; background: #F6CEEC;"| 10.7 %
|-
|style="text-align:left; background: #F6CEEC;"| Ovulation Disorders
|style="text-align:center; background: #F6CEEC;"| 14.0 %
|style="text-align:center; background: #F6CEEC;"| 29.5 %
|style="text-align:center; background: #F6CEEC;"| 22.4 %
|-
|style="text-align:left; background: #F6CEEC;"| Diminished ovarian reserve
|style="text-align:center; background: #F6CEEC;"| 16.9 %
|style="text-align:center; background: #F6CEEC;"| 3.2 %
|style="text-align:center; background: #F6CEEC;"| 2.4 %
|-
|style="text-align:left; background: #F6CEEC;"| Tubal factors
|style="text-align:center; background: #F6CEEC;"| 20.4 %
|style="text-align:center; background: #F6CEEC;"| 22.6 %
|style="text-align:center; background: #F6CEEC;"| 22.3 %
|-
|style="text-align:left; background: #F6CEEC;"| Uterine factors
|style="text-align:center; background: #F6CEEC;"| 5.1 %
|style="text-align:center; background: #F6CEEC;"| 4.3 %
|style="text-align:center; background: #F6CEEC;"| 3.1 %
|-
|style="text-align:left; background: #F6CEEC;"| Other factors
|style="text-align:center; background: #F6CEEC;"| 13.9 %
|style="text-align:center; background: #F6CEEC;"| 13.1 %
|style="text-align:center; background: #F6CEEC;"| 10.4 %
|-
|style="text-align:left; background: #F6CEEC;"| Unexplained factor
|style="text-align:center; background: #F6CEEC;"| 12.7 %
|style="text-align:center; background: #F6CEEC;"| 11.8 %
|style="text-align:center; background: #F6CEEC;"| 18.6 %
|-
|}
</div>

==Causative Agents==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

[[File:Follicular Development.jpeg|right|thumbnail|500px|Infertility treatments aim to facilitate follicular development and induce ovulation to improve chances of fertilisation <ref name="PMID24717179"><pubmed>24717179</pubmed></ref>]]

Normally a woman produces one egg per month from the ovaries, which travel down the Fallopian tube to be fertilized or be released from the body. In cases where women have difficulty falling pregnant, they are given medication which help them to produce and release eggs (as shown in the diagram to the right), further increasing their chances of fertilization and pregnancy <ref><pubmed>19573285</pubmed></ref>. Ovarian Hyper stimulation Syndrome generally occurs during infertility treatments when the ovaries are overstimulated by the fertility medication which causes the ovaries to swell and leak fluids into the belly and abdomen. The prevalence of OHSS onset is linked with excessive number of follicle development in response to the administration of injectable Follicle Stimulating Hormones (FSH) followed by the '''Human Chorionic Gonadotrophins''' (hCG) which triggers the release of the oocytes <ref><pubmed>26190539</pubmed></ref>.

'''Follicle Stimulating Hormones''' (FSH) <ref name="PMID9020850"><pubmed>9020850</pubmed></ref> are glycoprotein hormones that are produced and secreted from the Anterior Pituitary gland into the bloodstream, which regulate the developmental, growth, maturation and the reproductive processes within the body. In females, the Follicle Stimulating Hormones initiates the stages of growth and development of immature ovarian follicles within the ovaries before the release of an egg from a follicle at ovulation. When FSH is administered to a patient who is suffering from infertility, the increase FSH levels affect the rate of development and production, in turn increasing the amount of follicles which are ready to be released during ovulation.

</div>

==Symptoms==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

OHSS is classified based on a criteria from mild, moderate and severe <ref name="WikiOHSS" />:

'''Mild Symptoms'''- abdominal bloating, minimal weight gain, nausea, diarrhoea and a feeling of fullness.

'''Moderate Symptoms'''- Substantial weight gain (on average 2 or more pounds a day), increased abdominal girth, darkend urine and excessive thirst in addition to the mild symptoms.

'''Severe Symptoms'''- In addition to the symptoms associated with Mild and Moderate OHSS, in severe OHSS, you see shortness of breath, calf and chest pains and pleural effusion.

===<span style="font-size:100%">Classifications of Ovarian Hyper-stimulation Syndrome:</span> <ref name="PMID22065820"><pubmed>22065820</pubmed></ref>===

{| class="wikitable" style="text-align:center
|-
! scope="col" width="70px"| '''Classification'''
! scope="col" width="650px"| '''Symptoms'''
|-
|style="text-align:center; background: #F6CEEC;"| '''Mild'''
|style="height: 60px; background: #F6CEEC;"| '''Grade 1''' - Abdominal distention and discomfort
'''Grade 2''' - Abdominal distention, discomfort with nausea, vomiting and/or diarrhea and ovarian enlargement from 5~12cm
|-
|style="text-align:center; background: #F8E0F1;"| '''Moderate'''
|style="height: 60px; background: #F8E0F1;"| '''Grade 3''' - All features of Mild OHSS with ultrasonographic evidence of ascites
|-
|style="text-align:center; background: #F6CEEC;"| '''Severe'''
|style="height: 60px; background: #F6CEEC;"| '''Grade 4''' - All features of Moderate OHSS with the addition of clinical evidence of ascites and breathing difficulties present
'''Grade 5''' - All of the above symptoms along with a change in the blood volume, increased blood viscosity due to coagulation and diminished renal function
|}

</div>

==Diagnosis==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

Whilst symptoms of OHSS can occur as soon as 24 hours post hCG administration, they are usually seen in women 7-10 days post administration. Initially women with OHSS will present with abdominal bloating, as a result of fluid in the peritoneal cavity and an increase in ovary size. When women present with severe OHSS they are often dehydrated, due to increased vascular permeability, and have hemoconcentration. The above results in a decrease in intravascular volume, leading to '''oligouria''' <ref name="PMID22416285" />.

===History===

Initially a thorough history of the patient is taken during which the clinician looks for evidence of ovarian stimulation, followed by ovulation. During this history taking, the clinician will inquire into any weight gain noticed, urine output, and the woman's ability to maintain oral hydration. A key diagnostic tool for clinicians regarding women who are taking gonadotropins is to identify if they are at an increased risk of developing OHSS. Some risk factors include woman aged less than 30, women who have polycystic ovaries, woman with a previous history of OHSS and women who have had greater than 20 oocytes retrieved <ref name="PMID22416285" />.

===Physical Exam===
[[File:Vaginal_Ultrasonography_in_Sagittal_Plane.jpg|right|thumbnail|600px|Vaginal Ultrasonography in Sagittal plane <ref name="Wikiversity Journal of Medicine"> Häggström, Mikael. "Medical gallery of Mikael Häggström 2014". Wikiversity Journal of Medicine 1 (2). DOI:10.15347/wjm/2014.008. ISSN 20018762</ref>]]
After a history of the patient is taken, the next step is to perform a physical exam on the patient. Women who present with abdominal bloating will produce a shifting dullness upon abdominal percussion. Additionally the clinician will test the woman's vital signs, measure her abdominal girth, weight and will look for evidence of ascites or increase in calf size (usually unilateral)<ref name="PMID22416285" />.

===Investigations===

If the clinician further suspects a women of having OHSS, various investigations can be done such as an ultrasound.The intraperitoneal fluid is best imaged via vaginal ultrasound due to the enlarged ovaries making it difficult to image the pelvis using transabdominal ultrasound. The clinician can also order laboratory testing to look for urine specific gravity and and complete blood count to look for hemoconcentration with a hematocrit. Additionally, liver function tests can be ordered to look for elevated function. The clinician will also look for evidence of elevated D-dimers and fibrinogen and decreased levels of anti-thrombin 3 <ref name="SAHealth"> Government of South Australia Health [ http://www.sahealth.sa.gov.au/wps/wcm/connect/9b61ed004ee5348da663afd150ce4f37/Ovarian-hyperstimulation-syndrome-WCHN-PPG-17072012.pdf?MOD=AJPERES&CACHEID=9b61ed004ee5348da663afd150ce4f37 ], 'South Australian Paediatric Clinical Guidelines OHSS'</ref>.

====Ultrasound====

Typical appearances of the ultrasound include <ref name="Ultrasound"> Radiopaedia [ http://radiopaedia.org/articles/ovarian-hyperstimulation-syndrome-1 ], 'Ovarian Hyperstimulation Syndrome'</ref>:

*Bilaterally and symmetrically enlarged ovaries (>12cm)
* "Spoke-Wheel appearance" - presence of multiple cysts of varying size
*May also see ascites (fluid)

===Severity===

Once a clinician has deduced a women is suffering from OHSS, the severity of their condition needs to be established as either mild, moderate or severe. This is done by referring to the criteria under the sub-heading [[Symptoms]].The subsequent course of treatment for the woman will be based upon this evaluation.

{|
|-bgcolor="F6CEEC"
|
'''Further investigations''' can be done including a Chest X-ray to check for pleural effusions and oedema and USS with Doppler's to check for ascites or possible ovary torsion. <ref name="PMID22416285"><pubmed>22416285</pubmed></ref>
|}

===Differential Diagnosis===

Conditions presenting with similar symptoms or ultrasound images include <ref name="Ultrasound" />:

*Polycystic Ovaries (PO)
:: The difference is that with PO is that the cycts are typically smaller than OHSS cysts and there is no evidence of ascited or pleural effusion
*Mucinous Ovarian Malignancy
:: A type of Ovarian Epithelial tumour
*Ectopic Pregnancy <ref name="Casereport"> Australian Medical Student Journal [ http://www.amsj.org/wpcontent/uploads/files/articles/amsj_v2_i1/AMSJ_v2_i1_pg58-60.pdf ], 'Ovarian hyperstimulation syndrome'</ref>
::A pregnancy in which the foetus develops outside of the uterus e.g. in the fallopian tube

</div>

==Pathophysiology==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

The definition of Ovarian Stimulation is enlarged ovaries with many luteinized cysts, that can present with secondary complications. What distinguishes Ovarian Stimulation from OHSS is the presence of vascular hyper-permeability that results in fluids being redirected elsewhere in the body.

The key process to OHSS appears to be caused by '''Vascular Endothelial Growth Factor''' (VEGF), that is released along with other cytokines, estrogen and progesterone, due to the ovary undergoing luteinization as a result of stimulation by hCG. VEGF increases vascular permeability and as a result the capillaries become more "leaky" to the fluids in them. These fluids can then escape the capillaries and accumulate in the pleural and abdominal cavities as ascites. The woman then becomes hypovolemic and is at an increased risk of circulatory, renal and respiratory issues such as arterial thromboembolism due to the thickening of the blood. Note, the blood is thickened as fluid is leaving the capillaries, leaving behind red blood cells and other cellular components of the blood <ref name="WikiOHSS" />.

The increase in expression of VEGF and VEGF Receptor 2 (VEGFR2) is attributed to the greatly increased amount of their mRNA present in the body after stimulation with hCG <ref name="PMID21082502"><pubmed>21082502</pubmed></ref>. VEGF interacts with VEGF2 and VEGF Receptor 1 (VEGFR1) to create a strong angiogenic effect. Both VEGFR2 and VEGFR1 belong to a family of receptors called tyrosine kinases. VEGF2 is involved in the regulation of angiogenesis and vascular permeability whilst VEGF1 has a slightly contradictory role in that is is involved in the maintenance of the tight junctions between endothelial cells in blood vessels. A study by Gómez ''et. al.'' <ref name="PMID21082502" /> showed that women experiencing OHSS had substantially higher plasma levels of VEGF and lower levels of VEGFR1.

[[File:Pathogenesis_of_OHSS.png|600px|centre|thumb|Pathogenesis of OHSS <ref name="PMID20416867"><pubmed>20416867</pubmed></ref>]]

</div>

==Complications==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

Ovarian torsion or rupture, renal insufficiency and thrombophlebitis can all complicate OHSS. If a pregnancy occurs, symptoms may persist longer than the usual 1 to 2 weeks and become more severe, however, even with severe OHSS, they do not extend past the first trimester <ref name="WikiOHSS" />. [[File:Polycystic Ovaries.jpeg|right|thumbnail|360px|Comparison of Normal and Polycystic Ovary]]

<span style="color:#FA58D0"> '''1-2% of women who undergo ovarian stimulation develop a severe form of OHSS''' </span>. Complications from severe OHSS include:

*Fluid collection in the abdomen
*Electrolyte disturbances (sodium and potassium)
*Kidney failure
*Ovary twisting
*Rupture of a cyst in an ovary
*Breathing problems
*Blood clots in large vessels (most commonly the legs)
*Pregnancy loss from miscarriage or termination
*Rarely, death

A study by Nouri ''et. al.'' <ref name="PMID24996451"><pubmed>24996451</pubmed></ref> found that women with '''Polycystic Ovarian Syndrome''' (PCOS) and those that were induced with hCG experienced longer recovery times from severe OHSS than women who were not pregnant. They looked at a cohort of women hospitalised for the first time with severe OHSS and subject them to the same treatments. Based on a defined criteria, they established the recovery time of these women and compared the times between those that were pregnant to those that were not pregnant. They also found that whether a woman had PCOS or ovulation induction did not affect her risk of developing OHSS if she was not pregnant. It is only a risk factor for pregnant women.

===Thromboembolic events===

A frequent and deadly complication of OHSS are thromboembolic events due to increased blood clotting. This increase in blood clotting has been attributed to a variety of complications such as hemoconcentration (which thickens the blood), hypovolemia and an increase in the permeability of blood vessels as a result of increased vasoactive substances in the body of ovarian origin. Thromboembolic events include venous thromboses often in the upper extremities and arterial thromboses such as those in the cerebrovascular region. These events can lead to amputations of extremities, brain damage, miscarriage and death. To avoid this, anti-coagulants are given to pateitns with OHSS and they are fitted with compression stockings (see [[Treatment]]) <ref name="PMID23378404"><pubmed>23378404</pubmed></ref>.

{|
|-bgcolor="F8E0F1"
|
The risk of a woman developing OHSS is higher if she is having a '''twin pregnancy''', as she is exposed to higher concentration of hCG. <ref name="PMID9756273"><pubmed>9756273</pubmed></ref>
|}

</div>

==Treatment==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

'''General treatment
'''
*''Acetaminophen'' with or without a narcotic agent- used to treat abdominal discomfort
*Women are encouraged to drink 2-3 litres of water a day to prevent hemoconcentration
*Women are advised to avoid sexual intercourse and vigorous exercise at the risk of torsion or rupture of the ovaries
*NSAID's with anti-platelet properties should NOT be used as they may effect renal function in a women with OHSS
*Patients with significantly painful ascites or breathing problems may undergo ''Paracentesis'' (drainage of the ascites)
*''Culdocentesis'' (extraction of fluid from recto-uterine pouch) can be done to decrease the likelihood of a woman with moderate OHSS progressing to severe OHSS.<ref name="PMID22416285" />

===Mild to Moderate OHSS===

Mild OHSS can often resolve on its own, however, moderate OHSS may include treatments such as<ref name="WikiOHSS" />:

*Anti-nausea medication and prescription painkillers
*Regular physical examinations and ultrasounds
*Daily weigh-ins and waist measurements
*Measuring the amount of urine produced each day
*Frequent blood tests for monitoring dehydration and electrolyte imbalance
*Maintaining a high balance of fluids
*Drainage of excess abdominal fluid by inserting a needle in the abdominal cavity
*Wearing support stockings which help prevent blood clots/thrombosis

===Severe OHSS===

[[File:Abdominal Paracentesis.png|thumb|right|350px|Paracentesis is a common procedure done on women who have OHSS as it is used to drain the ascites in their abdomen. In this image you can see the puncture of the peritoneal cavity with a needle that then drains the fluid externally. <ref name="Wikiversity Journal of Medicine"> Blausen.com staff. "Blausen gallery 2014". Wikiversity Journal of Medicine. DOI:10.15347/wjm/2014.010. ISSN 20018762 </ref>]]

Severe OHSS requires hospital care in order for constant monitoring and treatment such as <ref name="WikiOHSS" />:

*Intravenous fluids with a crystalloid solution (100-150mL/hr)
*Intravenous Albumin is administered is IV fluids are insufficient (15-20mL/hr of 25% albumin for 4 hrs)
*In addition to Acetaminophen, ''Opioid analgesics'' can be administered for pain relief
*''Antiemetics'' can be used to subside nauseas and/or vomiting
*Woman administered to hospital of OHSS are considered at high risk of thromboembolic complications and are given low molecular weight ''heparin'', an anti-coagulant
*''Cabergoline''- lessens OHSS symptoms
*''GnRH agonist''- suppresses ovarian activity
**If at risk of OHSS, alternates include using a GnRH agonist instead of hCG however its effects on pregnancy rates are questionable. Using a GnRH agonist to replace the use of hCG for final oocyte stimulation will see a 6% decrease in delivery rate.
*Daily monitoring of creatine, urea, creatine clearance C-reactive protein (to rule out infection) are all required in combination with weekly tests such as liver and renal function tests and chest x-rays (to check for pleural effusion) <ref name="PMID12638783" />.

If there are serious complications then additional treatments are required:

*Surgery for a ruptured ovarian cyst
*Intensive care for the liver or lung complications

====Paracentesis====

For women with severe/grade 3 OHSS, paracentesis, the removal of fluid from the body using an aspiration needle, can be undertaken. It is a diagnostic and a therapeutic method that can be done trans-abdominally and trans-vaginally. It is used to relieve symptoms, improve haemodynamics e.g. Urinary output, and shorten the women's hospital stay. Complications of paracentesis include bleeding, infection and organ injury, however are note common <ref name="Paracentesis"> S. Monica Soni, HMS 3, Gillian Lieberman, MD [ http://eradiology.bidmc.harvard.edu/LearningLab/genito/Soni.pdf ], 'Ovarian Hyperstimulation Syndrome'</ref>.

{|
|-bgcolor="F8E0F1"
|
The most important aspect of treatment for any women with OHSS is close and constant '''monitoring''' with her healthcare professional. Counselling may also be provided to women and their partners or families in order to provide them with the best possible knowledge base to manage and treat their OHSS. It is important to note that there is '''no one cure or treatment''' for OHSS. Treatment involves managing and eliminating the symptoms until such time as the syndrome resolves itself <ref name="WikiOHSS" />.
|}

</div>

==Prevention==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

There are three key avenues through which the incidence of OHSS may be prevented. These include identifying risk factors to predict OHSS development, modifying treatment regimes on the basis of the identified risk factors and intervention to prevent progression to OHSS once the patient has undergone '''Controlled Ovarian Stimulation''' (COS).

=== Risk factors===

'''Primary risk factors'''

Pre-existing factors likely to exacerbate the ovarian stimulation response. Primary risk factors include <ref name="PMID26074966"><pubmed>26074966</pubmed></ref>:

*Young age
*Low body weight
*History of elevated response to gonadotropins
*Polycystic Ovary Syndrome (PCOS)
*Isolated PCOS characteristic
*Previous history of OHSS.
*High pretreatment basal Anti-Mullerian Hormone (AMH) concentration
*Large Antral Follicle Count (AFC)

'''Secondary risk factors'''

Secondary risk factors involve the monitoring of ovarian response parameters once COS has been initiated. These parameters are monitored for <ref name="PMID19007627"><pubmed>19007627</pubmed></ref>:

*rapidly rising E2 levels
*E2 concentration larger than 2500 pg/mL
*large number of developing follicles (10-14mm) on the day hCG is administered
*large number of oocytes retrieved

These factors in combination, act as a predictive tool to assess the likelihood of severe OHSS development, with a 83% sensitivity and 84% specificity. <ref name="PMID19007627"/>

=== Primary Prevention===
[[File:Severe OHSS Prevention.jpeg|right|thumbnail|400px|GnRH antagonists, embryo cryopreservation and cycle cancellation are key strategies in preventing OHSS progression in high-risk patients <ref name="PMID22938051"><pubmed>22938051</pubmed></ref>]]

Primary Prevention involves the modification of treatment regimens on the basis of OHSS risk classifications, in order to prevent OHSS occurrence.

'''Ovulation Induction'''

Unifollicular Ovulation Induction through Ovulation Induction (OI) is a primary means of avoiding OHSS in women with Polycystic Ovarian Syndrome, who are at an increased risk. In order to promote unifollicular development, the ovaries are stimulated with a low starting dose of FSH (75 IU).<ref name="PMID20416867"><pubmed>20416867</pubmed></ref> Studies suggests that a minimum gonadotropin dose lowers OHSS risk and thus a step-up regimen is utilised to achieve an ovarian response, whereby the FSH dosage is increased every 7 days until follicular development of greater than 10mm is noted.<ref name="PMID26074966" /> Alternatively, a step-down regimen may be followed, whereby a high initial FSH dosage is lowered according to the ovarian response. Another method to increase FSH levels during OI, is through '''Aromatase Inhibitors''' which promote folliculogenesis by increasing pituitary secretion of FSH, and downregulate oestrogen production through a negative feedback loop. However, Aromatase Inhibitors have not been shown to reduce OHSS incidence in comparison to other methods of OI.<ref name="PMID26074966" /> During OI, a key objective is to prevent early cycle cancellation due to premature luteinisation from pituitary secretion of LH. In order to downregulate LH secretion, '''Gonadotropin-releasing hormone agonists''' (GnRHa) are administered in addition to gonadotropins. Alternatively, '''GnRH antagonists''', which have a rapid onset of action, may be administered to downregulate endogenous LH secretion, with relative success as depicted in the diagram to the right.<ref name="PMID20416867" /> Comparative studies have shown that the GnRH antagonist protocol has a greater effect in lowering the incidence of mild to severe OHSS. However due to the rare nature of OHSS, and insufficient sample sizes, the difference was not found to be significant. <ref name="PMID21082508"><pubmed>21082508</pubmed></ref>. Generally, the duration of exposure to gonadotropins and subsequent risk of OHSS may be minimised through mild stimulation protocols which administer FSH only in the mid to late follicular phase.<ref name="PMID20416867" />

'''Adjuvant Metformin Therapy'''

Adjuvant Metformin Therapy has been found to lower the risk of OHSS by 63%.<ref name="PMID25406011"><pubmed>25406011</pubmed></ref> It involves the administration of metformin at a daily dosage of 1000 to 2000mg, 2 months prior to Controlled Ovarian Stimulation <ref name="PMID26074966"/>. Metformin lowers the elevated insulin levels in PCOS which consequently reduce intraovarian androgen levels. This leads to a reduced sensitivity and expression of granulosa cell-follicle stimulating hormone receptors which result in a less exaggerated response to gonadotropins. Furthermore, it is suggested that Metformin prevents OHSS by controlling vascular permeability through the inhibition of various vasoactive molecules, including VEGF.

'''Avoiding hCG during Luteal Phase Support

Following Controlled Ovarian Stimulation, the steroid levels of E2 and P4 are reduced during the luteal phase due to the negative feedback on the pituitary. This leads to low endogenous LH levels, which consequently reduce endometrial receptivity as well as the luteal phase duration itself. As a result, implantation and pregnancy rates are reduced and early pregnancy loss rates are increased.<ref name="PMID20416867" /> Luteal Phase Support (LPS) serves to combat these adverse events with the use of hCG. However, hCG has been found to increase the risk of OHSS. Alternatively, the use of progesterone has been found to not only halve the risk of OHSS, but also induce similar improvements in pregnancy and miscarriage rates as hCG.<ref name="PMID26148507"><pubmed>26148507</pubmed></ref>

===Secondary Prevention===

Secondary Prevention aims to prevent progression to OHSS once COS has been initiated and the patient has been found to mount an exaggerated response. <ref name="PMID20416867" />

'''Coasting'''

[[File:Cryopreservation of Porcine Embryos.jpeg|right|thumbnail|300px|Cryopreservation in the swine model: a) mature oocyte b) day 1 embryo c) day 4 embryo d) blastocyst from cryopreserved day 1 embryo with an intact zona pellucida excluding the lipid droplet. Scale bars=20μm <ref name="PMID26309801"><pubmed>26309801</pubmed></ref>]]
Coasting is a first-line secondary preventative strategy. It consists of the withdrawal of gonadotrophins when a critical number of follicles and/or E2 concentration is reached. hCG is administered once the E2 concentration reduces to a safe level, before the process of oocyte retrieval commences. This preventative strategy is conducted for a period of less than 3 days in order to avoid compromising IVF outcomes.<ref name="PMID26074966"/>

'''Cryopreservation'''

Cryopreservation of embryos after oocyte retrieval is another avenue which may avert OHSS progression. The cryopreserved embryos are only reimplanted once the patient's hormone serum levels have normalised. Using oocyte vitrification, crystal formation within embryo tissue is avoided and so cryopreserved embryos have been found to produce better pregnancy rates with a 32% increase, than fresh embryo transfer.<ref name="PMID26074966"/> Recent studies suggest cryopreservation itself does not reduce OHSS rates, but must be followed by a GnRHa trigger to avert OHSS.<ref name="PMID24753847"><pubmed>24753847></ref>

'''Cycle cancellation'''

Cycle cancellation is a guaranteed method to prevent early OHSS whereby hCG is withheld. This is a last resort strategy as it carries the risk of significant psychological distress and financial loss for the patient. <ref name="PMID20416867"/>

</div>

==Effect on the Newborn==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

</div>
Women who develop OHSS while undergoing Assisted Reproductive Technologies (ART) treatment are not only more likely to achieve a pregnancy, but have a live birth as the pregnancy outcome. This live birth is also more likely to be a multiple birth of two, three or more children. <ref name="PMID19591989"><pubmed>19591989</pubmed></ref> It has been postulated that a multi-fetal pregnancy leads to a more rapid increase in hCG levels, resulting in an increased risk of OHSS. However, the causal nature between multi-fetal pregnancy and OHSS development is disputed and further research is required to distinguish correlation from causation. <ref name="PMID19573292"><pubmed>19573292</pubmed></ref>

OHSS development is also associated with an increased risk of adverse outcomes including '''stillbirth, premature birth and low birth weight'''.<ref name="PMID19591989" /> Although the cause for the increased risk in adverse pregnancy outcomes is unknown, it is suggested that as the incidence of OHSS is reduced through various prevention strategies, the risk of such outcomes may be also be reduced.

'''<span style="color:#FA58D0"> [http://pregnancyperfect.com/emilyley/ The following link is to a podcast of a woman describing her pregnancy in which she underwent IVF, had OHSS and gave birth to healthy twins]<ref name="Emily"> Pregnancy Perfect[ http://pregnancyperfect.com/emilyley/ ], 'TWINS, IVF, OHSS AND C-SECTION WITH EMILY LEY'</ref> </span>'''

==Genetics==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

Despite OHSS typically being of iatrogenic origin as a result of ovarian stimulation with gonadotropins, research has been conducted into the potential genetics behind OHSS as many sporadic and familial cases have been observed. '''Mutations''' in the receptor for hormones such as Follicle Simulating Hormone (FSH), Lutenizing Hormone (LH) and hCG have all been targets of OHSS genetics research. Interestingly, they too also arise from a common ancestral gene.

===Follicle Stimulating Hormome===

Dr. Botros Rizk, of the University of South Alabama College of Medicine <ref name="PMID19573286"><pubmed>19573286</pubmed></ref>, has written extensively regarding the genetics behind OHSS. In particular, he talks about '''FSH receptors''' (FSHR) and their role in the syndrome. He hypothesises that mutations in these receptors could be activating or inactivating, leading to an increased risk of developing OHSS or sterility respectively. Currently, 744 single nucleotide polymorphisms (a type of mutation) have been found in the gene encoding the FSHR, 8 of which are located in its exons (coding regions of the gene). How the ovary responds is resultant on the FSHR genotype. For example, Ser680Asn, a polymorphism in the FSHR gene has been shown to aid in predicting the severity of a woman's OHSS. Ordinarily FSH stimulates the growth of ovarian follicles, however, when mutated, it is stimulated by the hCG resulting in excessive follicle development.

Spontaneous OHSS, OHSS that arises and cannot be attributed to any form of ovarian stimulation or Assisted Reproductive Technology, has been linked to activating mutations in the FSHR <ref name="PMID23499866"><pubmed>23499866</pubmed></ref>. This familial disorder is an autosomal dominant one. In most cases the FSHR can be stimulated by the presence of Thyroid Stimulating Hormone (TSH) or hCG, in the absence of FSH (the ligand for FSHR).

[[File:FSHR Gene.jpg|centre|thumbnail|700px|This image depicts the location of the FSHR Gene on chromosome 2. It is located on the short arm between positions 21 and 16. Changed to the FSHR gene has been linked to OHSS. <ref name="Genetcis"> Genetics Home Reference [http://ghr.nlm.nih.gov/gene/FSHR'</ref>]]

===Lutenizing Hormome===

The '''Lutenizing Hormone Receptor''' (LHR) gene in humans is comprised of 11 exons. Animal studies have shown that many primates exhibit a similar gene which is comprised of only 10 exons, however a gene lacking the 10th exon has been identified and termed the type 2 LHR. Expression of the type 2 LHR has been seen in humans. The type 2 LHR, compared to the wild-type LHR appears to be repaired with regard to its function. Defects in the type 2 LHR include a decrease in efficiency of transport to the plasma membrane and irregularities in signal transduction. Inactivating mutations in the LHR have been seen to cause infertility in women as well as amenorrhoea. Activating LHR gene mutations are asymptomatic and are not associated with OHSS in women.

===Bone Morphogenic Protein===

An imporant growth factor, derived from oocytes called '''BMP-15''' (Bone Morphogenic Protein 15) is vital for female fertility. It belongs to the family of growth factors, Transforming Growth Factor β (TGF-β) and is heavily involved in folliculogenesis. It has been found that mutations in the BMP-15 gene caused infertility in female sheep. Conversely, it has also been indicated in enhanced fertility when BMP-15 is present is high amounts in follicular fluid <ref name="PMID19573286" />.

A case study done by Hanevik ''et. al.'' in 2013 <ref name="PMID21565556"><pubmed>21565556</pubmed></ref> found that a Single Nuclear Polymorphism (SNP) in the BMP-15 gene is responsible for a high response to ovarian hyper-stimulation. The aim of the study was to test the effect the SNP had on BMP-15 with regard to high and low responders buy taking blood from 53 high responders, 38 low responders and 100 non-responders (controls) and analysing 5 noted SNP's. Results from their study showed a correlation between a high response to ovarian hyper-stimulation and the BMP-15 9G allele. The article does state however, that further research is required into the molecular effects of SNP's on the function of BMP-15.

===Vascular Endothelial Growth Factor===

'''Vascular endothelial growth factor''' (VEGF) has been indicated as one of the key agents causing vascular permeability and subsequent ascites in OHSS. The gene, which is located on chromosome 12, is made up of 8 exons (coding regions), of which exons 6 and 7 do not always appear due to the exons being spliced out.The splicing of this gene allows for various isoforms of the gene to exist of which VEGF 121 and 165 appear to play a role in angiogenesis. There are two VEGF Receptors, VEGFR-1 and VEGFR-2 that belong to the tyrosine kinase family of receptors (for more information on VEGF see [[Pathophysiology]]). Because of its distinct role in OHSS, it has been targeted as an area for research for potential treatments. The idea is that if the genetic expression of VEGF and its receptors can be controlled, OHSS can be avoided or treated.<ref name="PMID19573286" />

A different study by Hanevik ''et. al.'' , <ref name="PMID22587628"><pubmed>22587628</pubmed></ref> done in 2012 involved analysing blood samples from 53 women with OHSS and 100 women without it (controls) and analysing 6 SNP's in the VEGFR2 gene to find any genetic variations. They found a correlation between women with the VEGF +405cc genotype and the development of OHSS indicating women that undergo controlled ovarian hyper-stimulation and posses his genotype, are at an increased risk of developing OHSS.

</div>

== Current Research on Animal Models==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

{|
|-bgcolor="FFF5FF"
|<span style="font-size:120%">'''Inhibition of Cyclooxygenase-2 (COX-2) by Meloxican decreasing the incidence of OHSS in Rat Model'''</span> <ref name="PMID18166186"><pubmed>18166186</pubmed></ref>

Reasearch was carried out to investigate the effects of selective inhibition of the enzyme COX-2 on the Ovarian Hyperstimulation Syndrome (OHSS) using Female Wistar rates as the subjects. The research aimed to find results by measuring the number of antral and luteinized follicles, ovarian weight, vascualr endothelial growth factors and COX-2 immunohistochemistry. The rats being tested were all 22 days old and were divided into four equal groups;

'''Group 1 (Control group)''' was subject to a 0.1 ml of Intraperitoneal Saline from days 22 ~ 26

'''Group 2 (Mildly-stimulated group)''' subject to 10IU of pregnant mare serum gonadotrophin (PMSG) on day 24 and then 10IU of Human Chorionic Gonadotrophin (hCG) on day 26

'''Group 3 (OHSS positive group)''' was subject to 10IU of PMSG from days 22 ~ 26 and then administered 30IU of hCG on day 26 to induce OHSS

'''Group 4 (OHSS positive variant group)''' received 15mg/ml of Meloxicam 2 hours prior to administration of 10IU PMSG from days 22 ~ 26

Results showed there was no difference in ovarian weight in samples from Group 1 and Group 2, however Group 3 showed signs of significant ovarian weight increase which in group 4 was suppressed by the introduction of Meloxicam. No differences were observed in the number of antral follicles amongst the four test groups. Results from Group 2 and Group 3 showed that the granulosa cells of preovulatory follicles and the stromal cells were highly VEGF immunoreactive, however the Meloxicam treated Group 4 showed less immunoreactivity than Group 2 and Group 3 which indicated the correlation between Meloxicam and the diminished VEGF expression. Group 3 presented an increased COS-2 immunoreactivity which was highly diminished than in Group 4.

The research concluded that in a rat model, the enzyme Meloxicam has a beneficial effect on OHSS by reducing the increase of ovarian weight and the expression of VEGF associated with OHSS, the effects of which may be mediated by the inhibitory capacity of COX-2 on Meloxicam
|}

{|
|-bgcolor="FFF5FF"
|<span style="font-size:120%">'''Inhibition of Ovarian VEGF secretion by activation of Dopamine Receptor 2'''</span> <ref name="PMID25217874"><pubmed>25217874</pubmed></ref>

This research was carried out to investigate a possibility in whether a Dopamine Receptor 2 agonist '''(D2-ag)''' can assist in the prevention of Ovarian Hyperstimulation Syndrome, using rat models, by decreasing the ovarian vascular endothelial growth factor '''(VEGF)''' production. Using Immature Wistar rats (22 days old) as their animal model, the rats were initially stimulated with Gonadotrophins to mimic the onset and effects of OHSS and then subjected to treatment with a D2-agonist and/or a D2-antagonist (D2-ant). The vascular permeability was measured at the endpoint after day 26 by measuring the peritoneal extravasion of a previously injected dye and ovaries from all subjects were collected to assess the effects of D2-ag and D2-ant on the production of Ovarian VEGF. The expression of VEGF mRNA was measured by quantitative real time PCR and the levels of VEGF proteins were measured by Western Blots.

Results showed that the D2-ag caused a large reduction in the vascular permeability which was in turn associated with the great decreased in VEGF protein production in the OHSS rat ovaries, whereas the introduction of D2-ant showed opposite results with a increase in the vascular permeability leading to the increase of VEGF protein production in the ovaries. Ovarian VEGF mRNA levels were found to be unaffected by the introduction of these drugs in OHSS rat subjects. Conclusions were drawn on the fact that Dopamine Receptor 2 agonists prevent the increase of vascular permeability in subjects with OHSS by decreasing the ovarian production of VEGF and also that due to the dose-dependent inhibitory effect of the D2-ag on ovarian VEGF, current OHSS therapies used in humans can benefit by increasing the intraovarian concentration of D2-ag.
|}

</div>

==Glossary==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

'''Aromatase Inhibitor''' - A drug that inhibits enzyme aromatase, which in turn suppresses estrogen synthesis.

'''Ascites''' - An accumulation of fluid in the peritoneal cavity with resultant abdominal swelling.

'''Cabergoline''' - A dopamine receptor agonist used to treat hormone imbalance.

'''Controlled Ovarian Stimulation''' - female infertility treatment using medications to stimulate the ovaries to develop follicles.

'''Cryopreservation''' - Cooling and storing biological material at extremely low temperatures.

'''E2''' - Estradiol - Potent estrogen sex hormone.

'''FSH''' - Follicle Stimulating Hormone

'''Gonadotropin''' - Any hormone that has a stimulating effect on the gonads.

'''GnRH agonist''' - Gonadotropin Releasing Hormone - A class of compounds that mimic the effect of the natural Gonadotropin Releasing Hormone.

'''GnRH antagonist''' - Gonadotropin Releasing Hormone - A class of compounds that are similar in terms of the structure of natural Gonadotropin Releasing Hormone but has a antagonistic effect.

'''hCG'''- Human Chorionic Gonadotropin

'''Hemoconcentration''' - An increase in the concentration of circulating red blood cells in response to a decrease in blood plasma volume.

'''Hypovolemic''' - A decrease in circulating blood volume.

'''Iatrogenic''' - Illness caused as a result of a medical examination or treatment.

'''Intravenous fluids''' - Is the infusion of liquid substances directly into a vein.

'''IVF''' - In-vitro Fertilization

'''LH''' - Luteinizing Hormone

'''Metformin''' - A biguanide, antidiabetic drug used as an adjuvant to modify the effect of other agents.

'''NSAID''' - Non-steroidal Anti-Inflammatory Drug e.g. Ibuprofen

'''Oocyte vitrification''' - technique for cryopreservation of oocytes.

'''OHSS''' - Ovarian Hyper-stimulation Syndrome

'''Oliguria'''- Decreased urine output/small amounts of urine produced.

'''P4''' - Progesterone - endogenous progestogen sex hormone.

'''PCOS''' - Polycystic Ovarian Syndrome. An endrocrine system disorder whereby the ovaries are enlarged with small collections of fluid.

</div>

==References==

2015 Group Project 2

2015-10-23T16:43:14Z

Z3372824: /* Secondary Prevention */

{{ANAT2341Project2015header}}

==<span style="font-size:120%">'''Ovarian Hyper-stimulation Syndrome (OHSS)'''</span>==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

Ovarian Hyper stimulation Syndrome (OHSS) is an iatrogenic complication of '''Assisted Reproduction Technology''' (ART), in which women take medications to stimulate oocyte growth. It is generally identified by cystic enlargements of the ovaries and fluid accumulation in the peritoneal cavity due to the increased capillary permeability and ovarian neoangiogenesis <ref name="PMID22065820"><pubmed>22065820</pubmed></ref>. It is an occurrence which is dependent on the controlled stimulation of the ovaries in preparation for IVF i.e. administration of human Chorionic Gonadotropin (hCG).

OHSS was first described in 1943 as ''“syndrome d’hyperluteinisation massive des ovaries”''. It was during this time that gonadotropins were prepared from animals such as sheep to bring on ovulation in women. The first recorded death as a result of OHSS occurred in 1951 and was due to renal failure as a result of oligouria, a complication of the syndrome <ref name="OHSS"> Marie M. Budev, DO, MPH; Alejandro C. Arroliga, MD; Tommaso Falcone, MD, [ http://utilis.net/Morning%20Topics/REI/Ovarian%20Hyperstimulation.pdf ], 'Ovarian Hyperstimulation Syndrome'</ref> <ref name="PMID12638783"><pubmed>12638783</pubmed></ref>.

<span style="color:#FA58D0">'''This wikipage aims to provide clear information on various areas surrounding OHSS such as diagnosis, prevention and complications and will look into the genetics behind the disorder and the various animals models used to research it'''.</span>

<html5media height="350" width="450">https://www.youtube.com/watch?v=aXmjJw234a4</html5media>

'''Overview of Ovarian Hyperstimulation Syndrome''' <ref> Howcast (2013, August 27) Ovarian Hyperstimulation Syndrome | Infertility. Retrieved from https://www.youtube.com/watch?v=aXmjJw234a4</ref>

</div>

==Epidemiology==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

Ovarian Hyper-Stimulation Syndrome (OHSS) rarely occurs sporadically, and if it does, it is usually the result of an underlying genetic problem. The majority of OHSS is due to the ovaries being stimulated to mature and release an abundance of oocytes, in response to hormones Human Chorionic Gonadotropin (hCG) and Follicle Stimulating hormone (FSH), during IVF. Rarely, Clomifene Citrate therapy can cause OHSS.<ref name="WikiOHSS"> Wikipedia, [ https://en.wikipedia.org/wiki/Ovarian_hyperstimulation_syndrome ], 'Ovarian Hyperstimulation Syndrome'</ref>

OHSS only affects '''0.5-5%''' of women undergoing Ovarian Hyper-stimulation, but despite its small prevalence, it is a potentially fatal outcome of a non-vital procedure and remains a prevalent problem for fertility specialists <ref name="PMID12498425"><pubmed>12498425</pubmed></ref> <ref name="PMID12638783"><pubmed>12638783</pubmed></ref>. Age has been cited as a factor affecting those with OHSS, with younger women more at risk. Additionally, women with allergies were seen to have a higher incidence of OHSS. It is important to note that at this point in time, there is no positive correlation between gonadotropin dose and OHSS.

Of the 0.5-5% of women affected with OHSS mentioned above, 2% of those women will require hospitalisation. As of 2011, it has been reported that the incidence of OHSS was '''increasing''', resulting in approximately 3 deaths per 100,000 women undergoing ovarian stimulation per year <ref name="PMID21828116"><pubmed>21828116</pubmed></ref>. This is particularly worrying as in 2008, in the United States alone, there were around 150,000 IVF cycles undertaken.

{|
|-bgcolor="F8E0F1"
|
'''With the field of Assisted Reproductive Technologies expanding and more women partaking in IVF treatments, the threat of women developing OHSS is an ongoing and increasing one''' <ref name="PMID21828116" />.
|}
{| class="wikitable mw-collapsible mw-collapsed"
! colspan=4|Characteristics of women with OHSS by complication group <ref name="PMID19591989"><pubmed>19591989</pubmed></ref>
|-
! scope="col" width="100px" height="60px" style="text-align:center| '''Characteristic'''
! scope="col" width="100px" height="60px" style="text-align:center| '''No Complications
(N = 212,041)'''
! scope="col" width="100px" height="60px" style="text-align:center| '''Moderate OHSS
(N = 1,523)'''
! scope="col" width="100px" height="60px" style="text-align:center| '''Severe OHSS
(N = 655)'''
|-
|style="text-align:center; background: #FF99FF;"| '''Maternal Age (Mean ± SD)'''
|style="text-align:center; background: #F6CEEC;"| 35.6 ± 4.6
|style="text-align:center; background: #F6CEEC;"| 33.0 ± 4.3
|style="text-align:center; background: #F6CEEC;"| 33.1 ± 4.4
|-
|style="text-align:center; background: #FF99FF;"| '''Maternal Age (%)'''
|-
|style="text-align:left; background: #F6CEEC;"| <30 years
|style="text-align:center; background: #F6CEEC;"| 10 %
|style="text-align:center; background: #F6CEEC;"| 21.1 %
|style="text-align:center; background: #F6CEEC;"| 20.6 %
|-
|style="text-align:left; background: #F6CEEC;"| 30-34 years
|style="text-align:center; background: #F6CEEC;"| 30.4 %
|style="text-align:center; background: #F6CEEC;"| 43.2 %
|style="text-align:center; background: #F6CEEC;"| 40.5 %
|-
|style="text-align:left; background: #F6CEEC;"| 35-39 years
|style="text-align:center; background: #F6CEEC;"| 37.8 %
|style="text-align:center; background: #F6CEEC;"| 27.2 %
|style="text-align:center; background: #F6CEEC;"| 32.5 %
|-
|style="text-align:left; background: #F6CEEC;"| >40 years
|style="text-align:center; background: #F6CEEC;"| 21.8 %
|style="text-align:center; background: #F6CEEC;"| 8.4 %
|style="text-align:center; background: #F6CEEC;"| 6.4 %
|-
|style="text-align:center; background: #FF99FF;"| '''Nulligravida (%)'''
|style="text-align:center; background: #F6CEEC;"| 45.8 %
|style="text-align:center; background: #F6CEEC;"| 51.5 %
|style="text-align:center; background: #F6CEEC;"| 51.8 %
|-
|style="text-align:center; background: #FF99FF;"| '''Infertility Diagnosis (%)'''
|-
|style="text-align:left; background: #F6CEEC;"| Male factor
|style="text-align:center; background: #F6CEEC;"| 37.7 %
|style="text-align:center; background: #F6CEEC;"| 41.0 %
|style="text-align:center; background: #F6CEEC;"| 33.4 %
|-
|style="text-align:left; background: #F6CEEC;"| Endometriosis
|style="text-align:center; background: #F6CEEC;"| 13.5 %
|style="text-align:center; background: #F6CEEC;"| 13.5 %
|style="text-align:center; background: #F6CEEC;"| 10.7 %
|-
|style="text-align:left; background: #F6CEEC;"| Ovulation Disorders
|style="text-align:center; background: #F6CEEC;"| 14.0 %
|style="text-align:center; background: #F6CEEC;"| 29.5 %
|style="text-align:center; background: #F6CEEC;"| 22.4 %
|-
|style="text-align:left; background: #F6CEEC;"| Diminished ovarian reserve
|style="text-align:center; background: #F6CEEC;"| 16.9 %
|style="text-align:center; background: #F6CEEC;"| 3.2 %
|style="text-align:center; background: #F6CEEC;"| 2.4 %
|-
|style="text-align:left; background: #F6CEEC;"| Tubal factors
|style="text-align:center; background: #F6CEEC;"| 20.4 %
|style="text-align:center; background: #F6CEEC;"| 22.6 %
|style="text-align:center; background: #F6CEEC;"| 22.3 %
|-
|style="text-align:left; background: #F6CEEC;"| Uterine factors
|style="text-align:center; background: #F6CEEC;"| 5.1 %
|style="text-align:center; background: #F6CEEC;"| 4.3 %
|style="text-align:center; background: #F6CEEC;"| 3.1 %
|-
|style="text-align:left; background: #F6CEEC;"| Other factors
|style="text-align:center; background: #F6CEEC;"| 13.9 %
|style="text-align:center; background: #F6CEEC;"| 13.1 %
|style="text-align:center; background: #F6CEEC;"| 10.4 %
|-
|style="text-align:left; background: #F6CEEC;"| Unexplained factor
|style="text-align:center; background: #F6CEEC;"| 12.7 %
|style="text-align:center; background: #F6CEEC;"| 11.8 %
|style="text-align:center; background: #F6CEEC;"| 18.6 %
|-
|}
</div>

==Causative Agents==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

[[File:Follicular Development.jpeg|right|thumbnail|500px|Infertility treatments aim to facilitate follicular development and induce ovulation to improve chances of fertilisation <ref name="PMID24717179"><pubmed>24717179</pubmed></ref>]]

Normally a woman produces one egg per month from the ovaries, which travel down the Fallopian tube to be fertilized or be released from the body. In cases where women have difficulty falling pregnant, they are given medication which help them to produce and release eggs (as shown in the diagram to the right), further increasing their chances of fertilization and pregnancy <ref><pubmed>19573285</pubmed></ref>. Ovarian Hyper stimulation Syndrome generally occurs during infertility treatments when the ovaries are overstimulated by the fertility medication which causes the ovaries to swell and leak fluids into the belly and abdomen. The prevalence of OHSS onset is linked with excessive number of follicle development in response to the administration of injectable Follicle Stimulating Hormones (FSH) followed by the '''Human Chorionic Gonadotrophins''' (hCG) which triggers the release of the oocytes <ref><pubmed>26190539</pubmed></ref>.

'''Follicle Stimulating Hormones''' (FSH) <ref name="PMID9020850"><pubmed>9020850</pubmed></ref> are glycoprotein hormones that are produced and secreted from the Anterior Pituitary gland into the bloodstream, which regulate the developmental, growth, maturation and the reproductive processes within the body. In females, the Follicle Stimulating Hormones initiates the stages of growth and development of immature ovarian follicles within the ovaries before the release of an egg from a follicle at ovulation. When FSH is administered to a patient who is suffering from infertility, the increase FSH levels affect the rate of development and production, in turn increasing the amount of follicles which are ready to be released during ovulation.

</div>

==Symptoms==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

OHSS is classified based on a criteria from mild, moderate and severe <ref name="WikiOHSS" />:

'''Mild Symptoms'''- abdominal bloating, minimal weight gain, nausea, diarrhoea and a feeling of fullness.

'''Moderate Symptoms'''- Substantial weight gain (on average 2 or more pounds a day), increased abdominal girth, darkend urine and excessive thirst in addition to the mild symptoms.

'''Severe Symptoms'''- In addition to the symptoms associated with Mild and Moderate OHSS, in severe OHSS, you see shortness of breath, calf and chest pains and pleural effusion.

===<span style="font-size:100%">Classifications of Ovarian Hyper-stimulation Syndrome:</span> <ref name="PMID22065820"><pubmed>22065820</pubmed></ref>===

{| class="wikitable" style="text-align:center
|-
! scope="col" width="70px"| '''Classification'''
! scope="col" width="650px"| '''Symptoms'''
|-
|style="text-align:center; background: #F6CEEC;"| '''Mild'''
|style="height: 60px; background: #F6CEEC;"| '''Grade 1''' - Abdominal distention and discomfort
'''Grade 2''' - Abdominal distention, discomfort with nausea, vomiting and/or diarrhea and ovarian enlargement from 5~12cm
|-
|style="text-align:center; background: #F8E0F1;"| '''Moderate'''
|style="height: 60px; background: #F8E0F1;"| '''Grade 3''' - All features of Mild OHSS with ultrasonographic evidence of ascites
|-
|style="text-align:center; background: #F6CEEC;"| '''Severe'''
|style="height: 60px; background: #F6CEEC;"| '''Grade 4''' - All features of Moderate OHSS with the addition of clinical evidence of ascites and breathing difficulties present
'''Grade 5''' - All of the above symptoms along with a change in the blood volume, increased blood viscosity due to coagulation and diminished renal function
|}

</div>

==Diagnosis==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

Whilst symptoms of OHSS can occur as soon as 24 hours post hCG administration, they are usually seen in women 7-10 days post administration. Initially women with OHSS will present with abdominal bloating, as a result of fluid in the peritoneal cavity and an increase in ovary size. When women present with severe OHSS they are often dehydrated, due to increased vascular permeability, and have hemoconcentration. The above results in a decrease in intravascular volume, leading to '''oligouria''' <ref name="PMID22416285" />.

===History===

Initially a thorough history of the patient is taken during which the clinician looks for evidence of ovarian stimulation, followed by ovulation. During this history taking, the clinician will inquire into any weight gain noticed, urine output, and the woman's ability to maintain oral hydration. A key diagnostic tool for clinicians regarding women who are taking gonadotropins is to identify if they are at an increased risk of developing OHSS. Some risk factors include woman aged less than 30, women who have polycystic ovaries, woman with a previous history of OHSS and women who have had greater than 20 oocytes retrieved <ref name="PMID22416285" />.

===Physical Exam===
[[File:Vaginal_Ultrasonography_in_Sagittal_Plane.jpg|right|thumbnail|600px|Vaginal Ultrasonography in Sagittal plane <ref name="Wikiversity Journal of Medicine"> Häggström, Mikael. "Medical gallery of Mikael Häggström 2014". Wikiversity Journal of Medicine 1 (2). DOI:10.15347/wjm/2014.008. ISSN 20018762</ref>]]
After a history of the patient is taken, the next step is to perform a physical exam on the patient. Women who present with abdominal bloating will produce a shifting dullness upon abdominal percussion. Additionally the clinician will test the woman's vital signs, measure her abdominal girth, weight and will look for evidence of ascites or increase in calf size (usually unilateral)<ref name="PMID22416285" />.

===Investigations===

If the clinician further suspects a women of having OHSS, various investigations can be done such as an ultrasound.The intraperitoneal fluid is best imaged via vaginal ultrasound due to the enlarged ovaries making it difficult to image the pelvis using transabdominal ultrasound. The clinician can also order laboratory testing to look for urine specific gravity and and complete blood count to look for hemoconcentration with a hematocrit. Additionally, liver function tests can be ordered to look for elevated function. The clinician will also look for evidence of elevated D-dimers and fibrinogen and decreased levels of anti-thrombin 3 <ref name="SAHealth"> Government of South Australia Health [ http://www.sahealth.sa.gov.au/wps/wcm/connect/9b61ed004ee5348da663afd150ce4f37/Ovarian-hyperstimulation-syndrome-WCHN-PPG-17072012.pdf?MOD=AJPERES&CACHEID=9b61ed004ee5348da663afd150ce4f37 ], 'South Australian Paediatric Clinical Guidelines OHSS'</ref>.

====Ultrasound====

Typical appearances of the ultrasound include <ref name="Ultrasound"> Radiopaedia [ http://radiopaedia.org/articles/ovarian-hyperstimulation-syndrome-1 ], 'Ovarian Hyperstimulation Syndrome'</ref>:

*Bilaterally and symmetrically enlarged ovaries (>12cm)
* "Spoke-Wheel appearance" - presence of multiple cysts of varying size
*May also see ascites (fluid)

===Severity===

Once a clinician has deduced a women is suffering from OHSS, the severity of their condition needs to be established as either mild, moderate or severe. This is done by referring to the criteria under the sub-heading [[Symptoms]].The subsequent course of treatment for the woman will be based upon this evaluation.

{|
|-bgcolor="F6CEEC"
|
'''Further investigations''' can be done including a Chest X-ray to check for pleural effusions and oedema and USS with Doppler's to check for ascites or possible ovary torsion. <ref name="PMID22416285"><pubmed>22416285</pubmed></ref>
|}

===Differential Diagnosis===

Conditions presenting with similar symptoms or ultrasound images include <ref name="Ultrasound" />:

*Polycystic Ovaries (PO)
:: The difference is that with PO is that the cycts are typically smaller than OHSS cysts and there is no evidence of ascited or pleural effusion
*Mucinous Ovarian Malignancy
:: A type of Ovarian Epithelial tumour
*Ectopic Pregnancy <ref name="Casereport"> Australian Medical Student Journal [ http://www.amsj.org/wpcontent/uploads/files/articles/amsj_v2_i1/AMSJ_v2_i1_pg58-60.pdf ], 'Ovarian hyperstimulation syndrome'</ref>
::A pregnancy in which the foetus develops outside of the uterus e.g. in the fallopian tube

</div>

==Pathophysiology==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

The definition of Ovarian Stimulation is enlarged ovaries with many luteinized cysts, that can present with secondary complications. What distinguishes Ovarian Stimulation from OHSS is the presence of vascular hyper-permeability that results in fluids being redirected elsewhere in the body.

The key process to OHSS appears to be caused by '''Vascular Endothelial Growth Factor''' (VEGF), that is released along with other cytokines, estrogen and progesterone, due to the ovary undergoing luteinization as a result of stimulation by hCG. VEGF increases vascular permeability and as a result the capillaries become more "leaky" to the fluids in them. These fluids can then escape the capillaries and accumulate in the pleural and abdominal cavities as ascites. The woman then becomes hypovolemic and is at an increased risk of circulatory, renal and respiratory issues such as arterial thromboembolism due to the thickening of the blood. Note, the blood is thickened as fluid is leaving the capillaries, leaving behind red blood cells and other cellular components of the blood <ref name="WikiOHSS" />.

The increase in expression of VEGF and VEGF Receptor 2 (VEGFR2) is attributed to the greatly increased amount of their mRNA present in the body after stimulation with hCG <ref name="PMID21082502"><pubmed>21082502</pubmed></ref>. VEGF interacts with VEGF2 and VEGF Receptor 1 (VEGFR1) to create a strong angiogenic effect. Both VEGFR2 and VEGFR1 belong to a family of receptors called tyrosine kinases. VEGF2 is involved in the regulation of angiogenesis and vascular permeability whilst VEGF1 has a slightly contradictory role in that is is involved in the maintenance of the tight junctions between endothelial cells in blood vessels. A study by Gómez ''et. al.'' <ref name="PMID21082502" /> showed that women experiencing OHSS had substantially higher plasma levels of VEGF and lower levels of VEGFR1.

[[File:Pathogenesis_of_OHSS.png|600px|centre|thumb|Pathogenesis of OHSS <ref name="PMID20416867"><pubmed>20416867</pubmed></ref>]]

</div>

==Complications==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

Ovarian torsion or rupture, renal insufficiency and thrombophlebitis can all complicate OHSS. If a pregnancy occurs, symptoms may persist longer than the usual 1 to 2 weeks and become more severe, however, even with severe OHSS, they do not extend past the first trimester <ref name="WikiOHSS" />. [[File:Polycystic Ovaries.jpeg|right|thumbnail|360px|Comparison of Normal and Polycystic Ovary]]

<span style="color:#FA58D0"> '''1-2% of women who undergo ovarian stimulation develop a severe form of OHSS''' </span>. Complications from severe OHSS include:

*Fluid collection in the abdomen
*Electrolyte disturbances (sodium and potassium)
*Kidney failure
*Ovary twisting
*Rupture of a cyst in an ovary
*Breathing problems
*Blood clots in large vessels (most commonly the legs)
*Pregnancy loss from miscarriage or termination
*Rarely, death

A study by Nouri ''et. al.'' <ref name="PMID24996451"><pubmed>24996451</pubmed></ref> found that women with '''Polycystic Ovarian Syndrome''' (PCOS) and those that were induced with hCG experienced longer recovery times from severe OHSS than women who were not pregnant. They looked at a cohort of women hospitalised for the first time with severe OHSS and subject them to the same treatments. Based on a defined criteria, they established the recovery time of these women and compared the times between those that were pregnant to those that were not pregnant. They also found that whether a woman had PCOS or ovulation induction did not affect her risk of developing OHSS if she was not pregnant. It is only a risk factor for pregnant women.

===Thromboembolic events===

A frequent and deadly complication of OHSS are thromboembolic events due to increased blood clotting. This increase in blood clotting has been attributed to a variety of complications such as hemoconcentration (which thickens the blood), hypovolemia and an increase in the permeability of blood vessels as a result of increased vasoactive substances in the body of ovarian origin. Thromboembolic events include venous thromboses often in the upper extremities and arterial thromboses such as those in the cerebrovascular region. These events can lead to amputations of extremities, brain damage, miscarriage and death. To avoid this, anti-coagulants are given to pateitns with OHSS and they are fitted with compression stockings (see [[Treatment]]) <ref name="PMID23378404"><pubmed>23378404</pubmed></ref>.

{|
|-bgcolor="F8E0F1"
|
The risk of a woman developing OHSS is higher if she is having a '''twin pregnancy''', as she is exposed to higher concentration of hCG. <ref name="PMID9756273"><pubmed>9756273</pubmed></ref>
|}

</div>

==Treatment==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

'''General treatment
'''
*''Acetaminophen'' with or without a narcotic agent- used to treat abdominal discomfort
*Women are encouraged to drink 2-3 litres of water a day to prevent hemoconcentration
*Women are advised to avoid sexual intercourse and vigorous exercise at the risk of torsion or rupture of the ovaries
*NSAID's with anti-platelet properties should NOT be used as they may effect renal function in a women with OHSS
*Patients with significantly painful ascites or breathing problems may undergo ''Paracentesis'' (drainage of the ascites)
*''Culdocentesis'' (extraction of fluid from recto-uterine pouch) can be done to decrease the likelihood of a woman with moderate OHSS progressing to severe OHSS.<ref name="PMID22416285" />

===Mild to Moderate OHSS===

Mild OHSS can often resolve on its own, however, moderate OHSS may include treatments such as<ref name="WikiOHSS" />:

*Anti-nausea medication and prescription painkillers
*Regular physical examinations and ultrasounds
*Daily weigh-ins and waist measurements
*Measuring the amount of urine produced each day
*Frequent blood tests for monitoring dehydration and electrolyte imbalance
*Maintaining a high balance of fluids
*Drainage of excess abdominal fluid by inserting a needle in the abdominal cavity
*Wearing support stockings which help prevent blood clots/thrombosis

===Severe OHSS===

[[File:Abdominal Paracentesis.png|thumb|right|350px|Paracentesis is a common procedure done on women who have OHSS as it is used to drain the ascites in their abdomen. In this image you can see the puncture of the peritoneal cavity with a needle that then drains the fluid externally. <ref name="Wikiversity Journal of Medicine"> Blausen.com staff. "Blausen gallery 2014". Wikiversity Journal of Medicine. DOI:10.15347/wjm/2014.010. ISSN 20018762 </ref>]]

Severe OHSS requires hospital care in order for constant monitoring and treatment such as <ref name="WikiOHSS" />:

*Intravenous fluids with a crystalloid solution (100-150mL/hr)
*Intravenous Albumin is administered is IV fluids are insufficient (15-20mL/hr of 25% albumin for 4 hrs)
*In addition to Acetaminophen, ''Opioid analgesics'' can be administered for pain relief
*''Antiemetics'' can be used to subside nauseas and/or vomiting
*Woman administered to hospital of OHSS are considered at high risk of thromboembolic complications and are given low molecular weight ''heparin'', an anti-coagulant
*''Cabergoline''- lessens OHSS symptoms
*''GnRH agonist''- suppresses ovarian activity
**If at risk of OHSS, alternates include using a GnRH agonist instead of hCG however its effects on pregnancy rates are questionable. Using a GnRH agonist to replace the use of hCG for final oocyte stimulation will see a 6% decrease in delivery rate.
*Daily monitoring of creatine, urea, creatine clearance C-reactive protein (to rule out infection) are all required in combination with weekly tests such as liver and renal function tests and chest x-rays (to check for pleural effusion) <ref name="PMID12638783" />.

If there are serious complications then additional treatments are required:

*Surgery for a ruptured ovarian cyst
*Intensive care for the liver or lung complications

====Paracentesis====

For women with severe/grade 3 OHSS, paracentesis, the removal of fluid from the body using an aspiration needle, can be undertaken. It is a diagnostic and a therapeutic method that can be done trans-abdominally and trans-vaginally. It is used to relieve symptoms, improve haemodynamics e.g. Urinary output, and shorten the women's hospital stay. Complications of paracentesis include bleeding, infection and organ injury, however are note common <ref name="Paracentesis"> S. Monica Soni, HMS 3, Gillian Lieberman, MD [ http://eradiology.bidmc.harvard.edu/LearningLab/genito/Soni.pdf ], 'Ovarian Hyperstimulation Syndrome'</ref>.

{|
|-bgcolor="F8E0F1"
|
The most important aspect of treatment for any women with OHSS is close and constant '''monitoring''' with her healthcare professional. Counselling may also be provided to women and their partners or families in order to provide them with the best possible knowledge base to manage and treat their OHSS. It is important to note that there is '''no one cure or treatment''' for OHSS. Treatment involves managing and eliminating the symptoms until such time as the syndrome resolves itself <ref name="WikiOHSS" />.
|}

</div>

==Prevention==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

There are three key avenues through which the incidence of OHSS may be prevented. These include identifying risk factors to predict OHSS development, modifying treatment regimes on the basis of the identified risk factors and intervention to prevent progression to OHSS once the patient has undergone '''Controlled Ovarian Stimulation''' (COS).

=== Risk factors===

'''Primary risk factors'''

Pre-existing factors likely to exacerbate the ovarian stimulation response. Primary risk factors include <ref name="PMID26074966"><pubmed>26074966</pubmed></ref>:

*Young age
*Low body weight
*History of elevated response to gonadotropins
*Polycystic Ovary Syndrome (PCOS)
*Isolated PCOS characteristic
*Previous history of OHSS.
*High pretreatment basal Anti-Mullerian Hormone (AMH) concentration
*Large Antral Follicle Count (AFC)

'''Secondary risk factors'''

Secondary risk factors involve the monitoring of ovarian response parameters once COS has been initiated. These parameters are monitored for <ref name="PMID19007627"><pubmed>19007627</pubmed></ref>:

*rapidly rising E2 levels
*E2 concentration larger than 2500 pg/mL
*large number of developing follicles (10-14mm) on the day hCG is administered
*large number of oocytes retrieved

These factors in combination, act as a predictive tool to assess the likelihood of severe OHSS development, with a 83% sensitivity and 84% specificity. <ref name="PMID19007627"/>

=== Primary Prevention===
[[File:Severe OHSS Prevention.jpeg|right|thumbnail|400px|GnRH antagonists, embryo cryopreservation and cycle cancellation are key strategies in preventing OHSS progression in high-risk patients <ref name="PMID22938051"><pubmed>22938051</pubmed></ref>]]

Primary Prevention involves the modification of treatment regimens on the basis of OHSS risk classifications, in order to prevent OHSS occurrence.

'''Ovulation Induction'''

Unifollicular Ovulation Induction through Ovulation Induction (OI) is a primary means of avoiding OHSS in women with Polycystic Ovarian Syndrome, who are at an increased risk. In order to promote unifollicular development, the ovaries are stimulated with a low starting dose of FSH (75 IU).<ref name="PMID20416867"><pubmed>20416867</pubmed></ref> Studies suggests that a minimum gonadotropin dose lowers OHSS risk and thus a step-up regimen is utilised to achieve an ovarian response, whereby the FSH dosage is increased every 7 days until follicular development of greater than 10mm is noted.<ref name="PMID26074966" /> Alternatively, a step-down regimen may be followed, whereby a high initial FSH dosage is lowered according to the ovarian response. Another method to increase FSH levels during OI, is through '''Aromatase Inhibitors''' which promote folliculogenesis by increasing pituitary secretion of FSH, and downregulate oestrogen production through a negative feedback loop. However, Aromatase Inhibitors have not been shown to reduce OHSS incidence in comparison to other methods of OI.<ref name="PMID26074966" /> During OI, a key objective is to prevent early cycle cancellation due to premature luteinisation from pituitary secretion of LH. In order to downregulate LH secretion, '''Gonadotropin-releasing hormone agonists''' (GnRHa) are administered in addition to gonadotropins. Alternatively, '''GnRH antagonists''', which have a rapid onset of action, may be administered to downregulate endogenous LH secretion, with relative success as depicted in the diagram to the right.<ref name="PMID20416867" /> Comparative studies have shown that the GnRH antagonist protocol has a greater effect in lowering the incidence of mild to severe OHSS. However due to the rare nature of OHSS, and insufficient sample sizes, the difference was not found to be significant. <ref name="PMID21082508"><pubmed>21082508</pubmed></ref>. Generally, the duration of exposure to gonadotropins and subsequent risk of OHSS may be minimised through mild stimulation protocols which administer FSH only in the mid to late follicular phase.<ref name="PMID20416867" />

'''Adjuvant Metformin Therapy'''

Adjuvant Metformin Therapy has been found to lower the risk of OHSS by 63%.<ref name="PMID25406011"><pubmed>25406011</pubmed></ref> It involves the administration of metformin at a daily dosage of 1000 to 2000mg, 2 months prior to Controlled Ovarian Stimulation <ref name="PMID26074966"/>. Metformin lowers the elevated insulin levels in PCOS which consequently reduce intraovarian androgen levels. This leads to a reduced sensitivity and expression of granulosa cell-follicle stimulating hormone receptors which result in a less exaggerated response to gonadotropins. Furthermore, it is suggested that Metformin prevents OHSS by controlling vascular permeability through the inhibition of various vasoactive molecules, including VEGF.

'''Avoiding hCG during Luteal Phase Support

Following Controlled Ovarian Stimulation, the steroid levels of E2 and P4 are reduced during the luteal phase due to the negative feedback on the pituitary. This leads to low endogenous LH levels, which consequently reduce endometrial receptivity as well as the luteal phase duration itself. As a result, implantation and pregnancy rates are reduced and early pregnancy loss rates are increased.<ref name="PMID20416867" /> Luteal Phase Support (LPS) serves to combat these adverse events with the use of hCG. However, hCG has been found to increase the risk of OHSS. Alternatively, the use of progesterone has been found to not only halve the risk of OHSS, but also induce similar improvements in pregnancy and miscarriage rates as hCG.<ref name="PMID26148507"><pubmed>26148507</pubmed></ref>

===Secondary Prevention===

Secondary Prevention aims to prevent progression to OHSS once COS has been initiated and the patient has been found to mount an exaggerated response. <ref name="PMID20416867" />

'''Coasting'''

[[File:Cryopreservation of Porcine Embryos.jpeg|right|thumbnail|300px|Cryopreservation in the swine model: a) mature oocyte b) day 1 embryo c) day 4 embryo d) blastocyst from cryopreserved day 1 embryo with an intact zona pellucida excluding the lipid droplet. Scale bars=20 μm.b<ref name="PMID26309801"><pubmed>26309801</pubmed></ref>]]
Coasting is a first-line secondary preventative strategy. It consists of the withdrawal of gonadotrophins when a critical number of follicles and/or E2 concentration is reached. hCG is administered once the E2 concentration reduces to a safe level, before the process of oocyte retrieval commences. This preventative strategy is conducted for a period of less than 3 days in order to avoid compromising IVF outcomes.<ref name="PMID26074966"/>

'''Cryopreservation'''

Cryopreservation of embryos after oocyte retrieval is another avenue which may avert OHSS progression. The cryopreserved embryos are only reimplanted once the patient's hormone serum levels have normalised. Using oocyte vitrification, crystal formation within embryo tissue is avoided and so cryopreserved embryos have been found to produce better pregnancy rates with a 32% increase, than fresh embryo transfer.<ref name="PMID26074966"/> Recent studies suggest cryopreservation itself does not reduce OHSS rates, but must be followed by a GnRHa trigger to avert OHSS.<ref name="PMID24753847"><pubmed>24753847></ref>

'''Cycle cancellation'''

Cycle cancellation is a guaranteed method to prevent early OHSS whereby hCG is withheld. This is a last resort strategy as it carries the risk of significant psychological distress and financial loss for the patient. <ref name="PMID20416867"/>

</div>

==Effect on the Newborn==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

</div>
Women who develop OHSS while undergoing Assisted Reproductive Technologies (ART) treatment are not only more likely to achieve a pregnancy, but have a live birth as the pregnancy outcome. This live birth is also more likely to be a multiple birth of two, three or more children. <ref name="PMID19591989"><pubmed>19591989</pubmed></ref> It has been postulated that a multi-fetal pregnancy leads to a more rapid increase in hCG levels, resulting in an increased risk of OHSS. However, the causal nature between multi-fetal pregnancy and OHSS development is disputed and further research is required to distinguish correlation from causation. <ref name="PMID19573292"><pubmed>19573292</pubmed></ref>

OHSS development is also associated with an increased risk of adverse outcomes including '''stillbirth, premature birth and low birth weight'''.<ref name="PMID19591989" /> Although the cause for the increased risk in adverse pregnancy outcomes is unknown, it is suggested that as the incidence of OHSS is reduced through various prevention strategies, the risk of such outcomes may be also be reduced.

'''<span style="color:#FA58D0"> [http://pregnancyperfect.com/emilyley/ The following link is to a podcast of a woman describing her pregnancy in which she underwent IVF, had OHSS and gave birth to healthy twins]<ref name="Emily"> Pregnancy Perfect[ http://pregnancyperfect.com/emilyley/ ], 'TWINS, IVF, OHSS AND C-SECTION WITH EMILY LEY'</ref> </span>'''

==Genetics==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

Despite OHSS typically being of iatrogenic origin as a result of ovarian stimulation with gonadotropins, research has been conducted into the potential genetics behind OHSS as many sporadic and familial cases have been observed. '''Mutations''' in the receptor for hormones such as Follicle Simulating Hormone (FSH), Lutenizing Hormone (LH) and hCG have all been targets of OHSS genetics research. Interestingly, they too also arise from a common ancestral gene.

===Follicle Stimulating Hormome===

Dr. Botros Rizk, of the University of South Alabama College of Medicine <ref name="PMID19573286"><pubmed>19573286</pubmed></ref>, has written extensively regarding the genetics behind OHSS. In particular, he talks about '''FSH receptors''' (FSHR) and their role in the syndrome. He hypothesises that mutations in these receptors could be activating or inactivating, leading to an increased risk of developing OHSS or sterility respectively. Currently, 744 single nucleotide polymorphisms (a type of mutation) have been found in the gene encoding the FSHR, 8 of which are located in its exons (coding regions of the gene). How the ovary responds is resultant on the FSHR genotype. For example, Ser680Asn, a polymorphism in the FSHR gene has been shown to aid in predicting the severity of a woman's OHSS. Ordinarily FSH stimulates the growth of ovarian follicles, however, when mutated, it is stimulated by the hCG resulting in excessive follicle development.

Spontaneous OHSS, OHSS that arises and cannot be attributed to any form of ovarian stimulation or Assisted Reproductive Technology, has been linked to activating mutations in the FSHR <ref name="PMID23499866"><pubmed>23499866</pubmed></ref>. This familial disorder is an autosomal dominant one. In most cases the FSHR can be stimulated by the presence of Thyroid Stimulating Hormone (TSH) or hCG, in the absence of FSH (the ligand for FSHR).

[[File:FSHR Gene.jpg|centre|thumbnail|700px|This image depicts the location of the FSHR Gene on chromosome 2. It is located on the short arm between positions 21 and 16. Changed to the FSHR gene has been linked to OHSS. <ref name="Genetcis"> Genetics Home Reference [http://ghr.nlm.nih.gov/gene/FSHR'</ref>]]

===Lutenizing Hormome===

The '''Lutenizing Hormone Receptor''' (LHR) gene in humans is comprised of 11 exons. Animal studies have shown that many primates exhibit a similar gene which is comprised of only 10 exons, however a gene lacking the 10th exon has been identified and termed the type 2 LHR. Expression of the type 2 LHR has been seen in humans. The type 2 LHR, compared to the wild-type LHR appears to be repaired with regard to its function. Defects in the type 2 LHR include a decrease in efficiency of transport to the plasma membrane and irregularities in signal transduction. Inactivating mutations in the LHR have been seen to cause infertility in women as well as amenorrhoea. Activating LHR gene mutations are asymptomatic and are not associated with OHSS in women.

===Bone Morphogenic Protein===

An imporant growth factor, derived from oocytes called '''BMP-15''' (Bone Morphogenic Protein 15) is vital for female fertility. It belongs to the family of growth factors, Transforming Growth Factor β (TGF-β) and is heavily involved in folliculogenesis. It has been found that mutations in the BMP-15 gene caused infertility in female sheep. Conversely, it has also been indicated in enhanced fertility when BMP-15 is present is high amounts in follicular fluid <ref name="PMID19573286" />.

A case study done by Hanevik ''et. al.'' in 2013 <ref name="PMID21565556"><pubmed>21565556</pubmed></ref> found that a Single Nuclear Polymorphism (SNP) in the BMP-15 gene is responsible for a high response to ovarian hyper-stimulation. The aim of the study was to test the effect the SNP had on BMP-15 with regard to high and low responders buy taking blood from 53 high responders, 38 low responders and 100 non-responders (controls) and analysing 5 noted SNP's. Results from their study showed a correlation between a high response to ovarian hyper-stimulation and the BMP-15 9G allele. The article does state however, that further research is required into the molecular effects of SNP's on the function of BMP-15.

===Vascular Endothelial Growth Factor===

'''Vascular endothelial growth factor''' (VEGF) has been indicated as one of the key agents causing vascular permeability and subsequent ascites in OHSS. The gene, which is located on chromosome 12, is made up of 8 exons (coding regions), of which exons 6 and 7 do not always appear due to the exons being spliced out.The splicing of this gene allows for various isoforms of the gene to exist of which VEGF 121 and 165 appear to play a role in angiogenesis. There are two VEGF Receptors, VEGFR-1 and VEGFR-2 that belong to the tyrosine kinase family of receptors (for more information on VEGF see [[Pathophysiology]]). Because of its distinct role in OHSS, it has been targeted as an area for research for potential treatments. The idea is that if the genetic expression of VEGF and its receptors can be controlled, OHSS can be avoided or treated.<ref name="PMID19573286" />

A different study by Hanevik ''et. al.'' , <ref name="PMID22587628"><pubmed>22587628</pubmed></ref> done in 2012 involved analysing blood samples from 53 women with OHSS and 100 women without it (controls) and analysing 6 SNP's in the VEGFR2 gene to find any genetic variations. They found a correlation between women with the VEGF +405cc genotype and the development of OHSS indicating women that undergo controlled ovarian hyper-stimulation and posses his genotype, are at an increased risk of developing OHSS.

</div>

== Current Research on Animal Models==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

{|
|-bgcolor="FFF5FF"
|<span style="font-size:120%">'''Inhibition of Cyclooxygenase-2 (COX-2) by Meloxican decreasing the incidence of OHSS in Rat Model'''</span> <ref name="PMID18166186"><pubmed>18166186</pubmed></ref>

Reasearch was carried out to investigate the effects of selective inhibition of the enzyme COX-2 on the Ovarian Hyperstimulation Syndrome (OHSS) using Female Wistar rates as the subjects. The research aimed to find results by measuring the number of antral and luteinized follicles, ovarian weight, vascualr endothelial growth factors and COX-2 immunohistochemistry. The rats being tested were all 22 days old and were divided into four equal groups;

'''Group 1 (Control group)''' was subject to a 0.1 ml of Intraperitoneal Saline from days 22 ~ 26

'''Group 2 (Mildly-stimulated group)''' subject to 10IU of pregnant mare serum gonadotrophin (PMSG) on day 24 and then 10IU of Human Chorionic Gonadotrophin (hCG) on day 26

'''Group 3 (OHSS positive group)''' was subject to 10IU of PMSG from days 22 ~ 26 and then administered 30IU of hCG on day 26 to induce OHSS

'''Group 4 (OHSS positive variant group)''' received 15mg/ml of Meloxicam 2 hours prior to administration of 10IU PMSG from days 22 ~ 26

Results showed there was no difference in ovarian weight in samples from Group 1 and Group 2, however Group 3 showed signs of significant ovarian weight increase which in group 4 was suppressed by the introduction of Meloxicam. No differences were observed in the number of antral follicles amongst the four test groups. Results from Group 2 and Group 3 showed that the granulosa cells of preovulatory follicles and the stromal cells were highly VEGF immunoreactive, however the Meloxicam treated Group 4 showed less immunoreactivity than Group 2 and Group 3 which indicated the correlation between Meloxicam and the diminished VEGF expression. Group 3 presented an increased COS-2 immunoreactivity which was highly diminished than in Group 4.

The research concluded that in a rat model, the enzyme Meloxicam has a beneficial effect on OHSS by reducing the increase of ovarian weight and the expression of VEGF associated with OHSS, the effects of which may be mediated by the inhibitory capacity of COX-2 on Meloxicam
|}

{|
|-bgcolor="FFF5FF"
|<span style="font-size:120%">'''Inhibition of Ovarian VEGF secretion by activation of Dopamine Receptor 2'''</span> <ref name="PMID25217874"><pubmed>25217874</pubmed></ref>

This research was carried out to investigate a possibility in whether a Dopamine Receptor 2 agonist '''(D2-ag)''' can assist in the prevention of Ovarian Hyperstimulation Syndrome, using rat models, by decreasing the ovarian vascular endothelial growth factor '''(VEGF)''' production. Using Immature Wistar rats (22 days old) as their animal model, the rats were initially stimulated with Gonadotrophins to mimic the onset and effects of OHSS and then subjected to treatment with a D2-agonist and/or a D2-antagonist (D2-ant). The vascular permeability was measured at the endpoint after day 26 by measuring the peritoneal extravasion of a previously injected dye and ovaries from all subjects were collected to assess the effects of D2-ag and D2-ant on the production of Ovarian VEGF. The expression of VEGF mRNA was measured by quantitative real time PCR and the levels of VEGF proteins were measured by Western Blots.

Results showed that the D2-ag caused a large reduction in the vascular permeability which was in turn associated with the great decreased in VEGF protein production in the OHSS rat ovaries, whereas the introduction of D2-ant showed opposite results with a increase in the vascular permeability leading to the increase of VEGF protein production in the ovaries. Ovarian VEGF mRNA levels were found to be unaffected by the introduction of these drugs in OHSS rat subjects. Conclusions were drawn on the fact that Dopamine Receptor 2 agonists prevent the increase of vascular permeability in subjects with OHSS by decreasing the ovarian production of VEGF and also that due to the dose-dependent inhibitory effect of the D2-ag on ovarian VEGF, current OHSS therapies used in humans can benefit by increasing the intraovarian concentration of D2-ag.
|}

</div>

==Glossary==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

'''Aromatase Inhibitor''' - A drug that inhibits enzyme aromatase, which in turn suppresses estrogen synthesis.

'''Ascites''' - An accumulation of fluid in the peritoneal cavity with resultant abdominal swelling.

'''Cabergoline''' - A dopamine receptor agonist used to treat hormone imbalance.

'''Controlled Ovarian Stimulation''' - female infertility treatment using medications to stimulate the ovaries to develop follicles.

'''Cryopreservation''' - Cooling and storing biological material at extremely low temperatures.

'''E2''' - Estradiol - Potent estrogen sex hormone.

'''FSH''' - Follicle Stimulating Hormone

'''Gonadotropin''' - Any hormone that has a stimulating effect on the gonads.

'''GnRH agonist''' - Gonadotropin Releasing Hormone - A class of compounds that mimic the effect of the natural Gonadotropin Releasing Hormone.

'''GnRH antagonist''' - Gonadotropin Releasing Hormone - A class of compounds that are similar in terms of the structure of natural Gonadotropin Releasing Hormone but has a antagonistic effect.

'''hCG'''- Human Chorionic Gonadotropin

'''Hemoconcentration''' - An increase in the concentration of circulating red blood cells in response to a decrease in blood plasma volume.

'''Hypovolemic''' - A decrease in circulating blood volume.

'''Iatrogenic''' - Illness caused as a result of a medical examination or treatment.

'''Intravenous fluids''' - Is the infusion of liquid substances directly into a vein.

'''IVF''' - In-vitro Fertilization

'''LH''' - Luteinizing Hormone

'''Metformin''' - A biguanide, antidiabetic drug used as an adjuvant to modify the effect of other agents.

'''NSAID''' - Non-steroidal Anti-Inflammatory Drug e.g. Ibuprofen

'''Oocyte vitrification''' - technique for cryopreservation of oocytes.

'''OHSS''' - Ovarian Hyper-stimulation Syndrome

'''Oliguria'''- Decreased urine output/small amounts of urine produced.

'''P4''' - Progesterone - endogenous progestogen sex hormone.

'''PCOS''' - Polycystic Ovarian Syndrome. An endrocrine system disorder whereby the ovaries are enlarged with small collections of fluid.

</div>

==References==

2015 Group Project 2

2015-10-23T16:42:02Z

Z3372824: /* Secondary Prevention */

{{ANAT2341Project2015header}}

==<span style="font-size:120%">'''Ovarian Hyper-stimulation Syndrome (OHSS)'''</span>==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

Ovarian Hyper stimulation Syndrome (OHSS) is an iatrogenic complication of '''Assisted Reproduction Technology''' (ART), in which women take medications to stimulate oocyte growth. It is generally identified by cystic enlargements of the ovaries and fluid accumulation in the peritoneal cavity due to the increased capillary permeability and ovarian neoangiogenesis <ref name="PMID22065820"><pubmed>22065820</pubmed></ref>. It is an occurrence which is dependent on the controlled stimulation of the ovaries in preparation for IVF i.e. administration of human Chorionic Gonadotropin (hCG).

OHSS was first described in 1943 as ''“syndrome d’hyperluteinisation massive des ovaries”''. It was during this time that gonadotropins were prepared from animals such as sheep to bring on ovulation in women. The first recorded death as a result of OHSS occurred in 1951 and was due to renal failure as a result of oligouria, a complication of the syndrome <ref name="OHSS"> Marie M. Budev, DO, MPH; Alejandro C. Arroliga, MD; Tommaso Falcone, MD, [ http://utilis.net/Morning%20Topics/REI/Ovarian%20Hyperstimulation.pdf ], 'Ovarian Hyperstimulation Syndrome'</ref> <ref name="PMID12638783"><pubmed>12638783</pubmed></ref>.

<span style="color:#FA58D0">'''This wikipage aims to provide clear information on various areas surrounding OHSS such as diagnosis, prevention and complications and will look into the genetics behind the disorder and the various animals models used to research it'''.</span>

<html5media height="350" width="450">https://www.youtube.com/watch?v=aXmjJw234a4</html5media>

'''Overview of Ovarian Hyperstimulation Syndrome''' <ref> Howcast (2013, August 27) Ovarian Hyperstimulation Syndrome | Infertility. Retrieved from https://www.youtube.com/watch?v=aXmjJw234a4</ref>

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==Epidemiology==
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Ovarian Hyper-Stimulation Syndrome (OHSS) rarely occurs sporadically, and if it does, it is usually the result of an underlying genetic problem. The majority of OHSS is due to the ovaries being stimulated to mature and release an abundance of oocytes, in response to hormones Human Chorionic Gonadotropin (hCG) and Follicle Stimulating hormone (FSH), during IVF. Rarely, Clomifene Citrate therapy can cause OHSS.<ref name="WikiOHSS"> Wikipedia, [ https://en.wikipedia.org/wiki/Ovarian_hyperstimulation_syndrome ], 'Ovarian Hyperstimulation Syndrome'</ref>

OHSS only affects '''0.5-5%''' of women undergoing Ovarian Hyper-stimulation, but despite its small prevalence, it is a potentially fatal outcome of a non-vital procedure and remains a prevalent problem for fertility specialists <ref name="PMID12498425"><pubmed>12498425</pubmed></ref> <ref name="PMID12638783"><pubmed>12638783</pubmed></ref>. Age has been cited as a factor affecting those with OHSS, with younger women more at risk. Additionally, women with allergies were seen to have a higher incidence of OHSS. It is important to note that at this point in time, there is no positive correlation between gonadotropin dose and OHSS.

Of the 0.5-5% of women affected with OHSS mentioned above, 2% of those women will require hospitalisation. As of 2011, it has been reported that the incidence of OHSS was '''increasing''', resulting in approximately 3 deaths per 100,000 women undergoing ovarian stimulation per year <ref name="PMID21828116"><pubmed>21828116</pubmed></ref>. This is particularly worrying as in 2008, in the United States alone, there were around 150,000 IVF cycles undertaken.

{|
|-bgcolor="F8E0F1"
|
'''With the field of Assisted Reproductive Technologies expanding and more women partaking in IVF treatments, the threat of women developing OHSS is an ongoing and increasing one''' <ref name="PMID21828116" />.
|}
{| class="wikitable mw-collapsible mw-collapsed"
! colspan=4|Characteristics of women with OHSS by complication group <ref name="PMID19591989"><pubmed>19591989</pubmed></ref>
|-
! scope="col" width="100px" height="60px" style="text-align:center| '''Characteristic'''
! scope="col" width="100px" height="60px" style="text-align:center| '''No Complications
(N = 212,041)'''
! scope="col" width="100px" height="60px" style="text-align:center| '''Moderate OHSS
(N = 1,523)'''
! scope="col" width="100px" height="60px" style="text-align:center| '''Severe OHSS
(N = 655)'''
|-
|style="text-align:center; background: #FF99FF;"| '''Maternal Age (Mean ± SD)'''
|style="text-align:center; background: #F6CEEC;"| 35.6 ± 4.6
|style="text-align:center; background: #F6CEEC;"| 33.0 ± 4.3
|style="text-align:center; background: #F6CEEC;"| 33.1 ± 4.4
|-
|style="text-align:center; background: #FF99FF;"| '''Maternal Age (%)'''
|-
|style="text-align:left; background: #F6CEEC;"| <30 years
|style="text-align:center; background: #F6CEEC;"| 10 %
|style="text-align:center; background: #F6CEEC;"| 21.1 %
|style="text-align:center; background: #F6CEEC;"| 20.6 %
|-
|style="text-align:left; background: #F6CEEC;"| 30-34 years
|style="text-align:center; background: #F6CEEC;"| 30.4 %
|style="text-align:center; background: #F6CEEC;"| 43.2 %
|style="text-align:center; background: #F6CEEC;"| 40.5 %
|-
|style="text-align:left; background: #F6CEEC;"| 35-39 years
|style="text-align:center; background: #F6CEEC;"| 37.8 %
|style="text-align:center; background: #F6CEEC;"| 27.2 %
|style="text-align:center; background: #F6CEEC;"| 32.5 %
|-
|style="text-align:left; background: #F6CEEC;"| >40 years
|style="text-align:center; background: #F6CEEC;"| 21.8 %
|style="text-align:center; background: #F6CEEC;"| 8.4 %
|style="text-align:center; background: #F6CEEC;"| 6.4 %
|-
|style="text-align:center; background: #FF99FF;"| '''Nulligravida (%)'''
|style="text-align:center; background: #F6CEEC;"| 45.8 %
|style="text-align:center; background: #F6CEEC;"| 51.5 %
|style="text-align:center; background: #F6CEEC;"| 51.8 %
|-
|style="text-align:center; background: #FF99FF;"| '''Infertility Diagnosis (%)'''
|-
|style="text-align:left; background: #F6CEEC;"| Male factor
|style="text-align:center; background: #F6CEEC;"| 37.7 %
|style="text-align:center; background: #F6CEEC;"| 41.0 %
|style="text-align:center; background: #F6CEEC;"| 33.4 %
|-
|style="text-align:left; background: #F6CEEC;"| Endometriosis
|style="text-align:center; background: #F6CEEC;"| 13.5 %
|style="text-align:center; background: #F6CEEC;"| 13.5 %
|style="text-align:center; background: #F6CEEC;"| 10.7 %
|-
|style="text-align:left; background: #F6CEEC;"| Ovulation Disorders
|style="text-align:center; background: #F6CEEC;"| 14.0 %
|style="text-align:center; background: #F6CEEC;"| 29.5 %
|style="text-align:center; background: #F6CEEC;"| 22.4 %
|-
|style="text-align:left; background: #F6CEEC;"| Diminished ovarian reserve
|style="text-align:center; background: #F6CEEC;"| 16.9 %
|style="text-align:center; background: #F6CEEC;"| 3.2 %
|style="text-align:center; background: #F6CEEC;"| 2.4 %
|-
|style="text-align:left; background: #F6CEEC;"| Tubal factors
|style="text-align:center; background: #F6CEEC;"| 20.4 %
|style="text-align:center; background: #F6CEEC;"| 22.6 %
|style="text-align:center; background: #F6CEEC;"| 22.3 %
|-
|style="text-align:left; background: #F6CEEC;"| Uterine factors
|style="text-align:center; background: #F6CEEC;"| 5.1 %
|style="text-align:center; background: #F6CEEC;"| 4.3 %
|style="text-align:center; background: #F6CEEC;"| 3.1 %
|-
|style="text-align:left; background: #F6CEEC;"| Other factors
|style="text-align:center; background: #F6CEEC;"| 13.9 %
|style="text-align:center; background: #F6CEEC;"| 13.1 %
|style="text-align:center; background: #F6CEEC;"| 10.4 %
|-
|style="text-align:left; background: #F6CEEC;"| Unexplained factor
|style="text-align:center; background: #F6CEEC;"| 12.7 %
|style="text-align:center; background: #F6CEEC;"| 11.8 %
|style="text-align:center; background: #F6CEEC;"| 18.6 %
|-
|}
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==Causative Agents==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

[[File:Follicular Development.jpeg|right|thumbnail|500px|Infertility treatments aim to facilitate follicular development and induce ovulation to improve chances of fertilisation <ref name="PMID24717179"><pubmed>24717179</pubmed></ref>]]

Normally a woman produces one egg per month from the ovaries, which travel down the Fallopian tube to be fertilized or be released from the body. In cases where women have difficulty falling pregnant, they are given medication which help them to produce and release eggs (as shown in the diagram to the right), further increasing their chances of fertilization and pregnancy <ref><pubmed>19573285</pubmed></ref>. Ovarian Hyper stimulation Syndrome generally occurs during infertility treatments when the ovaries are overstimulated by the fertility medication which causes the ovaries to swell and leak fluids into the belly and abdomen. The prevalence of OHSS onset is linked with excessive number of follicle development in response to the administration of injectable Follicle Stimulating Hormones (FSH) followed by the '''Human Chorionic Gonadotrophins''' (hCG) which triggers the release of the oocytes <ref><pubmed>26190539</pubmed></ref>.

'''Follicle Stimulating Hormones''' (FSH) <ref name="PMID9020850"><pubmed>9020850</pubmed></ref> are glycoprotein hormones that are produced and secreted from the Anterior Pituitary gland into the bloodstream, which regulate the developmental, growth, maturation and the reproductive processes within the body. In females, the Follicle Stimulating Hormones initiates the stages of growth and development of immature ovarian follicles within the ovaries before the release of an egg from a follicle at ovulation. When FSH is administered to a patient who is suffering from infertility, the increase FSH levels affect the rate of development and production, in turn increasing the amount of follicles which are ready to be released during ovulation.

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==Symptoms==
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OHSS is classified based on a criteria from mild, moderate and severe <ref name="WikiOHSS" />:

'''Mild Symptoms'''- abdominal bloating, minimal weight gain, nausea, diarrhoea and a feeling of fullness.

'''Moderate Symptoms'''- Substantial weight gain (on average 2 or more pounds a day), increased abdominal girth, darkend urine and excessive thirst in addition to the mild symptoms.

'''Severe Symptoms'''- In addition to the symptoms associated with Mild and Moderate OHSS, in severe OHSS, you see shortness of breath, calf and chest pains and pleural effusion.

===<span style="font-size:100%">Classifications of Ovarian Hyper-stimulation Syndrome:</span> <ref name="PMID22065820"><pubmed>22065820</pubmed></ref>===

{| class="wikitable" style="text-align:center
|-
! scope="col" width="70px"| '''Classification'''
! scope="col" width="650px"| '''Symptoms'''
|-
|style="text-align:center; background: #F6CEEC;"| '''Mild'''
|style="height: 60px; background: #F6CEEC;"| '''Grade 1''' - Abdominal distention and discomfort
'''Grade 2''' - Abdominal distention, discomfort with nausea, vomiting and/or diarrhea and ovarian enlargement from 5~12cm
|-
|style="text-align:center; background: #F8E0F1;"| '''Moderate'''
|style="height: 60px; background: #F8E0F1;"| '''Grade 3''' - All features of Mild OHSS with ultrasonographic evidence of ascites
|-
|style="text-align:center; background: #F6CEEC;"| '''Severe'''
|style="height: 60px; background: #F6CEEC;"| '''Grade 4''' - All features of Moderate OHSS with the addition of clinical evidence of ascites and breathing difficulties present
'''Grade 5''' - All of the above symptoms along with a change in the blood volume, increased blood viscosity due to coagulation and diminished renal function
|}

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==Diagnosis==
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Whilst symptoms of OHSS can occur as soon as 24 hours post hCG administration, they are usually seen in women 7-10 days post administration. Initially women with OHSS will present with abdominal bloating, as a result of fluid in the peritoneal cavity and an increase in ovary size. When women present with severe OHSS they are often dehydrated, due to increased vascular permeability, and have hemoconcentration. The above results in a decrease in intravascular volume, leading to '''oligouria''' <ref name="PMID22416285" />.

===History===

Initially a thorough history of the patient is taken during which the clinician looks for evidence of ovarian stimulation, followed by ovulation. During this history taking, the clinician will inquire into any weight gain noticed, urine output, and the woman's ability to maintain oral hydration. A key diagnostic tool for clinicians regarding women who are taking gonadotropins is to identify if they are at an increased risk of developing OHSS. Some risk factors include woman aged less than 30, women who have polycystic ovaries, woman with a previous history of OHSS and women who have had greater than 20 oocytes retrieved <ref name="PMID22416285" />.

===Physical Exam===
[[File:Vaginal_Ultrasonography_in_Sagittal_Plane.jpg|right|thumbnail|600px|Vaginal Ultrasonography in Sagittal plane <ref name="Wikiversity Journal of Medicine"> Häggström, Mikael. "Medical gallery of Mikael Häggström 2014". Wikiversity Journal of Medicine 1 (2). DOI:10.15347/wjm/2014.008. ISSN 20018762</ref>]]
After a history of the patient is taken, the next step is to perform a physical exam on the patient. Women who present with abdominal bloating will produce a shifting dullness upon abdominal percussion. Additionally the clinician will test the woman's vital signs, measure her abdominal girth, weight and will look for evidence of ascites or increase in calf size (usually unilateral)<ref name="PMID22416285" />.

===Investigations===

If the clinician further suspects a women of having OHSS, various investigations can be done such as an ultrasound.The intraperitoneal fluid is best imaged via vaginal ultrasound due to the enlarged ovaries making it difficult to image the pelvis using transabdominal ultrasound. The clinician can also order laboratory testing to look for urine specific gravity and and complete blood count to look for hemoconcentration with a hematocrit. Additionally, liver function tests can be ordered to look for elevated function. The clinician will also look for evidence of elevated D-dimers and fibrinogen and decreased levels of anti-thrombin 3 <ref name="SAHealth"> Government of South Australia Health [ http://www.sahealth.sa.gov.au/wps/wcm/connect/9b61ed004ee5348da663afd150ce4f37/Ovarian-hyperstimulation-syndrome-WCHN-PPG-17072012.pdf?MOD=AJPERES&CACHEID=9b61ed004ee5348da663afd150ce4f37 ], 'South Australian Paediatric Clinical Guidelines OHSS'</ref>.

====Ultrasound====

Typical appearances of the ultrasound include <ref name="Ultrasound"> Radiopaedia [ http://radiopaedia.org/articles/ovarian-hyperstimulation-syndrome-1 ], 'Ovarian Hyperstimulation Syndrome'</ref>:

*Bilaterally and symmetrically enlarged ovaries (>12cm)
* "Spoke-Wheel appearance" - presence of multiple cysts of varying size
*May also see ascites (fluid)

===Severity===

Once a clinician has deduced a women is suffering from OHSS, the severity of their condition needs to be established as either mild, moderate or severe. This is done by referring to the criteria under the sub-heading [[Symptoms]].The subsequent course of treatment for the woman will be based upon this evaluation.

{|
|-bgcolor="F6CEEC"
|
'''Further investigations''' can be done including a Chest X-ray to check for pleural effusions and oedema and USS with Doppler's to check for ascites or possible ovary torsion. <ref name="PMID22416285"><pubmed>22416285</pubmed></ref>
|}

===Differential Diagnosis===

Conditions presenting with similar symptoms or ultrasound images include <ref name="Ultrasound" />:

*Polycystic Ovaries (PO)
:: The difference is that with PO is that the cycts are typically smaller than OHSS cysts and there is no evidence of ascited or pleural effusion
*Mucinous Ovarian Malignancy
:: A type of Ovarian Epithelial tumour
*Ectopic Pregnancy <ref name="Casereport"> Australian Medical Student Journal [ http://www.amsj.org/wpcontent/uploads/files/articles/amsj_v2_i1/AMSJ_v2_i1_pg58-60.pdf ], 'Ovarian hyperstimulation syndrome'</ref>
::A pregnancy in which the foetus develops outside of the uterus e.g. in the fallopian tube

</div>

==Pathophysiology==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

The definition of Ovarian Stimulation is enlarged ovaries with many luteinized cysts, that can present with secondary complications. What distinguishes Ovarian Stimulation from OHSS is the presence of vascular hyper-permeability that results in fluids being redirected elsewhere in the body.

The key process to OHSS appears to be caused by '''Vascular Endothelial Growth Factor''' (VEGF), that is released along with other cytokines, estrogen and progesterone, due to the ovary undergoing luteinization as a result of stimulation by hCG. VEGF increases vascular permeability and as a result the capillaries become more "leaky" to the fluids in them. These fluids can then escape the capillaries and accumulate in the pleural and abdominal cavities as ascites. The woman then becomes hypovolemic and is at an increased risk of circulatory, renal and respiratory issues such as arterial thromboembolism due to the thickening of the blood. Note, the blood is thickened as fluid is leaving the capillaries, leaving behind red blood cells and other cellular components of the blood <ref name="WikiOHSS" />.

The increase in expression of VEGF and VEGF Receptor 2 (VEGFR2) is attributed to the greatly increased amount of their mRNA present in the body after stimulation with hCG <ref name="PMID21082502"><pubmed>21082502</pubmed></ref>. VEGF interacts with VEGF2 and VEGF Receptor 1 (VEGFR1) to create a strong angiogenic effect. Both VEGFR2 and VEGFR1 belong to a family of receptors called tyrosine kinases. VEGF2 is involved in the regulation of angiogenesis and vascular permeability whilst VEGF1 has a slightly contradictory role in that is is involved in the maintenance of the tight junctions between endothelial cells in blood vessels. A study by Gómez ''et. al.'' <ref name="PMID21082502" /> showed that women experiencing OHSS had substantially higher plasma levels of VEGF and lower levels of VEGFR1.

[[File:Pathogenesis_of_OHSS.png|600px|centre|thumb|Pathogenesis of OHSS <ref name="PMID20416867"><pubmed>20416867</pubmed></ref>]]

</div>

==Complications==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

Ovarian torsion or rupture, renal insufficiency and thrombophlebitis can all complicate OHSS. If a pregnancy occurs, symptoms may persist longer than the usual 1 to 2 weeks and become more severe, however, even with severe OHSS, they do not extend past the first trimester <ref name="WikiOHSS" />. [[File:Polycystic Ovaries.jpeg|right|thumbnail|360px|Comparison of Normal and Polycystic Ovary]]

<span style="color:#FA58D0"> '''1-2% of women who undergo ovarian stimulation develop a severe form of OHSS''' </span>. Complications from severe OHSS include:

*Fluid collection in the abdomen
*Electrolyte disturbances (sodium and potassium)
*Kidney failure
*Ovary twisting
*Rupture of a cyst in an ovary
*Breathing problems
*Blood clots in large vessels (most commonly the legs)
*Pregnancy loss from miscarriage or termination
*Rarely, death

A study by Nouri ''et. al.'' <ref name="PMID24996451"><pubmed>24996451</pubmed></ref> found that women with '''Polycystic Ovarian Syndrome''' (PCOS) and those that were induced with hCG experienced longer recovery times from severe OHSS than women who were not pregnant. They looked at a cohort of women hospitalised for the first time with severe OHSS and subject them to the same treatments. Based on a defined criteria, they established the recovery time of these women and compared the times between those that were pregnant to those that were not pregnant. They also found that whether a woman had PCOS or ovulation induction did not affect her risk of developing OHSS if she was not pregnant. It is only a risk factor for pregnant women.

===Thromboembolic events===

A frequent and deadly complication of OHSS are thromboembolic events due to increased blood clotting. This increase in blood clotting has been attributed to a variety of complications such as hemoconcentration (which thickens the blood), hypovolemia and an increase in the permeability of blood vessels as a result of increased vasoactive substances in the body of ovarian origin. Thromboembolic events include venous thromboses often in the upper extremities and arterial thromboses such as those in the cerebrovascular region. These events can lead to amputations of extremities, brain damage, miscarriage and death. To avoid this, anti-coagulants are given to pateitns with OHSS and they are fitted with compression stockings (see [[Treatment]]) <ref name="PMID23378404"><pubmed>23378404</pubmed></ref>.

{|
|-bgcolor="F8E0F1"
|
The risk of a woman developing OHSS is higher if she is having a '''twin pregnancy''', as she is exposed to higher concentration of hCG. <ref name="PMID9756273"><pubmed>9756273</pubmed></ref>
|}

</div>

==Treatment==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

'''General treatment
'''
*''Acetaminophen'' with or without a narcotic agent- used to treat abdominal discomfort
*Women are encouraged to drink 2-3 litres of water a day to prevent hemoconcentration
*Women are advised to avoid sexual intercourse and vigorous exercise at the risk of torsion or rupture of the ovaries
*NSAID's with anti-platelet properties should NOT be used as they may effect renal function in a women with OHSS
*Patients with significantly painful ascites or breathing problems may undergo ''Paracentesis'' (drainage of the ascites)
*''Culdocentesis'' (extraction of fluid from recto-uterine pouch) can be done to decrease the likelihood of a woman with moderate OHSS progressing to severe OHSS.<ref name="PMID22416285" />

===Mild to Moderate OHSS===

Mild OHSS can often resolve on its own, however, moderate OHSS may include treatments such as<ref name="WikiOHSS" />:

*Anti-nausea medication and prescription painkillers
*Regular physical examinations and ultrasounds
*Daily weigh-ins and waist measurements
*Measuring the amount of urine produced each day
*Frequent blood tests for monitoring dehydration and electrolyte imbalance
*Maintaining a high balance of fluids
*Drainage of excess abdominal fluid by inserting a needle in the abdominal cavity
*Wearing support stockings which help prevent blood clots/thrombosis

===Severe OHSS===

[[File:Abdominal Paracentesis.png|thumb|right|350px|Paracentesis is a common procedure done on women who have OHSS as it is used to drain the ascites in their abdomen. In this image you can see the puncture of the peritoneal cavity with a needle that then drains the fluid externally. <ref name="Wikiversity Journal of Medicine"> Blausen.com staff. "Blausen gallery 2014". Wikiversity Journal of Medicine. DOI:10.15347/wjm/2014.010. ISSN 20018762 </ref>]]

Severe OHSS requires hospital care in order for constant monitoring and treatment such as <ref name="WikiOHSS" />:

*Intravenous fluids with a crystalloid solution (100-150mL/hr)
*Intravenous Albumin is administered is IV fluids are insufficient (15-20mL/hr of 25% albumin for 4 hrs)
*In addition to Acetaminophen, ''Opioid analgesics'' can be administered for pain relief
*''Antiemetics'' can be used to subside nauseas and/or vomiting
*Woman administered to hospital of OHSS are considered at high risk of thromboembolic complications and are given low molecular weight ''heparin'', an anti-coagulant
*''Cabergoline''- lessens OHSS symptoms
*''GnRH agonist''- suppresses ovarian activity
**If at risk of OHSS, alternates include using a GnRH agonist instead of hCG however its effects on pregnancy rates are questionable. Using a GnRH agonist to replace the use of hCG for final oocyte stimulation will see a 6% decrease in delivery rate.
*Daily monitoring of creatine, urea, creatine clearance C-reactive protein (to rule out infection) are all required in combination with weekly tests such as liver and renal function tests and chest x-rays (to check for pleural effusion) <ref name="PMID12638783" />.

If there are serious complications then additional treatments are required:

*Surgery for a ruptured ovarian cyst
*Intensive care for the liver or lung complications

====Paracentesis====

For women with severe/grade 3 OHSS, paracentesis, the removal of fluid from the body using an aspiration needle, can be undertaken. It is a diagnostic and a therapeutic method that can be done trans-abdominally and trans-vaginally. It is used to relieve symptoms, improve haemodynamics e.g. Urinary output, and shorten the women's hospital stay. Complications of paracentesis include bleeding, infection and organ injury, however are note common <ref name="Paracentesis"> S. Monica Soni, HMS 3, Gillian Lieberman, MD [ http://eradiology.bidmc.harvard.edu/LearningLab/genito/Soni.pdf ], 'Ovarian Hyperstimulation Syndrome'</ref>.

{|
|-bgcolor="F8E0F1"
|
The most important aspect of treatment for any women with OHSS is close and constant '''monitoring''' with her healthcare professional. Counselling may also be provided to women and their partners or families in order to provide them with the best possible knowledge base to manage and treat their OHSS. It is important to note that there is '''no one cure or treatment''' for OHSS. Treatment involves managing and eliminating the symptoms until such time as the syndrome resolves itself <ref name="WikiOHSS" />.
|}

</div>

==Prevention==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

There are three key avenues through which the incidence of OHSS may be prevented. These include identifying risk factors to predict OHSS development, modifying treatment regimes on the basis of the identified risk factors and intervention to prevent progression to OHSS once the patient has undergone '''Controlled Ovarian Stimulation''' (COS).

=== Risk factors===

'''Primary risk factors'''

Pre-existing factors likely to exacerbate the ovarian stimulation response. Primary risk factors include <ref name="PMID26074966"><pubmed>26074966</pubmed></ref>:

*Young age
*Low body weight
*History of elevated response to gonadotropins
*Polycystic Ovary Syndrome (PCOS)
*Isolated PCOS characteristic
*Previous history of OHSS.
*High pretreatment basal Anti-Mullerian Hormone (AMH) concentration
*Large Antral Follicle Count (AFC)

'''Secondary risk factors'''

Secondary risk factors involve the monitoring of ovarian response parameters once COS has been initiated. These parameters are monitored for <ref name="PMID19007627"><pubmed>19007627</pubmed></ref>:

*rapidly rising E2 levels
*E2 concentration larger than 2500 pg/mL
*large number of developing follicles (10-14mm) on the day hCG is administered
*large number of oocytes retrieved

These factors in combination, act as a predictive tool to assess the likelihood of severe OHSS development, with a 83% sensitivity and 84% specificity. <ref name="PMID19007627"/>

=== Primary Prevention===
[[File:Severe OHSS Prevention.jpeg|right|thumbnail|400px|GnRH antagonists, embryo cryopreservation and cycle cancellation are key strategies in preventing OHSS progression in high-risk patients <ref name="PMID22938051"><pubmed>22938051</pubmed></ref>]]

Primary Prevention involves the modification of treatment regimens on the basis of OHSS risk classifications, in order to prevent OHSS occurrence.

'''Ovulation Induction'''

Unifollicular Ovulation Induction through Ovulation Induction (OI) is a primary means of avoiding OHSS in women with Polycystic Ovarian Syndrome, who are at an increased risk. In order to promote unifollicular development, the ovaries are stimulated with a low starting dose of FSH (75 IU).<ref name="PMID20416867"><pubmed>20416867</pubmed></ref> Studies suggests that a minimum gonadotropin dose lowers OHSS risk and thus a step-up regimen is utilised to achieve an ovarian response, whereby the FSH dosage is increased every 7 days until follicular development of greater than 10mm is noted.<ref name="PMID26074966" /> Alternatively, a step-down regimen may be followed, whereby a high initial FSH dosage is lowered according to the ovarian response. Another method to increase FSH levels during OI, is through '''Aromatase Inhibitors''' which promote folliculogenesis by increasing pituitary secretion of FSH, and downregulate oestrogen production through a negative feedback loop. However, Aromatase Inhibitors have not been shown to reduce OHSS incidence in comparison to other methods of OI.<ref name="PMID26074966" /> During OI, a key objective is to prevent early cycle cancellation due to premature luteinisation from pituitary secretion of LH. In order to downregulate LH secretion, '''Gonadotropin-releasing hormone agonists''' (GnRHa) are administered in addition to gonadotropins. Alternatively, '''GnRH antagonists''', which have a rapid onset of action, may be administered to downregulate endogenous LH secretion, with relative success as depicted in the diagram to the right.<ref name="PMID20416867" /> Comparative studies have shown that the GnRH antagonist protocol has a greater effect in lowering the incidence of mild to severe OHSS. However due to the rare nature of OHSS, and insufficient sample sizes, the difference was not found to be significant. <ref name="PMID21082508"><pubmed>21082508</pubmed></ref>. Generally, the duration of exposure to gonadotropins and subsequent risk of OHSS may be minimised through mild stimulation protocols which administer FSH only in the mid to late follicular phase.<ref name="PMID20416867" />

'''Adjuvant Metformin Therapy'''

Adjuvant Metformin Therapy has been found to lower the risk of OHSS by 63%.<ref name="PMID25406011"><pubmed>25406011</pubmed></ref> It involves the administration of metformin at a daily dosage of 1000 to 2000mg, 2 months prior to Controlled Ovarian Stimulation <ref name="PMID26074966"/>. Metformin lowers the elevated insulin levels in PCOS which consequently reduce intraovarian androgen levels. This leads to a reduced sensitivity and expression of granulosa cell-follicle stimulating hormone receptors which result in a less exaggerated response to gonadotropins. Furthermore, it is suggested that Metformin prevents OHSS by controlling vascular permeability through the inhibition of various vasoactive molecules, including VEGF.

'''Avoiding hCG during Luteal Phase Support

Following Controlled Ovarian Stimulation, the steroid levels of E2 and P4 are reduced during the luteal phase due to the negative feedback on the pituitary. This leads to low endogenous LH levels, which consequently reduce endometrial receptivity as well as the luteal phase duration itself. As a result, implantation and pregnancy rates are reduced and early pregnancy loss rates are increased.<ref name="PMID20416867" /> Luteal Phase Support (LPS) serves to combat these adverse events with the use of hCG. However, hCG has been found to increase the risk of OHSS. Alternatively, the use of progesterone has been found to not only halve the risk of OHSS, but also induce similar improvements in pregnancy and miscarriage rates as hCG.<ref name="PMID26148507"><pubmed>26148507</pubmed></ref>

===Secondary Prevention===

Secondary Prevention aims to prevent progression to OHSS once COS has been initiated and the patient has been found to mount an exaggerated response. <ref name="PMID20416867" />

'''Coasting'''

[[File:Cryopreservation of Porcine Embryos.jpeg|right|thumbnail|300px|Cryopreserved embryos of the swine model: a) mature oocyte b) day 1 embryo c) day 4 embryo d) blastocyst from cryopreserved day 1 embryo with an intact zona pellucida excluding the lipid droplet. Scale bars=20 μm.b<ref name="PMID26309801"><pubmed>26309801</pubmed></ref>]]
Coasting is a first-line secondary preventative strategy. It consists of the withdrawal of gonadotrophins when a critical number of follicles and/or E2 concentration is reached. hCG is administered once the E2 concentration reduces to a safe level, before the process of oocyte retrieval commences. This preventative strategy is conducted for a period of less than 3 days in order to avoid compromising IVF outcomes.<ref name="PMID26074966"/>

'''Cryopreservation'''

Cryopreservation of embryos after oocyte retrieval is another avenue which may avert OHSS progression. The cryopreserved embryos are only reimplanted once the patient's hormone serum levels have normalised. Using oocyte vitrification, crystal formation within embryo tissue is avoided and so cryopreserved embryos have been found to produce better pregnancy rates with a 32% increase, than fresh embryo transfer.<ref name="PMID26074966"/> Recent studies suggest cryopreservation itself does not reduce OHSS rates, but must be followed by a GnRHa trigger to avert OHSS.<ref name="PMID24753847"><pubmed>24753847></ref>

'''Cycle cancellation'''

Cycle cancellation is a guaranteed method to prevent early OHSS whereby hCG is withheld. This is a last resort strategy as it carries the risk of significant psychological distress and financial loss for the patient. <ref name="PMID20416867"/>

</div>

==Effect on the Newborn==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

</div>
Women who develop OHSS while undergoing Assisted Reproductive Technologies (ART) treatment are not only more likely to achieve a pregnancy, but have a live birth as the pregnancy outcome. This live birth is also more likely to be a multiple birth of two, three or more children. <ref name="PMID19591989"><pubmed>19591989</pubmed></ref> It has been postulated that a multi-fetal pregnancy leads to a more rapid increase in hCG levels, resulting in an increased risk of OHSS. However, the causal nature between multi-fetal pregnancy and OHSS development is disputed and further research is required to distinguish correlation from causation. <ref name="PMID19573292"><pubmed>19573292</pubmed></ref>

OHSS development is also associated with an increased risk of adverse outcomes including '''stillbirth, premature birth and low birth weight'''.<ref name="PMID19591989" /> Although the cause for the increased risk in adverse pregnancy outcomes is unknown, it is suggested that as the incidence of OHSS is reduced through various prevention strategies, the risk of such outcomes may be also be reduced.

'''<span style="color:#FA58D0"> [http://pregnancyperfect.com/emilyley/ The following link is to a podcast of a woman describing her pregnancy in which she underwent IVF, had OHSS and gave birth to healthy twins]<ref name="Emily"> Pregnancy Perfect[ http://pregnancyperfect.com/emilyley/ ], 'TWINS, IVF, OHSS AND C-SECTION WITH EMILY LEY'</ref> </span>'''

==Genetics==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

Despite OHSS typically being of iatrogenic origin as a result of ovarian stimulation with gonadotropins, research has been conducted into the potential genetics behind OHSS as many sporadic and familial cases have been observed. '''Mutations''' in the receptor for hormones such as Follicle Simulating Hormone (FSH), Lutenizing Hormone (LH) and hCG have all been targets of OHSS genetics research. Interestingly, they too also arise from a common ancestral gene.

===Follicle Stimulating Hormome===

Dr. Botros Rizk, of the University of South Alabama College of Medicine <ref name="PMID19573286"><pubmed>19573286</pubmed></ref>, has written extensively regarding the genetics behind OHSS. In particular, he talks about '''FSH receptors''' (FSHR) and their role in the syndrome. He hypothesises that mutations in these receptors could be activating or inactivating, leading to an increased risk of developing OHSS or sterility respectively. Currently, 744 single nucleotide polymorphisms (a type of mutation) have been found in the gene encoding the FSHR, 8 of which are located in its exons (coding regions of the gene). How the ovary responds is resultant on the FSHR genotype. For example, Ser680Asn, a polymorphism in the FSHR gene has been shown to aid in predicting the severity of a woman's OHSS. Ordinarily FSH stimulates the growth of ovarian follicles, however, when mutated, it is stimulated by the hCG resulting in excessive follicle development.

Spontaneous OHSS, OHSS that arises and cannot be attributed to any form of ovarian stimulation or Assisted Reproductive Technology, has been linked to activating mutations in the FSHR <ref name="PMID23499866"><pubmed>23499866</pubmed></ref>. This familial disorder is an autosomal dominant one. In most cases the FSHR can be stimulated by the presence of Thyroid Stimulating Hormone (TSH) or hCG, in the absence of FSH (the ligand for FSHR).

[[File:FSHR Gene.jpg|centre|thumbnail|700px|This image depicts the location of the FSHR Gene on chromosome 2. It is located on the short arm between positions 21 and 16. Changed to the FSHR gene has been linked to OHSS. <ref name="Genetcis"> Genetics Home Reference [http://ghr.nlm.nih.gov/gene/FSHR'</ref>]]

===Lutenizing Hormome===

The '''Lutenizing Hormone Receptor''' (LHR) gene in humans is comprised of 11 exons. Animal studies have shown that many primates exhibit a similar gene which is comprised of only 10 exons, however a gene lacking the 10th exon has been identified and termed the type 2 LHR. Expression of the type 2 LHR has been seen in humans. The type 2 LHR, compared to the wild-type LHR appears to be repaired with regard to its function. Defects in the type 2 LHR include a decrease in efficiency of transport to the plasma membrane and irregularities in signal transduction. Inactivating mutations in the LHR have been seen to cause infertility in women as well as amenorrhoea. Activating LHR gene mutations are asymptomatic and are not associated with OHSS in women.

===Bone Morphogenic Protein===

An imporant growth factor, derived from oocytes called '''BMP-15''' (Bone Morphogenic Protein 15) is vital for female fertility. It belongs to the family of growth factors, Transforming Growth Factor β (TGF-β) and is heavily involved in folliculogenesis. It has been found that mutations in the BMP-15 gene caused infertility in female sheep. Conversely, it has also been indicated in enhanced fertility when BMP-15 is present is high amounts in follicular fluid <ref name="PMID19573286" />.

A case study done by Hanevik ''et. al.'' in 2013 <ref name="PMID21565556"><pubmed>21565556</pubmed></ref> found that a Single Nuclear Polymorphism (SNP) in the BMP-15 gene is responsible for a high response to ovarian hyper-stimulation. The aim of the study was to test the effect the SNP had on BMP-15 with regard to high and low responders buy taking blood from 53 high responders, 38 low responders and 100 non-responders (controls) and analysing 5 noted SNP's. Results from their study showed a correlation between a high response to ovarian hyper-stimulation and the BMP-15 9G allele. The article does state however, that further research is required into the molecular effects of SNP's on the function of BMP-15.

===Vascular Endothelial Growth Factor===

'''Vascular endothelial growth factor''' (VEGF) has been indicated as one of the key agents causing vascular permeability and subsequent ascites in OHSS. The gene, which is located on chromosome 12, is made up of 8 exons (coding regions), of which exons 6 and 7 do not always appear due to the exons being spliced out.The splicing of this gene allows for various isoforms of the gene to exist of which VEGF 121 and 165 appear to play a role in angiogenesis. There are two VEGF Receptors, VEGFR-1 and VEGFR-2 that belong to the tyrosine kinase family of receptors (for more information on VEGF see [[Pathophysiology]]). Because of its distinct role in OHSS, it has been targeted as an area for research for potential treatments. The idea is that if the genetic expression of VEGF and its receptors can be controlled, OHSS can be avoided or treated.<ref name="PMID19573286" />

A different study by Hanevik ''et. al.'' , <ref name="PMID22587628"><pubmed>22587628</pubmed></ref> done in 2012 involved analysing blood samples from 53 women with OHSS and 100 women without it (controls) and analysing 6 SNP's in the VEGFR2 gene to find any genetic variations. They found a correlation between women with the VEGF +405cc genotype and the development of OHSS indicating women that undergo controlled ovarian hyper-stimulation and posses his genotype, are at an increased risk of developing OHSS.

</div>

== Current Research on Animal Models==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

{|
|-bgcolor="FFF5FF"
|<span style="font-size:120%">'''Inhibition of Cyclooxygenase-2 (COX-2) by Meloxican decreasing the incidence of OHSS in Rat Model'''</span> <ref name="PMID18166186"><pubmed>18166186</pubmed></ref>

Reasearch was carried out to investigate the effects of selective inhibition of the enzyme COX-2 on the Ovarian Hyperstimulation Syndrome (OHSS) using Female Wistar rates as the subjects. The research aimed to find results by measuring the number of antral and luteinized follicles, ovarian weight, vascualr endothelial growth factors and COX-2 immunohistochemistry. The rats being tested were all 22 days old and were divided into four equal groups;

'''Group 1 (Control group)''' was subject to a 0.1 ml of Intraperitoneal Saline from days 22 ~ 26

'''Group 2 (Mildly-stimulated group)''' subject to 10IU of pregnant mare serum gonadotrophin (PMSG) on day 24 and then 10IU of Human Chorionic Gonadotrophin (hCG) on day 26

'''Group 3 (OHSS positive group)''' was subject to 10IU of PMSG from days 22 ~ 26 and then administered 30IU of hCG on day 26 to induce OHSS

'''Group 4 (OHSS positive variant group)''' received 15mg/ml of Meloxicam 2 hours prior to administration of 10IU PMSG from days 22 ~ 26

Results showed there was no difference in ovarian weight in samples from Group 1 and Group 2, however Group 3 showed signs of significant ovarian weight increase which in group 4 was suppressed by the introduction of Meloxicam. No differences were observed in the number of antral follicles amongst the four test groups. Results from Group 2 and Group 3 showed that the granulosa cells of preovulatory follicles and the stromal cells were highly VEGF immunoreactive, however the Meloxicam treated Group 4 showed less immunoreactivity than Group 2 and Group 3 which indicated the correlation between Meloxicam and the diminished VEGF expression. Group 3 presented an increased COS-2 immunoreactivity which was highly diminished than in Group 4.

The research concluded that in a rat model, the enzyme Meloxicam has a beneficial effect on OHSS by reducing the increase of ovarian weight and the expression of VEGF associated with OHSS, the effects of which may be mediated by the inhibitory capacity of COX-2 on Meloxicam
|}

{|
|-bgcolor="FFF5FF"
|<span style="font-size:120%">'''Inhibition of Ovarian VEGF secretion by activation of Dopamine Receptor 2'''</span> <ref name="PMID25217874"><pubmed>25217874</pubmed></ref>

This research was carried out to investigate a possibility in whether a Dopamine Receptor 2 agonist '''(D2-ag)''' can assist in the prevention of Ovarian Hyperstimulation Syndrome, using rat models, by decreasing the ovarian vascular endothelial growth factor '''(VEGF)''' production. Using Immature Wistar rats (22 days old) as their animal model, the rats were initially stimulated with Gonadotrophins to mimic the onset and effects of OHSS and then subjected to treatment with a D2-agonist and/or a D2-antagonist (D2-ant). The vascular permeability was measured at the endpoint after day 26 by measuring the peritoneal extravasion of a previously injected dye and ovaries from all subjects were collected to assess the effects of D2-ag and D2-ant on the production of Ovarian VEGF. The expression of VEGF mRNA was measured by quantitative real time PCR and the levels of VEGF proteins were measured by Western Blots.

Results showed that the D2-ag caused a large reduction in the vascular permeability which was in turn associated with the great decreased in VEGF protein production in the OHSS rat ovaries, whereas the introduction of D2-ant showed opposite results with a increase in the vascular permeability leading to the increase of VEGF protein production in the ovaries. Ovarian VEGF mRNA levels were found to be unaffected by the introduction of these drugs in OHSS rat subjects. Conclusions were drawn on the fact that Dopamine Receptor 2 agonists prevent the increase of vascular permeability in subjects with OHSS by decreasing the ovarian production of VEGF and also that due to the dose-dependent inhibitory effect of the D2-ag on ovarian VEGF, current OHSS therapies used in humans can benefit by increasing the intraovarian concentration of D2-ag.
|}

</div>

==Glossary==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

'''Aromatase Inhibitor''' - A drug that inhibits enzyme aromatase, which in turn suppresses estrogen synthesis.

'''Ascites''' - An accumulation of fluid in the peritoneal cavity with resultant abdominal swelling.

'''Cabergoline''' - A dopamine receptor agonist used to treat hormone imbalance.

'''Controlled Ovarian Stimulation''' - female infertility treatment using medications to stimulate the ovaries to develop follicles.

'''Cryopreservation''' - Cooling and storing biological material at extremely low temperatures.

'''E2''' - Estradiol - Potent estrogen sex hormone.

'''FSH''' - Follicle Stimulating Hormone

'''Gonadotropin''' - Any hormone that has a stimulating effect on the gonads.

'''GnRH agonist''' - Gonadotropin Releasing Hormone - A class of compounds that mimic the effect of the natural Gonadotropin Releasing Hormone.

'''GnRH antagonist''' - Gonadotropin Releasing Hormone - A class of compounds that are similar in terms of the structure of natural Gonadotropin Releasing Hormone but has a antagonistic effect.

'''hCG'''- Human Chorionic Gonadotropin

'''Hemoconcentration''' - An increase in the concentration of circulating red blood cells in response to a decrease in blood plasma volume.

'''Hypovolemic''' - A decrease in circulating blood volume.

'''Iatrogenic''' - Illness caused as a result of a medical examination or treatment.

'''Intravenous fluids''' - Is the infusion of liquid substances directly into a vein.

'''IVF''' - In-vitro Fertilization

'''LH''' - Luteinizing Hormone

'''Metformin''' - A biguanide, antidiabetic drug used as an adjuvant to modify the effect of other agents.

'''NSAID''' - Non-steroidal Anti-Inflammatory Drug e.g. Ibuprofen

'''Oocyte vitrification''' - technique for cryopreservation of oocytes.

'''OHSS''' - Ovarian Hyper-stimulation Syndrome

'''Oliguria'''- Decreased urine output/small amounts of urine produced.

'''P4''' - Progesterone - endogenous progestogen sex hormone.

'''PCOS''' - Polycystic Ovarian Syndrome. An endrocrine system disorder whereby the ovaries are enlarged with small collections of fluid.

</div>

==References==

File:Cryopreservation of Porcine Embryos.jpeg

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Z3372824:

==Cryopreservation of Porcine embryos==

Representative image of cryopreserved embryos of the swine model: a) mature oocyte b) day 1 embryo c) day 4 embryo d) blastocyst from cryopreserved day 1 embryo with an intact zona pellucida excluding the lipid droplet. Scale bars=20 μm.

(Derived from original figure legend, based on article by Men et al. PMID 26309801)

Cryopreservation of embryos allows for embryos to be preserved at sub-zero temperatures. The embryo may be implanted when patient serum levels have normalised and the risk of OHSS progression is reduced.

===References===

<pubmed>26309801</pubmed>| [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4497712/]

====Copyright====

© Hongsheng Men et al. 2015; Published by Mary Ann Liebert, Inc.
This Open Access article is distributed under the terms of the Creative Commons License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited.

fig-2.jpeg

{{Template:Student Image}}

2015 Group Project 2

2015-10-23T16:32:56Z

Z3372824: /* Primary Prevention */

{{ANAT2341Project2015header}}

==<span style="font-size:120%">'''Ovarian Hyper-stimulation Syndrome (OHSS)'''</span>==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

Ovarian Hyper stimulation Syndrome (OHSS) is an iatrogenic complication of '''Assisted Reproduction Technology''' (ART), in which women take medications to stimulate oocyte growth. It is generally identified by cystic enlargements of the ovaries and fluid accumulation in the peritoneal cavity due to the increased capillary permeability and ovarian neoangiogenesis <ref name="PMID22065820"><pubmed>22065820</pubmed></ref>. It is an occurrence which is dependent on the controlled stimulation of the ovaries in preparation for IVF i.e. administration of human Chorionic Gonadotropin (hCG).

OHSS was first described in 1943 as ''“syndrome d’hyperluteinisation massive des ovaries”''. It was during this time that gonadotropins were prepared from animals such as sheep to bring on ovulation in women. The first recorded death as a result of OHSS occurred in 1951 and was due to renal failure as a result of oligouria, a complication of the syndrome <ref name="OHSS"> Marie M. Budev, DO, MPH; Alejandro C. Arroliga, MD; Tommaso Falcone, MD, [ http://utilis.net/Morning%20Topics/REI/Ovarian%20Hyperstimulation.pdf ], 'Ovarian Hyperstimulation Syndrome'</ref> <ref name="PMID12638783"><pubmed>12638783</pubmed></ref>.

<span style="color:#FA58D0">'''This wikipage aims to provide clear information on various areas surrounding OHSS such as diagnosis, prevention and complications and will look into the genetics behind the disorder and the various animals models used to research it'''.</span>

<html5media height="350" width="450">https://www.youtube.com/watch?v=aXmjJw234a4</html5media>

'''Overview of Ovarian Hyperstimulation Syndrome''' <ref> Howcast (2013, August 27) Ovarian Hyperstimulation Syndrome | Infertility. Retrieved from https://www.youtube.com/watch?v=aXmjJw234a4</ref>

</div>

==Epidemiology==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

Ovarian Hyper-Stimulation Syndrome (OHSS) rarely occurs sporadically, and if it does, it is usually the result of an underlying genetic problem. The majority of OHSS is due to the ovaries being stimulated to mature and release an abundance of oocytes, in response to hormones Human Chorionic Gonadotropin (hCG) and Follicle Stimulating hormone (FSH), during IVF. Rarely, Clomifene Citrate therapy can cause OHSS.<ref name="WikiOHSS"> Wikipedia, [ https://en.wikipedia.org/wiki/Ovarian_hyperstimulation_syndrome ], 'Ovarian Hyperstimulation Syndrome'</ref>

OHSS only affects '''0.5-5%''' of women undergoing Ovarian Hyper-stimulation, but despite its small prevalence, it is a potentially fatal outcome of a non-vital procedure and remains a prevalent problem for fertility specialists <ref name="PMID12498425"><pubmed>12498425</pubmed></ref> <ref name="PMID12638783"><pubmed>12638783</pubmed></ref>. Age has been cited as a factor affecting those with OHSS, with younger women more at risk. Additionally, women with allergies were seen to have a higher incidence of OHSS. It is important to note that at this point in time, there is no positive correlation between gonadotropin dose and OHSS.

Of the 0.5-5% of women affected with OHSS mentioned above, 2% of those women will require hospitalisation. As of 2011, it has been reported that the incidence of OHSS was '''increasing''', resulting in approximately 3 deaths per 100,000 women undergoing ovarian stimulation per year <ref name="PMID21828116"><pubmed>21828116</pubmed></ref>. This is particularly worrying as in 2008, in the United States alone, there were around 150,000 IVF cycles undertaken.

{|
|-bgcolor="F8E0F1"
|
'''With the field of Assisted Reproductive Technologies expanding and more women partaking in IVF treatments, the threat of women developing OHSS is an ongoing and increasing one''' <ref name="PMID21828116" />.
|}
{| class="wikitable mw-collapsible mw-collapsed"
! colspan=4|Characteristics of women with OHSS by complication group <ref name="PMID19591989"><pubmed>19591989</pubmed></ref>
|-
! scope="col" width="100px" height="60px" style="text-align:center| '''Characteristic'''
! scope="col" width="100px" height="60px" style="text-align:center| '''No Complications
(N = 212,041)'''
! scope="col" width="100px" height="60px" style="text-align:center| '''Moderate OHSS
(N = 1,523)'''
! scope="col" width="100px" height="60px" style="text-align:center| '''Severe OHSS
(N = 655)'''
|-
|style="text-align:center; background: #FF99FF;"| '''Maternal Age (Mean ± SD)'''
|style="text-align:center; background: #F6CEEC;"| 35.6 ± 4.6
|style="text-align:center; background: #F6CEEC;"| 33.0 ± 4.3
|style="text-align:center; background: #F6CEEC;"| 33.1 ± 4.4
|-
|style="text-align:center; background: #FF99FF;"| '''Maternal Age (%)'''
|-
|style="text-align:left; background: #F6CEEC;"| <30 years
|style="text-align:center; background: #F6CEEC;"| 10 %
|style="text-align:center; background: #F6CEEC;"| 21.1 %
|style="text-align:center; background: #F6CEEC;"| 20.6 %
|-
|style="text-align:left; background: #F6CEEC;"| 30-34 years
|style="text-align:center; background: #F6CEEC;"| 30.4 %
|style="text-align:center; background: #F6CEEC;"| 43.2 %
|style="text-align:center; background: #F6CEEC;"| 40.5 %
|-
|style="text-align:left; background: #F6CEEC;"| 35-39 years
|style="text-align:center; background: #F6CEEC;"| 37.8 %
|style="text-align:center; background: #F6CEEC;"| 27.2 %
|style="text-align:center; background: #F6CEEC;"| 32.5 %
|-
|style="text-align:left; background: #F6CEEC;"| >40 years
|style="text-align:center; background: #F6CEEC;"| 21.8 %
|style="text-align:center; background: #F6CEEC;"| 8.4 %
|style="text-align:center; background: #F6CEEC;"| 6.4 %
|-
|style="text-align:center; background: #FF99FF;"| '''Nulligravida (%)'''
|style="text-align:center; background: #F6CEEC;"| 45.8 %
|style="text-align:center; background: #F6CEEC;"| 51.5 %
|style="text-align:center; background: #F6CEEC;"| 51.8 %
|-
|style="text-align:center; background: #FF99FF;"| '''Infertility Diagnosis (%)'''
|-
|style="text-align:left; background: #F6CEEC;"| Male factor
|style="text-align:center; background: #F6CEEC;"| 37.7 %
|style="text-align:center; background: #F6CEEC;"| 41.0 %
|style="text-align:center; background: #F6CEEC;"| 33.4 %
|-
|style="text-align:left; background: #F6CEEC;"| Endometriosis
|style="text-align:center; background: #F6CEEC;"| 13.5 %
|style="text-align:center; background: #F6CEEC;"| 13.5 %
|style="text-align:center; background: #F6CEEC;"| 10.7 %
|-
|style="text-align:left; background: #F6CEEC;"| Ovulation Disorders
|style="text-align:center; background: #F6CEEC;"| 14.0 %
|style="text-align:center; background: #F6CEEC;"| 29.5 %
|style="text-align:center; background: #F6CEEC;"| 22.4 %
|-
|style="text-align:left; background: #F6CEEC;"| Diminished ovarian reserve
|style="text-align:center; background: #F6CEEC;"| 16.9 %
|style="text-align:center; background: #F6CEEC;"| 3.2 %
|style="text-align:center; background: #F6CEEC;"| 2.4 %
|-
|style="text-align:left; background: #F6CEEC;"| Tubal factors
|style="text-align:center; background: #F6CEEC;"| 20.4 %
|style="text-align:center; background: #F6CEEC;"| 22.6 %
|style="text-align:center; background: #F6CEEC;"| 22.3 %
|-
|style="text-align:left; background: #F6CEEC;"| Uterine factors
|style="text-align:center; background: #F6CEEC;"| 5.1 %
|style="text-align:center; background: #F6CEEC;"| 4.3 %
|style="text-align:center; background: #F6CEEC;"| 3.1 %
|-
|style="text-align:left; background: #F6CEEC;"| Other factors
|style="text-align:center; background: #F6CEEC;"| 13.9 %
|style="text-align:center; background: #F6CEEC;"| 13.1 %
|style="text-align:center; background: #F6CEEC;"| 10.4 %
|-
|style="text-align:left; background: #F6CEEC;"| Unexplained factor
|style="text-align:center; background: #F6CEEC;"| 12.7 %
|style="text-align:center; background: #F6CEEC;"| 11.8 %
|style="text-align:center; background: #F6CEEC;"| 18.6 %
|-
|}
</div>

==Causative Agents==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

[[File:Follicular Development.jpeg|right|thumbnail|500px|Infertility treatments aim to facilitate follicular development and induce ovulation to improve chances of fertilisation <ref name="PMID24717179"><pubmed>24717179</pubmed></ref>]]

Normally a woman produces one egg per month from the ovaries, which travel down the Fallopian tube to be fertilized or be released from the body. In cases where women have difficulty falling pregnant, they are given medication which help them to produce and release eggs (as shown in the diagram to the right), further increasing their chances of fertilization and pregnancy <ref><pubmed>19573285</pubmed></ref>. Ovarian Hyper stimulation Syndrome generally occurs during infertility treatments when the ovaries are overstimulated by the fertility medication which causes the ovaries to swell and leak fluids into the belly and abdomen. The prevalence of OHSS onset is linked with excessive number of follicle development in response to the administration of injectable Follicle Stimulating Hormones (FSH) followed by the '''Human Chorionic Gonadotrophins''' (hCG) which triggers the release of the oocytes <ref><pubmed>26190539</pubmed></ref>.

'''Follicle Stimulating Hormones''' (FSH) <ref name="PMID9020850"><pubmed>9020850</pubmed></ref> are glycoprotein hormones that are produced and secreted from the Anterior Pituitary gland into the bloodstream, which regulate the developmental, growth, maturation and the reproductive processes within the body. In females, the Follicle Stimulating Hormones initiates the stages of growth and development of immature ovarian follicles within the ovaries before the release of an egg from a follicle at ovulation. When FSH is administered to a patient who is suffering from infertility, the increase FSH levels affect the rate of development and production, in turn increasing the amount of follicles which are ready to be released during ovulation.

</div>

==Symptoms==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

OHSS is classified based on a criteria from mild, moderate and severe <ref name="WikiOHSS" />:

'''Mild Symptoms'''- abdominal bloating, minimal weight gain, nausea, diarrhoea and a feeling of fullness.

'''Moderate Symptoms'''- Substantial weight gain (on average 2 or more pounds a day), increased abdominal girth, darkend urine and excessive thirst in addition to the mild symptoms.

'''Severe Symptoms'''- In addition to the symptoms associated with Mild and Moderate OHSS, in severe OHSS, you see shortness of breath, calf and chest pains and pleural effusion.

===<span style="font-size:100%">Classifications of Ovarian Hyper-stimulation Syndrome:</span> <ref name="PMID22065820"><pubmed>22065820</pubmed></ref>===

{| class="wikitable" style="text-align:center
|-
! scope="col" width="70px"| '''Classification'''
! scope="col" width="650px"| '''Symptoms'''
|-
|style="text-align:center; background: #F6CEEC;"| '''Mild'''
|style="height: 60px; background: #F6CEEC;"| '''Grade 1''' - Abdominal distention and discomfort
'''Grade 2''' - Abdominal distention, discomfort with nausea, vomiting and/or diarrhea and ovarian enlargement from 5~12cm
|-
|style="text-align:center; background: #F8E0F1;"| '''Moderate'''
|style="height: 60px; background: #F8E0F1;"| '''Grade 3''' - All features of Mild OHSS with ultrasonographic evidence of ascites
|-
|style="text-align:center; background: #F6CEEC;"| '''Severe'''
|style="height: 60px; background: #F6CEEC;"| '''Grade 4''' - All features of Moderate OHSS with the addition of clinical evidence of ascites and breathing difficulties present
'''Grade 5''' - All of the above symptoms along with a change in the blood volume, increased blood viscosity due to coagulation and diminished renal function
|}

</div>

==Diagnosis==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

Whilst symptoms of OHSS can occur as soon as 24 hours post hCG administration, they are usually seen in women 7-10 days post administration. Initially women with OHSS will present with abdominal bloating, as a result of fluid in the peritoneal cavity and an increase in ovary size. When women present with severe OHSS they are often dehydrated, due to increased vascular permeability, and have hemoconcentration. The above results in a decrease in intravascular volume, leading to '''oligouria''' <ref name="PMID22416285" />.

===History===

Initially a thorough history of the patient is taken during which the clinician looks for evidence of ovarian stimulation, followed by ovulation. During this history taking, the clinician will inquire into any weight gain noticed, urine output, and the woman's ability to maintain oral hydration. A key diagnostic tool for clinicians regarding women who are taking gonadotropins is to identify if they are at an increased risk of developing OHSS. Some risk factors include woman aged less than 30, women who have polycystic ovaries, woman with a previous history of OHSS and women who have had greater than 20 oocytes retrieved <ref name="PMID22416285" />.

===Physical Exam===
[[File:Vaginal_Ultrasonography_in_Sagittal_Plane.jpg|right|thumbnail|600px|Vaginal Ultrasonography in Sagittal plane <ref name="Wikiversity Journal of Medicine"> Häggström, Mikael. "Medical gallery of Mikael Häggström 2014". Wikiversity Journal of Medicine 1 (2). DOI:10.15347/wjm/2014.008. ISSN 20018762</ref>]]
After a history of the patient is taken, the next step is to perform a physical exam on the patient. Women who present with abdominal bloating will produce a shifting dullness upon abdominal percussion. Additionally the clinician will test the woman's vital signs, measure her abdominal girth, weight and will look for evidence of ascites or increase in calf size (usually unilateral)<ref name="PMID22416285" />.

===Investigations===

If the clinician further suspects a women of having OHSS, various investigations can be done such as an ultrasound.The intraperitoneal fluid is best imaged via vaginal ultrasound due to the enlarged ovaries making it difficult to image the pelvis using transabdominal ultrasound. The clinician can also order laboratory testing to look for urine specific gravity and and complete blood count to look for hemoconcentration with a hematocrit. Additionally, liver function tests can be ordered to look for elevated function. The clinician will also look for evidence of elevated D-dimers and fibrinogen and decreased levels of anti-thrombin 3 <ref name="SAHealth"> Government of South Australia Health [ http://www.sahealth.sa.gov.au/wps/wcm/connect/9b61ed004ee5348da663afd150ce4f37/Ovarian-hyperstimulation-syndrome-WCHN-PPG-17072012.pdf?MOD=AJPERES&CACHEID=9b61ed004ee5348da663afd150ce4f37 ], 'South Australian Paediatric Clinical Guidelines OHSS'</ref>.

====Ultrasound====

Typical appearances of the ultrasound include <ref name="Ultrasound"> Radiopaedia [ http://radiopaedia.org/articles/ovarian-hyperstimulation-syndrome-1 ], 'Ovarian Hyperstimulation Syndrome'</ref>:

*Bilaterally and symmetrically enlarged ovaries (>12cm)
* "Spoke-Wheel appearance" - presence of multiple cysts of varying size
*May also see ascites (fluid)

===Severity===

Once a clinician has deduced a women is suffering from OHSS, the severity of their condition needs to be established as either mild, moderate or severe. This is done by referring to the criteria under the sub-heading [[Symptoms]].The subsequent course of treatment for the woman will be based upon this evaluation.

{|
|-bgcolor="F6CEEC"
|
'''Further investigations''' can be done including a Chest X-ray to check for pleural effusions and oedema and USS with Doppler's to check for ascites or possible ovary torsion. <ref name="PMID22416285"><pubmed>22416285</pubmed></ref>
|}

===Differential Diagnosis===

Conditions presenting with similar symptoms or ultrasound images include <ref name="Ultrasound" />:

*Polycystic Ovaries (PO)
:: The difference is that with PO is that the cycts are typically smaller than OHSS cysts and there is no evidence of ascited or pleural effusion
*Mucinous Ovarian Malignancy
:: A type of Ovarian Epithelial tumour
*Ectopic Pregnancy <ref name="Casereport"> Australian Medical Student Journal [ http://www.amsj.org/wpcontent/uploads/files/articles/amsj_v2_i1/AMSJ_v2_i1_pg58-60.pdf ], 'Ovarian hyperstimulation syndrome'</ref>
::A pregnancy in which the foetus develops outside of the uterus e.g. in the fallopian tube

</div>

==Pathophysiology==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

The definition of Ovarian Stimulation is enlarged ovaries with many luteinized cysts, that can present with secondary complications. What distinguishes Ovarian Stimulation from OHSS is the presence of vascular hyper-permeability that results in fluids being redirected elsewhere in the body.

The key process to OHSS appears to be caused by '''Vascular Endothelial Growth Factor''' (VEGF), that is released along with other cytokines, estrogen and progesterone, due to the ovary undergoing luteinization as a result of stimulation by hCG. VEGF increases vascular permeability and as a result the capillaries become more "leaky" to the fluids in them. These fluids can then escape the capillaries and accumulate in the pleural and abdominal cavities as ascites. The woman then becomes hypovolemic and is at an increased risk of circulatory, renal and respiratory issues such as arterial thromboembolism due to the thickening of the blood. Note, the blood is thickened as fluid is leaving the capillaries, leaving behind red blood cells and other cellular components of the blood <ref name="WikiOHSS" />.

The increase in expression of VEGF and VEGF Receptor 2 (VEGFR2) is attributed to the greatly increased amount of their mRNA present in the body after stimulation with hCG <ref name="PMID21082502"><pubmed>21082502</pubmed></ref>. VEGF interacts with VEGF2 and VEGF Receptor 1 (VEGFR1) to create a strong angiogenic effect. Both VEGFR2 and VEGFR1 belong to a family of receptors called tyrosine kinases. VEGF2 is involved in the regulation of angiogenesis and vascular permeability whilst VEGF1 has a slightly contradictory role in that is is involved in the maintenance of the tight junctions between endothelial cells in blood vessels. A study by Gómez ''et. al.'' <ref name="PMID21082502" /> showed that women experiencing OHSS had substantially higher plasma levels of VEGF and lower levels of VEGFR1.

[[File:Pathogenesis_of_OHSS.png|600px|centre|thumb|Pathogenesis of OHSS <ref name="PMID20416867"><pubmed>20416867</pubmed></ref>]]

</div>

==Complications==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

Ovarian torsion or rupture, renal insufficiency and thrombophlebitis can all complicate OHSS. If a pregnancy occurs, symptoms may persist longer than the usual 1 to 2 weeks and become more severe, however, even with severe OHSS, they do not extend past the first trimester <ref name="WikiOHSS" />. [[File:Polycystic Ovaries.jpeg|right|thumbnail|360px|Comparison of Normal and Polycystic Ovary]]

<span style="color:#FA58D0"> '''1-2% of women who undergo ovarian stimulation develop a severe form of OHSS''' </span>. Complications from severe OHSS include:

*Fluid collection in the abdomen
*Electrolyte disturbances (sodium and potassium)
*Kidney failure
*Ovary twisting
*Rupture of a cyst in an ovary
*Breathing problems
*Blood clots in large vessels (most commonly the legs)
*Pregnancy loss from miscarriage or termination
*Rarely, death

A study by Nouri ''et. al.'' <ref name="PMID24996451"><pubmed>24996451</pubmed></ref> found that women with '''Polycystic Ovarian Syndrome''' (PCOS) and those that were induced with hCG experienced longer recovery times from severe OHSS than women who were not pregnant. They looked at a cohort of women hospitalised for the first time with severe OHSS and subject them to the same treatments. Based on a defined criteria, they established the recovery time of these women and compared the times between those that were pregnant to those that were not pregnant. They also found that whether a woman had PCOS or ovulation induction did not affect her risk of developing OHSS if she was not pregnant. It is only a risk factor for pregnant women.

===Thromboembolic events===

A frequent and deadly complication of OHSS are thromboembolic events due to increased blood clotting. This increase in blood clotting has been attributed to a variety of complications such as hemoconcentration (which thickens the blood), hypovolemia and an increase in the permeability of blood vessels as a result of increased vasoactive substances in the body of ovarian origin. Thromboembolic events include venous thromboses often in the upper extremities and arterial thromboses such as those in the cerebrovascular region. These events can lead to amputations of extremities, brain damage, miscarriage and death. To avoid this, anti-coagulants are given to pateitns with OHSS and they are fitted with compression stockings (see [[Treatment]]) <ref name="PMID23378404"><pubmed>23378404</pubmed></ref>.

{|
|-bgcolor="F8E0F1"
|
The risk of a woman developing OHSS is higher if she is having a '''twin pregnancy''', as she is exposed to higher concentration of hCG. <ref name="PMID9756273"><pubmed>9756273</pubmed></ref>
|}

</div>

==Treatment==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

'''General treatment
'''
*''Acetaminophen'' with or without a narcotic agent- used to treat abdominal discomfort
*Women are encouraged to drink 2-3 litres of water a day to prevent hemoconcentration
*Women are advised to avoid sexual intercourse and vigorous exercise at the risk of torsion or rupture of the ovaries
*NSAID's with anti-platelet properties should NOT be used as they may effect renal function in a women with OHSS
*Patients with significantly painful ascites or breathing problems may undergo ''Paracentesis'' (drainage of the ascites)
*''Culdocentesis'' (extraction of fluid from recto-uterine pouch) can be done to decrease the likelihood of a woman with moderate OHSS progressing to severe OHSS.<ref name="PMID22416285" />

===Mild to Moderate OHSS===

Mild OHSS can often resolve on its own, however, moderate OHSS may include treatments such as<ref name="WikiOHSS" />:

*Anti-nausea medication and prescription painkillers
*Regular physical examinations and ultrasounds
*Daily weigh-ins and waist measurements
*Measuring the amount of urine produced each day
*Frequent blood tests for monitoring dehydration and electrolyte imbalance
*Maintaining a high balance of fluids
*Drainage of excess abdominal fluid by inserting a needle in the abdominal cavity
*Wearing support stockings which help prevent blood clots/thrombosis

===Severe OHSS===

[[File:Abdominal Paracentesis.png|thumb|right|350px|Paracentesis is a common procedure done on women who have OHSS as it is used to drain the ascites in their abdomen. In this image you can see the puncture of the peritoneal cavity with a needle that then drains the fluid externally. <ref name="Wikiversity Journal of Medicine"> Blausen.com staff. "Blausen gallery 2014". Wikiversity Journal of Medicine. DOI:10.15347/wjm/2014.010. ISSN 20018762 </ref>]]

Severe OHSS requires hospital care in order for constant monitoring and treatment such as <ref name="WikiOHSS" />:

*Intravenous fluids with a crystalloid solution (100-150mL/hr)
*Intravenous Albumin is administered is IV fluids are insufficient (15-20mL/hr of 25% albumin for 4 hrs)
*In addition to Acetaminophen, ''Opioid analgesics'' can be administered for pain relief
*''Antiemetics'' can be used to subside nauseas and/or vomiting
*Woman administered to hospital of OHSS are considered at high risk of thromboembolic complications and are given low molecular weight ''heparin'', an anti-coagulant
*''Cabergoline''- lessens OHSS symptoms
*''GnRH agonist''- suppresses ovarian activity
**If at risk of OHSS, alternates include using a GnRH agonist instead of hCG however its effects on pregnancy rates are questionable. Using a GnRH agonist to replace the use of hCG for final oocyte stimulation will see a 6% decrease in delivery rate.
*Daily monitoring of creatine, urea, creatine clearance C-reactive protein (to rule out infection) are all required in combination with weekly tests such as liver and renal function tests and chest x-rays (to check for pleural effusion) <ref name="PMID12638783" />.

If there are serious complications then additional treatments are required:

*Surgery for a ruptured ovarian cyst
*Intensive care for the liver or lung complications

====Paracentesis====

For women with severe/grade 3 OHSS, paracentesis, the removal of fluid from the body using an aspiration needle, can be undertaken. It is a diagnostic and a therapeutic method that can be done trans-abdominally and trans-vaginally. It is used to relieve symptoms, improve haemodynamics e.g. Urinary output, and shorten the women's hospital stay. Complications of paracentesis include bleeding, infection and organ injury, however are note common <ref name="Paracentesis"> S. Monica Soni, HMS 3, Gillian Lieberman, MD [ http://eradiology.bidmc.harvard.edu/LearningLab/genito/Soni.pdf ], 'Ovarian Hyperstimulation Syndrome'</ref>.

{|
|-bgcolor="F8E0F1"
|
The most important aspect of treatment for any women with OHSS is close and constant '''monitoring''' with her healthcare professional. Counselling may also be provided to women and their partners or families in order to provide them with the best possible knowledge base to manage and treat their OHSS. It is important to note that there is '''no one cure or treatment''' for OHSS. Treatment involves managing and eliminating the symptoms until such time as the syndrome resolves itself <ref name="WikiOHSS" />.
|}

</div>

==Prevention==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

There are three key avenues through which the incidence of OHSS may be prevented. These include identifying risk factors to predict OHSS development, modifying treatment regimes on the basis of the identified risk factors and intervention to prevent progression to OHSS once the patient has undergone '''Controlled Ovarian Stimulation''' (COS).

=== Risk factors===

'''Primary risk factors'''

Pre-existing factors likely to exacerbate the ovarian stimulation response. Primary risk factors include <ref name="PMID26074966"><pubmed>26074966</pubmed></ref>:

*Young age
*Low body weight
*History of elevated response to gonadotropins
*Polycystic Ovary Syndrome (PCOS)
*Isolated PCOS characteristic
*Previous history of OHSS.
*High pretreatment basal Anti-Mullerian Hormone (AMH) concentration
*Large Antral Follicle Count (AFC)

'''Secondary risk factors'''

Secondary risk factors involve the monitoring of ovarian response parameters once COS has been initiated. These parameters are monitored for <ref name="PMID19007627"><pubmed>19007627</pubmed></ref>:

*rapidly rising E2 levels
*E2 concentration larger than 2500 pg/mL
*large number of developing follicles (10-14mm) on the day hCG is administered
*large number of oocytes retrieved

These factors in combination, act as a predictive tool to assess the likelihood of severe OHSS development, with a 83% sensitivity and 84% specificity. <ref name="PMID19007627"/>

=== Primary Prevention===
[[File:Severe OHSS Prevention.jpeg|right|thumbnail|400px|GnRH antagonists, embryo cryopreservation and cycle cancellation are key strategies in preventing OHSS progression in high-risk patients <ref name="PMID22938051"><pubmed>22938051</pubmed></ref>]]

Primary Prevention involves the modification of treatment regimens on the basis of OHSS risk classifications, in order to prevent OHSS occurrence.

'''Ovulation Induction'''

Unifollicular Ovulation Induction through Ovulation Induction (OI) is a primary means of avoiding OHSS in women with Polycystic Ovarian Syndrome, who are at an increased risk. In order to promote unifollicular development, the ovaries are stimulated with a low starting dose of FSH (75 IU).<ref name="PMID20416867"><pubmed>20416867</pubmed></ref> Studies suggests that a minimum gonadotropin dose lowers OHSS risk and thus a step-up regimen is utilised to achieve an ovarian response, whereby the FSH dosage is increased every 7 days until follicular development of greater than 10mm is noted.<ref name="PMID26074966" /> Alternatively, a step-down regimen may be followed, whereby a high initial FSH dosage is lowered according to the ovarian response. Another method to increase FSH levels during OI, is through '''Aromatase Inhibitors''' which promote folliculogenesis by increasing pituitary secretion of FSH, and downregulate oestrogen production through a negative feedback loop. However, Aromatase Inhibitors have not been shown to reduce OHSS incidence in comparison to other methods of OI.<ref name="PMID26074966" /> During OI, a key objective is to prevent early cycle cancellation due to premature luteinisation from pituitary secretion of LH. In order to downregulate LH secretion, '''Gonadotropin-releasing hormone agonists''' (GnRHa) are administered in addition to gonadotropins. Alternatively, '''GnRH antagonists''', which have a rapid onset of action, may be administered to downregulate endogenous LH secretion, with relative success as depicted in the diagram to the right.<ref name="PMID20416867" /> Comparative studies have shown that the GnRH antagonist protocol has a greater effect in lowering the incidence of mild to severe OHSS. However due to the rare nature of OHSS, and insufficient sample sizes, the difference was not found to be significant. <ref name="PMID21082508"><pubmed>21082508</pubmed></ref>. Generally, the duration of exposure to gonadotropins and subsequent risk of OHSS may be minimised through mild stimulation protocols which administer FSH only in the mid to late follicular phase.<ref name="PMID20416867" />

'''Adjuvant Metformin Therapy'''

Adjuvant Metformin Therapy has been found to lower the risk of OHSS by 63%.<ref name="PMID25406011"><pubmed>25406011</pubmed></ref> It involves the administration of metformin at a daily dosage of 1000 to 2000mg, 2 months prior to Controlled Ovarian Stimulation <ref name="PMID26074966"/>. Metformin lowers the elevated insulin levels in PCOS which consequently reduce intraovarian androgen levels. This leads to a reduced sensitivity and expression of granulosa cell-follicle stimulating hormone receptors which result in a less exaggerated response to gonadotropins. Furthermore, it is suggested that Metformin prevents OHSS by controlling vascular permeability through the inhibition of various vasoactive molecules, including VEGF.

'''Avoiding hCG during Luteal Phase Support

Following Controlled Ovarian Stimulation, the steroid levels of E2 and P4 are reduced during the luteal phase due to the negative feedback on the pituitary. This leads to low endogenous LH levels, which consequently reduce endometrial receptivity as well as the luteal phase duration itself. As a result, implantation and pregnancy rates are reduced and early pregnancy loss rates are increased.<ref name="PMID20416867" /> Luteal Phase Support (LPS) serves to combat these adverse events with the use of hCG. However, hCG has been found to increase the risk of OHSS. Alternatively, the use of progesterone has been found to not only halve the risk of OHSS, but also induce similar improvements in pregnancy and miscarriage rates as hCG.<ref name="PMID26148507"><pubmed>26148507</pubmed></ref>

===Secondary Prevention===

Secondary Prevention aims to prevent progression to OHSS once COS has been initiated and the patient has been found to mount an exaggerated response. <ref name="PMID20416867" />

'''Coasting'''

Coasting is a first-line secondary preventative strategy. It consists of the withdrawal of gonadotrophins when a critical number of follicles and/or E2 concentration is reached. hCG is administered once the E2 concentration reduces to a safe level, before the process of oocyte retrieval commences. This preventative strategy is conducted for a period of less than 3 days in order to avoid compromising IVF outcomes.<ref name="PMID26074966"/>

[[File:Cryopreservation of Porcine Embryos.jpeg|right|thumbnail|300px|Cryopreserved embryos of the swine model<ref name="PMID26309801"><pubmed>4497712</pubmed></ref>]]

'''Cryopreservation'''

Cryopreservation of embryos after oocyte retrieval is another avenue which may avert OHSS progression. The cryopreserved embryos are only reimplanted once the patient's hormone serum levels have normalised. Using oocyte vitrification, crystal formation within embryo tissue is avoided and so cryopreserved embryos have been found to produce better pregnancy rates with a 32% increase, than fresh embryo transfer.<ref name="PMID26074966"/> Recent studies suggest cryopreservation itself does not reduce OHSS rates, but must be followed by a GnRHa trigger to avert OHSS.<ref name="PMID24753847"><pubmed>24753847></ref>

'''Cycle cancellation'''

Cycle cancellation is a guaranteed method to prevent early OHSS whereby hCG is withheld. This is a last resort strategy as it carries the risk of significant psychological distress and financial loss for the patient. <ref name="PMID20416867"/>

</div>

==Effect on the Newborn==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

</div>
Women who develop OHSS while undergoing Assisted Reproductive Technologies (ART) treatment are not only more likely to achieve a pregnancy, but have a live birth as the pregnancy outcome. This live birth is also more likely to be a multiple birth of two, three or more children. <ref name="PMID19591989"><pubmed>19591989</pubmed></ref> It has been postulated that a multi-fetal pregnancy leads to a more rapid increase in hCG levels, resulting in an increased risk of OHSS. However, the causal nature between multi-fetal pregnancy and OHSS development is disputed and further research is required to distinguish correlation from causation. <ref name="PMID19573292"><pubmed>19573292</pubmed></ref>

OHSS development is also associated with an increased risk of adverse outcomes including '''stillbirth, premature birth and low birth weight'''.<ref name="PMID19591989" /> Although the cause for the increased risk in adverse pregnancy outcomes is unknown, it is suggested that as the incidence of OHSS is reduced through various prevention strategies, the risk of such outcomes may be also be reduced.

'''<span style="color:#FA58D0"> [http://pregnancyperfect.com/emilyley/ The following link is to a podcast of a woman describing her pregnancy in which she underwent IVF, had OHSS and gave birth to healthy twins]<ref name="Emily"> Pregnancy Perfect[ http://pregnancyperfect.com/emilyley/ ], 'TWINS, IVF, OHSS AND C-SECTION WITH EMILY LEY'</ref> </span>'''

==Genetics==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

Despite OHSS typically being of iatrogenic origin as a result of ovarian stimulation with gonadotropins, research has been conducted into the potential genetics behind OHSS as many sporadic and familial cases have been observed. '''Mutations''' in the receptor for hormones such as Follicle Simulating Hormone (FSH), Lutenizing Hormone (LH) and hCG have all been targets of OHSS genetics research. Interestingly, they too also arise from a common ancestral gene.

===Follicle Stimulating Hormome===

Dr. Botros Rizk, of the University of South Alabama College of Medicine <ref name="PMID19573286"><pubmed>19573286</pubmed></ref>, has written extensively regarding the genetics behind OHSS. In particular, he talks about '''FSH receptors''' (FSHR) and their role in the syndrome. He hypothesises that mutations in these receptors could be activating or inactivating, leading to an increased risk of developing OHSS or sterility respectively. Currently, 744 single nucleotide polymorphisms (a type of mutation) have been found in the gene encoding the FSHR, 8 of which are located in its exons (coding regions of the gene). How the ovary responds is resultant on the FSHR genotype. For example, Ser680Asn, a polymorphism in the FSHR gene has been shown to aid in predicting the severity of a woman's OHSS. Ordinarily FSH stimulates the growth of ovarian follicles, however, when mutated, it is stimulated by the hCG resulting in excessive follicle development.

Spontaneous OHSS, OHSS that arises and cannot be attributed to any form of ovarian stimulation or Assisted Reproductive Technology, has been linked to activating mutations in the FSHR <ref name="PMID23499866"><pubmed>23499866</pubmed></ref>. This familial disorder is an autosomal dominant one. In most cases the FSHR can be stimulated by the presence of Thyroid Stimulating Hormone (TSH) or hCG, in the absence of FSH (the ligand for FSHR).

[[File:FSHR Gene.jpg|centre|thumbnail|700px|This image depicts the location of the FSHR Gene on chromosome 2. It is located on the short arm between positions 21 and 16. Changed to the FSHR gene has been linked to OHSS. <ref name="Genetcis"> Genetics Home Reference [http://ghr.nlm.nih.gov/gene/FSHR'</ref>]]

===Lutenizing Hormome===

The '''Lutenizing Hormone Receptor''' (LHR) gene in humans is comprised of 11 exons. Animal studies have shown that many primates exhibit a similar gene which is comprised of only 10 exons, however a gene lacking the 10th exon has been identified and termed the type 2 LHR. Expression of the type 2 LHR has been seen in humans. The type 2 LHR, compared to the wild-type LHR appears to be repaired with regard to its function. Defects in the type 2 LHR include a decrease in efficiency of transport to the plasma membrane and irregularities in signal transduction. Inactivating mutations in the LHR have been seen to cause infertility in women as well as amenorrhoea. Activating LHR gene mutations are asymptomatic and are not associated with OHSS in women.

===Bone Morphogenic Protein===

An imporant growth factor, derived from oocytes called '''BMP-15''' (Bone Morphogenic Protein 15) is vital for female fertility. It belongs to the family of growth factors, Transforming Growth Factor β (TGF-β) and is heavily involved in folliculogenesis. It has been found that mutations in the BMP-15 gene caused infertility in female sheep. Conversely, it has also been indicated in enhanced fertility when BMP-15 is present is high amounts in follicular fluid <ref name="PMID19573286" />.

A case study done by Hanevik ''et. al.'' in 2013 <ref name="PMID21565556"><pubmed>21565556</pubmed></ref> found that a Single Nuclear Polymorphism (SNP) in the BMP-15 gene is responsible for a high response to ovarian hyper-stimulation. The aim of the study was to test the effect the SNP had on BMP-15 with regard to high and low responders buy taking blood from 53 high responders, 38 low responders and 100 non-responders (controls) and analysing 5 noted SNP's. Results from their study showed a correlation between a high response to ovarian hyper-stimulation and the BMP-15 9G allele. The article does state however, that further research is required into the molecular effects of SNP's on the function of BMP-15.

===Vascular Endothelial Growth Factor===

'''Vascular endothelial growth factor''' (VEGF) has been indicated as one of the key agents causing vascular permeability and subsequent ascites in OHSS. The gene, which is located on chromosome 12, is made up of 8 exons (coding regions), of which exons 6 and 7 do not always appear due to the exons being spliced out.The splicing of this gene allows for various isoforms of the gene to exist of which VEGF 121 and 165 appear to play a role in angiogenesis. There are two VEGF Receptors, VEGFR-1 and VEGFR-2 that belong to the tyrosine kinase family of receptors (for more information on VEGF see [[Pathophysiology]]). Because of its distinct role in OHSS, it has been targeted as an area for research for potential treatments. The idea is that if the genetic expression of VEGF and its receptors can be controlled, OHSS can be avoided or treated.<ref name="PMID19573286" />

A different study by Hanevik ''et. al.'' , <ref name="PMID22587628"><pubmed>22587628</pubmed></ref> done in 2012 involved analysing blood samples from 53 women with OHSS and 100 women without it (controls) and analysing 6 SNP's in the VEGFR2 gene to find any genetic variations. They found a correlation between women with the VEGF +405cc genotype and the development of OHSS indicating women that undergo controlled ovarian hyper-stimulation and posses his genotype, are at an increased risk of developing OHSS.

</div>

== Current Research on Animal Models==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

{|
|-bgcolor="FFF5FF"
|<span style="font-size:120%">'''Inhibition of Cyclooxygenase-2 (COX-2) by Meloxican decreasing the incidence of OHSS in Rat Model'''</span> <ref name="PMID18166186"><pubmed>18166186</pubmed></ref>

Reasearch was carried out to investigate the effects of selective inhibition of the enzyme COX-2 on the Ovarian Hyperstimulation Syndrome (OHSS) using Female Wistar rates as the subjects. The research aimed to find results by measuring the number of antral and luteinized follicles, ovarian weight, vascualr endothelial growth factors and COX-2 immunohistochemistry. The rats being tested were all 22 days old and were divided into four equal groups;

'''Group 1 (Control group)''' was subject to a 0.1 ml of Intraperitoneal Saline from days 22 ~ 26

'''Group 2 (Mildly-stimulated group)''' subject to 10IU of pregnant mare serum gonadotrophin (PMSG) on day 24 and then 10IU of Human Chorionic Gonadotrophin (hCG) on day 26

'''Group 3 (OHSS positive group)''' was subject to 10IU of PMSG from days 22 ~ 26 and then administered 30IU of hCG on day 26 to induce OHSS

'''Group 4 (OHSS positive variant group)''' received 15mg/ml of Meloxicam 2 hours prior to administration of 10IU PMSG from days 22 ~ 26

Results showed there was no difference in ovarian weight in samples from Group 1 and Group 2, however Group 3 showed signs of significant ovarian weight increase which in group 4 was suppressed by the introduction of Meloxicam. No differences were observed in the number of antral follicles amongst the four test groups. Results from Group 2 and Group 3 showed that the granulosa cells of preovulatory follicles and the stromal cells were highly VEGF immunoreactive, however the Meloxicam treated Group 4 showed less immunoreactivity than Group 2 and Group 3 which indicated the correlation between Meloxicam and the diminished VEGF expression. Group 3 presented an increased COS-2 immunoreactivity which was highly diminished than in Group 4.

The research concluded that in a rat model, the enzyme Meloxicam has a beneficial effect on OHSS by reducing the increase of ovarian weight and the expression of VEGF associated with OHSS, the effects of which may be mediated by the inhibitory capacity of COX-2 on Meloxicam
|}

{|
|-bgcolor="FFF5FF"
|<span style="font-size:120%">'''Inhibition of Ovarian VEGF secretion by activation of Dopamine Receptor 2'''</span> <ref name="PMID25217874"><pubmed>25217874</pubmed></ref>

This research was carried out to investigate a possibility in whether a Dopamine Receptor 2 agonist '''(D2-ag)''' can assist in the prevention of Ovarian Hyperstimulation Syndrome, using rat models, by decreasing the ovarian vascular endothelial growth factor '''(VEGF)''' production. Using Immature Wistar rats (22 days old) as their animal model, the rats were initially stimulated with Gonadotrophins to mimic the onset and effects of OHSS and then subjected to treatment with a D2-agonist and/or a D2-antagonist (D2-ant). The vascular permeability was measured at the endpoint after day 26 by measuring the peritoneal extravasion of a previously injected dye and ovaries from all subjects were collected to assess the effects of D2-ag and D2-ant on the production of Ovarian VEGF. The expression of VEGF mRNA was measured by quantitative real time PCR and the levels of VEGF proteins were measured by Western Blots.

Results showed that the D2-ag caused a large reduction in the vascular permeability which was in turn associated with the great decreased in VEGF protein production in the OHSS rat ovaries, whereas the introduction of D2-ant showed opposite results with a increase in the vascular permeability leading to the increase of VEGF protein production in the ovaries. Ovarian VEGF mRNA levels were found to be unaffected by the introduction of these drugs in OHSS rat subjects. Conclusions were drawn on the fact that Dopamine Receptor 2 agonists prevent the increase of vascular permeability in subjects with OHSS by decreasing the ovarian production of VEGF and also that due to the dose-dependent inhibitory effect of the D2-ag on ovarian VEGF, current OHSS therapies used in humans can benefit by increasing the intraovarian concentration of D2-ag.
|}

</div>

==Glossary==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

'''Aromatase Inhibitor''' - A drug that inhibits enzyme aromatase, which in turn suppresses estrogen synthesis.

'''Ascites''' - An accumulation of fluid in the peritoneal cavity with resultant abdominal swelling.

'''Cabergoline''' - A dopamine receptor agonist used to treat hormone imbalance.

'''Controlled Ovarian Stimulation''' - female infertility treatment using medications to stimulate the ovaries to develop follicles.

'''Cryopreservation''' - Cooling and storing biological material at extremely low temperatures.

'''E2''' - Estradiol - Potent estrogen sex hormone.

'''FSH''' - Follicle Stimulating Hormone

'''Gonadotropin''' - Any hormone that has a stimulating effect on the gonads.

'''GnRH agonist''' - Gonadotropin Releasing Hormone - A class of compounds that mimic the effect of the natural Gonadotropin Releasing Hormone.

'''GnRH antagonist''' - Gonadotropin Releasing Hormone - A class of compounds that are similar in terms of the structure of natural Gonadotropin Releasing Hormone but has a antagonistic effect.

'''hCG'''- Human Chorionic Gonadotropin

'''Hemoconcentration''' - An increase in the concentration of circulating red blood cells in response to a decrease in blood plasma volume.

'''Hypovolemic''' - A decrease in circulating blood volume.

'''Iatrogenic''' - Illness caused as a result of a medical examination or treatment.

'''Intravenous fluids''' - Is the infusion of liquid substances directly into a vein.

'''IVF''' - In-vitro Fertilization

'''LH''' - Luteinizing Hormone

'''Metformin''' - A biguanide, antidiabetic drug used as an adjuvant to modify the effect of other agents.

'''NSAID''' - Non-steroidal Anti-Inflammatory Drug e.g. Ibuprofen

'''Oocyte vitrification''' - technique for cryopreservation of oocytes.

'''OHSS''' - Ovarian Hyper-stimulation Syndrome

'''Oliguria'''- Decreased urine output/small amounts of urine produced.

'''P4''' - Progesterone - endogenous progestogen sex hormone.

'''PCOS''' - Polycystic Ovarian Syndrome. An endrocrine system disorder whereby the ovaries are enlarged with small collections of fluid.

</div>

==References==

2015 Group Project 2

2015-10-23T16:29:53Z

Z3372824:

{{ANAT2341Project2015header}}

==<span style="font-size:120%">'''Ovarian Hyper-stimulation Syndrome (OHSS)'''</span>==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

Ovarian Hyper stimulation Syndrome (OHSS) is an iatrogenic complication of '''Assisted Reproduction Technology''' (ART), in which women take medications to stimulate oocyte growth. It is generally identified by cystic enlargements of the ovaries and fluid accumulation in the peritoneal cavity due to the increased capillary permeability and ovarian neoangiogenesis <ref name="PMID22065820"><pubmed>22065820</pubmed></ref>. It is an occurrence which is dependent on the controlled stimulation of the ovaries in preparation for IVF i.e. administration of human Chorionic Gonadotropin (hCG).

OHSS was first described in 1943 as ''“syndrome d’hyperluteinisation massive des ovaries”''. It was during this time that gonadotropins were prepared from animals such as sheep to bring on ovulation in women. The first recorded death as a result of OHSS occurred in 1951 and was due to renal failure as a result of oligouria, a complication of the syndrome <ref name="OHSS"> Marie M. Budev, DO, MPH; Alejandro C. Arroliga, MD; Tommaso Falcone, MD, [ http://utilis.net/Morning%20Topics/REI/Ovarian%20Hyperstimulation.pdf ], 'Ovarian Hyperstimulation Syndrome'</ref> <ref name="PMID12638783"><pubmed>12638783</pubmed></ref>.

<span style="color:#FA58D0">'''This wikipage aims to provide clear information on various areas surrounding OHSS such as diagnosis, prevention and complications and will look into the genetics behind the disorder and the various animals models used to research it'''.</span>

<html5media height="350" width="450">https://www.youtube.com/watch?v=aXmjJw234a4</html5media>

'''Overview of Ovarian Hyperstimulation Syndrome''' <ref> Howcast (2013, August 27) Ovarian Hyperstimulation Syndrome | Infertility. Retrieved from https://www.youtube.com/watch?v=aXmjJw234a4</ref>

</div>

==Epidemiology==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

Ovarian Hyper-Stimulation Syndrome (OHSS) rarely occurs sporadically, and if it does, it is usually the result of an underlying genetic problem. The majority of OHSS is due to the ovaries being stimulated to mature and release an abundance of oocytes, in response to hormones Human Chorionic Gonadotropin (hCG) and Follicle Stimulating hormone (FSH), during IVF. Rarely, Clomifene Citrate therapy can cause OHSS.<ref name="WikiOHSS"> Wikipedia, [ https://en.wikipedia.org/wiki/Ovarian_hyperstimulation_syndrome ], 'Ovarian Hyperstimulation Syndrome'</ref>

OHSS only affects '''0.5-5%''' of women undergoing Ovarian Hyper-stimulation, but despite its small prevalence, it is a potentially fatal outcome of a non-vital procedure and remains a prevalent problem for fertility specialists <ref name="PMID12498425"><pubmed>12498425</pubmed></ref> <ref name="PMID12638783"><pubmed>12638783</pubmed></ref>. Age has been cited as a factor affecting those with OHSS, with younger women more at risk. Additionally, women with allergies were seen to have a higher incidence of OHSS. It is important to note that at this point in time, there is no positive correlation between gonadotropin dose and OHSS.

Of the 0.5-5% of women affected with OHSS mentioned above, 2% of those women will require hospitalisation. As of 2011, it has been reported that the incidence of OHSS was '''increasing''', resulting in approximately 3 deaths per 100,000 women undergoing ovarian stimulation per year <ref name="PMID21828116"><pubmed>21828116</pubmed></ref>. This is particularly worrying as in 2008, in the United States alone, there were around 150,000 IVF cycles undertaken.

{|
|-bgcolor="F8E0F1"
|
'''With the field of Assisted Reproductive Technologies expanding and more women partaking in IVF treatments, the threat of women developing OHSS is an ongoing and increasing one''' <ref name="PMID21828116" />.
|}
{| class="wikitable mw-collapsible mw-collapsed"
! colspan=4|Characteristics of women with OHSS by complication group <ref name="PMID19591989"><pubmed>19591989</pubmed></ref>
|-
! scope="col" width="100px" height="60px" style="text-align:center| '''Characteristic'''
! scope="col" width="100px" height="60px" style="text-align:center| '''No Complications
(N = 212,041)'''
! scope="col" width="100px" height="60px" style="text-align:center| '''Moderate OHSS
(N = 1,523)'''
! scope="col" width="100px" height="60px" style="text-align:center| '''Severe OHSS
(N = 655)'''
|-
|style="text-align:center; background: #FF99FF;"| '''Maternal Age (Mean ± SD)'''
|style="text-align:center; background: #F6CEEC;"| 35.6 ± 4.6
|style="text-align:center; background: #F6CEEC;"| 33.0 ± 4.3
|style="text-align:center; background: #F6CEEC;"| 33.1 ± 4.4
|-
|style="text-align:center; background: #FF99FF;"| '''Maternal Age (%)'''
|-
|style="text-align:left; background: #F6CEEC;"| <30 years
|style="text-align:center; background: #F6CEEC;"| 10 %
|style="text-align:center; background: #F6CEEC;"| 21.1 %
|style="text-align:center; background: #F6CEEC;"| 20.6 %
|-
|style="text-align:left; background: #F6CEEC;"| 30-34 years
|style="text-align:center; background: #F6CEEC;"| 30.4 %
|style="text-align:center; background: #F6CEEC;"| 43.2 %
|style="text-align:center; background: #F6CEEC;"| 40.5 %
|-
|style="text-align:left; background: #F6CEEC;"| 35-39 years
|style="text-align:center; background: #F6CEEC;"| 37.8 %
|style="text-align:center; background: #F6CEEC;"| 27.2 %
|style="text-align:center; background: #F6CEEC;"| 32.5 %
|-
|style="text-align:left; background: #F6CEEC;"| >40 years
|style="text-align:center; background: #F6CEEC;"| 21.8 %
|style="text-align:center; background: #F6CEEC;"| 8.4 %
|style="text-align:center; background: #F6CEEC;"| 6.4 %
|-
|style="text-align:center; background: #FF99FF;"| '''Nulligravida (%)'''
|style="text-align:center; background: #F6CEEC;"| 45.8 %
|style="text-align:center; background: #F6CEEC;"| 51.5 %
|style="text-align:center; background: #F6CEEC;"| 51.8 %
|-
|style="text-align:center; background: #FF99FF;"| '''Infertility Diagnosis (%)'''
|-
|style="text-align:left; background: #F6CEEC;"| Male factor
|style="text-align:center; background: #F6CEEC;"| 37.7 %
|style="text-align:center; background: #F6CEEC;"| 41.0 %
|style="text-align:center; background: #F6CEEC;"| 33.4 %
|-
|style="text-align:left; background: #F6CEEC;"| Endometriosis
|style="text-align:center; background: #F6CEEC;"| 13.5 %
|style="text-align:center; background: #F6CEEC;"| 13.5 %
|style="text-align:center; background: #F6CEEC;"| 10.7 %
|-
|style="text-align:left; background: #F6CEEC;"| Ovulation Disorders
|style="text-align:center; background: #F6CEEC;"| 14.0 %
|style="text-align:center; background: #F6CEEC;"| 29.5 %
|style="text-align:center; background: #F6CEEC;"| 22.4 %
|-
|style="text-align:left; background: #F6CEEC;"| Diminished ovarian reserve
|style="text-align:center; background: #F6CEEC;"| 16.9 %
|style="text-align:center; background: #F6CEEC;"| 3.2 %
|style="text-align:center; background: #F6CEEC;"| 2.4 %
|-
|style="text-align:left; background: #F6CEEC;"| Tubal factors
|style="text-align:center; background: #F6CEEC;"| 20.4 %
|style="text-align:center; background: #F6CEEC;"| 22.6 %
|style="text-align:center; background: #F6CEEC;"| 22.3 %
|-
|style="text-align:left; background: #F6CEEC;"| Uterine factors
|style="text-align:center; background: #F6CEEC;"| 5.1 %
|style="text-align:center; background: #F6CEEC;"| 4.3 %
|style="text-align:center; background: #F6CEEC;"| 3.1 %
|-
|style="text-align:left; background: #F6CEEC;"| Other factors
|style="text-align:center; background: #F6CEEC;"| 13.9 %
|style="text-align:center; background: #F6CEEC;"| 13.1 %
|style="text-align:center; background: #F6CEEC;"| 10.4 %
|-
|style="text-align:left; background: #F6CEEC;"| Unexplained factor
|style="text-align:center; background: #F6CEEC;"| 12.7 %
|style="text-align:center; background: #F6CEEC;"| 11.8 %
|style="text-align:center; background: #F6CEEC;"| 18.6 %
|-
|}
</div>

==Causative Agents==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

[[File:Follicular Development.jpeg|right|thumbnail|500px|Infertility treatments aim to facilitate follicular development and induce ovulation to improve chances of fertilisation <ref name="PMID24717179"><pubmed>24717179</pubmed></ref>]]

Normally a woman produces one egg per month from the ovaries, which travel down the Fallopian tube to be fertilized or be released from the body. In cases where women have difficulty falling pregnant, they are given medication which help them to produce and release eggs (as shown in the diagram to the right), further increasing their chances of fertilization and pregnancy <ref><pubmed>19573285</pubmed></ref>. Ovarian Hyper stimulation Syndrome generally occurs during infertility treatments when the ovaries are overstimulated by the fertility medication which causes the ovaries to swell and leak fluids into the belly and abdomen. The prevalence of OHSS onset is linked with excessive number of follicle development in response to the administration of injectable Follicle Stimulating Hormones (FSH) followed by the '''Human Chorionic Gonadotrophins''' (hCG) which triggers the release of the oocytes <ref><pubmed>26190539</pubmed></ref>.

'''Follicle Stimulating Hormones''' (FSH) <ref name="PMID9020850"><pubmed>9020850</pubmed></ref> are glycoprotein hormones that are produced and secreted from the Anterior Pituitary gland into the bloodstream, which regulate the developmental, growth, maturation and the reproductive processes within the body. In females, the Follicle Stimulating Hormones initiates the stages of growth and development of immature ovarian follicles within the ovaries before the release of an egg from a follicle at ovulation. When FSH is administered to a patient who is suffering from infertility, the increase FSH levels affect the rate of development and production, in turn increasing the amount of follicles which are ready to be released during ovulation.

</div>

==Symptoms==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

OHSS is classified based on a criteria from mild, moderate and severe <ref name="WikiOHSS" />:

'''Mild Symptoms'''- abdominal bloating, minimal weight gain, nausea, diarrhoea and a feeling of fullness.

'''Moderate Symptoms'''- Substantial weight gain (on average 2 or more pounds a day), increased abdominal girth, darkend urine and excessive thirst in addition to the mild symptoms.

'''Severe Symptoms'''- In addition to the symptoms associated with Mild and Moderate OHSS, in severe OHSS, you see shortness of breath, calf and chest pains and pleural effusion.

===<span style="font-size:100%">Classifications of Ovarian Hyper-stimulation Syndrome:</span> <ref name="PMID22065820"><pubmed>22065820</pubmed></ref>===

{| class="wikitable" style="text-align:center
|-
! scope="col" width="70px"| '''Classification'''
! scope="col" width="650px"| '''Symptoms'''
|-
|style="text-align:center; background: #F6CEEC;"| '''Mild'''
|style="height: 60px; background: #F6CEEC;"| '''Grade 1''' - Abdominal distention and discomfort
'''Grade 2''' - Abdominal distention, discomfort with nausea, vomiting and/or diarrhea and ovarian enlargement from 5~12cm
|-
|style="text-align:center; background: #F8E0F1;"| '''Moderate'''
|style="height: 60px; background: #F8E0F1;"| '''Grade 3''' - All features of Mild OHSS with ultrasonographic evidence of ascites
|-
|style="text-align:center; background: #F6CEEC;"| '''Severe'''
|style="height: 60px; background: #F6CEEC;"| '''Grade 4''' - All features of Moderate OHSS with the addition of clinical evidence of ascites and breathing difficulties present
'''Grade 5''' - All of the above symptoms along with a change in the blood volume, increased blood viscosity due to coagulation and diminished renal function
|}

</div>

==Diagnosis==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

Whilst symptoms of OHSS can occur as soon as 24 hours post hCG administration, they are usually seen in women 7-10 days post administration. Initially women with OHSS will present with abdominal bloating, as a result of fluid in the peritoneal cavity and an increase in ovary size. When women present with severe OHSS they are often dehydrated, due to increased vascular permeability, and have hemoconcentration. The above results in a decrease in intravascular volume, leading to '''oligouria''' <ref name="PMID22416285" />.

===History===

Initially a thorough history of the patient is taken during which the clinician looks for evidence of ovarian stimulation, followed by ovulation. During this history taking, the clinician will inquire into any weight gain noticed, urine output, and the woman's ability to maintain oral hydration. A key diagnostic tool for clinicians regarding women who are taking gonadotropins is to identify if they are at an increased risk of developing OHSS. Some risk factors include woman aged less than 30, women who have polycystic ovaries, woman with a previous history of OHSS and women who have had greater than 20 oocytes retrieved <ref name="PMID22416285" />.

===Physical Exam===
[[File:Vaginal_Ultrasonography_in_Sagittal_Plane.jpg|right|thumbnail|600px|Vaginal Ultrasonography in Sagittal plane <ref name="Wikiversity Journal of Medicine"> Häggström, Mikael. "Medical gallery of Mikael Häggström 2014". Wikiversity Journal of Medicine 1 (2). DOI:10.15347/wjm/2014.008. ISSN 20018762</ref>]]
After a history of the patient is taken, the next step is to perform a physical exam on the patient. Women who present with abdominal bloating will produce a shifting dullness upon abdominal percussion. Additionally the clinician will test the woman's vital signs, measure her abdominal girth, weight and will look for evidence of ascites or increase in calf size (usually unilateral)<ref name="PMID22416285" />.

===Investigations===

If the clinician further suspects a women of having OHSS, various investigations can be done such as an ultrasound.The intraperitoneal fluid is best imaged via vaginal ultrasound due to the enlarged ovaries making it difficult to image the pelvis using transabdominal ultrasound. The clinician can also order laboratory testing to look for urine specific gravity and and complete blood count to look for hemoconcentration with a hematocrit. Additionally, liver function tests can be ordered to look for elevated function. The clinician will also look for evidence of elevated D-dimers and fibrinogen and decreased levels of anti-thrombin 3 <ref name="SAHealth"> Government of South Australia Health [ http://www.sahealth.sa.gov.au/wps/wcm/connect/9b61ed004ee5348da663afd150ce4f37/Ovarian-hyperstimulation-syndrome-WCHN-PPG-17072012.pdf?MOD=AJPERES&CACHEID=9b61ed004ee5348da663afd150ce4f37 ], 'South Australian Paediatric Clinical Guidelines OHSS'</ref>.

====Ultrasound====

Typical appearances of the ultrasound include <ref name="Ultrasound"> Radiopaedia [ http://radiopaedia.org/articles/ovarian-hyperstimulation-syndrome-1 ], 'Ovarian Hyperstimulation Syndrome'</ref>:

*Bilaterally and symmetrically enlarged ovaries (>12cm)
* "Spoke-Wheel appearance" - presence of multiple cysts of varying size
*May also see ascites (fluid)

===Severity===

Once a clinician has deduced a women is suffering from OHSS, the severity of their condition needs to be established as either mild, moderate or severe. This is done by referring to the criteria under the sub-heading [[Symptoms]].The subsequent course of treatment for the woman will be based upon this evaluation.

{|
|-bgcolor="F6CEEC"
|
'''Further investigations''' can be done including a Chest X-ray to check for pleural effusions and oedema and USS with Doppler's to check for ascites or possible ovary torsion. <ref name="PMID22416285"><pubmed>22416285</pubmed></ref>
|}

===Differential Diagnosis===

Conditions presenting with similar symptoms or ultrasound images include <ref name="Ultrasound" />:

*Polycystic Ovaries (PO)
:: The difference is that with PO is that the cycts are typically smaller than OHSS cysts and there is no evidence of ascited or pleural effusion
*Mucinous Ovarian Malignancy
:: A type of Ovarian Epithelial tumour
*Ectopic Pregnancy <ref name="Casereport"> Australian Medical Student Journal [ http://www.amsj.org/wpcontent/uploads/files/articles/amsj_v2_i1/AMSJ_v2_i1_pg58-60.pdf ], 'Ovarian hyperstimulation syndrome'</ref>
::A pregnancy in which the foetus develops outside of the uterus e.g. in the fallopian tube

</div>

==Pathophysiology==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

The definition of Ovarian Stimulation is enlarged ovaries with many luteinized cysts, that can present with secondary complications. What distinguishes Ovarian Stimulation from OHSS is the presence of vascular hyper-permeability that results in fluids being redirected elsewhere in the body.

The key process to OHSS appears to be caused by '''Vascular Endothelial Growth Factor''' (VEGF), that is released along with other cytokines, estrogen and progesterone, due to the ovary undergoing luteinization as a result of stimulation by hCG. VEGF increases vascular permeability and as a result the capillaries become more "leaky" to the fluids in them. These fluids can then escape the capillaries and accumulate in the pleural and abdominal cavities as ascites. The woman then becomes hypovolemic and is at an increased risk of circulatory, renal and respiratory issues such as arterial thromboembolism due to the thickening of the blood. Note, the blood is thickened as fluid is leaving the capillaries, leaving behind red blood cells and other cellular components of the blood <ref name="WikiOHSS" />.

The increase in expression of VEGF and VEGF Receptor 2 (VEGFR2) is attributed to the greatly increased amount of their mRNA present in the body after stimulation with hCG <ref name="PMID21082502"><pubmed>21082502</pubmed></ref>. VEGF interacts with VEGF2 and VEGF Receptor 1 (VEGFR1) to create a strong angiogenic effect. Both VEGFR2 and VEGFR1 belong to a family of receptors called tyrosine kinases. VEGF2 is involved in the regulation of angiogenesis and vascular permeability whilst VEGF1 has a slightly contradictory role in that is is involved in the maintenance of the tight junctions between endothelial cells in blood vessels. A study by Gómez ''et. al.'' <ref name="PMID21082502" /> showed that women experiencing OHSS had substantially higher plasma levels of VEGF and lower levels of VEGFR1.

[[File:Pathogenesis_of_OHSS.png|600px|centre|thumb|Pathogenesis of OHSS <ref name="PMID20416867"><pubmed>20416867</pubmed></ref>]]

</div>

==Complications==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

Ovarian torsion or rupture, renal insufficiency and thrombophlebitis can all complicate OHSS. If a pregnancy occurs, symptoms may persist longer than the usual 1 to 2 weeks and become more severe, however, even with severe OHSS, they do not extend past the first trimester <ref name="WikiOHSS" />. [[File:Polycystic Ovaries.jpeg|right|thumbnail|360px|Comparison of Normal and Polycystic Ovary]]

<span style="color:#FA58D0"> '''1-2% of women who undergo ovarian stimulation develop a severe form of OHSS''' </span>. Complications from severe OHSS include:

*Fluid collection in the abdomen
*Electrolyte disturbances (sodium and potassium)
*Kidney failure
*Ovary twisting
*Rupture of a cyst in an ovary
*Breathing problems
*Blood clots in large vessels (most commonly the legs)
*Pregnancy loss from miscarriage or termination
*Rarely, death

A study by Nouri ''et. al.'' <ref name="PMID24996451"><pubmed>24996451</pubmed></ref> found that women with '''Polycystic Ovarian Syndrome''' (PCOS) and those that were induced with hCG experienced longer recovery times from severe OHSS than women who were not pregnant. They looked at a cohort of women hospitalised for the first time with severe OHSS and subject them to the same treatments. Based on a defined criteria, they established the recovery time of these women and compared the times between those that were pregnant to those that were not pregnant. They also found that whether a woman had PCOS or ovulation induction did not affect her risk of developing OHSS if she was not pregnant. It is only a risk factor for pregnant women.

===Thromboembolic events===

A frequent and deadly complication of OHSS are thromboembolic events due to increased blood clotting. This increase in blood clotting has been attributed to a variety of complications such as hemoconcentration (which thickens the blood), hypovolemia and an increase in the permeability of blood vessels as a result of increased vasoactive substances in the body of ovarian origin. Thromboembolic events include venous thromboses often in the upper extremities and arterial thromboses such as those in the cerebrovascular region. These events can lead to amputations of extremities, brain damage, miscarriage and death. To avoid this, anti-coagulants are given to pateitns with OHSS and they are fitted with compression stockings (see [[Treatment]]) <ref name="PMID23378404"><pubmed>23378404</pubmed></ref>.

{|
|-bgcolor="F8E0F1"
|
The risk of a woman developing OHSS is higher if she is having a '''twin pregnancy''', as she is exposed to higher concentration of hCG. <ref name="PMID9756273"><pubmed>9756273</pubmed></ref>
|}

</div>

==Treatment==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

'''General treatment
'''
*''Acetaminophen'' with or without a narcotic agent- used to treat abdominal discomfort
*Women are encouraged to drink 2-3 litres of water a day to prevent hemoconcentration
*Women are advised to avoid sexual intercourse and vigorous exercise at the risk of torsion or rupture of the ovaries
*NSAID's with anti-platelet properties should NOT be used as they may effect renal function in a women with OHSS
*Patients with significantly painful ascites or breathing problems may undergo ''Paracentesis'' (drainage of the ascites)
*''Culdocentesis'' (extraction of fluid from recto-uterine pouch) can be done to decrease the likelihood of a woman with moderate OHSS progressing to severe OHSS.<ref name="PMID22416285" />

===Mild to Moderate OHSS===

Mild OHSS can often resolve on its own, however, moderate OHSS may include treatments such as<ref name="WikiOHSS" />:

*Anti-nausea medication and prescription painkillers
*Regular physical examinations and ultrasounds
*Daily weigh-ins and waist measurements
*Measuring the amount of urine produced each day
*Frequent blood tests for monitoring dehydration and electrolyte imbalance
*Maintaining a high balance of fluids
*Drainage of excess abdominal fluid by inserting a needle in the abdominal cavity
*Wearing support stockings which help prevent blood clots/thrombosis

===Severe OHSS===

[[File:Abdominal Paracentesis.png|thumb|right|350px|Paracentesis is a common procedure done on women who have OHSS as it is used to drain the ascites in their abdomen. In this image you can see the puncture of the peritoneal cavity with a needle that then drains the fluid externally. <ref name="Wikiversity Journal of Medicine"> Blausen.com staff. "Blausen gallery 2014". Wikiversity Journal of Medicine. DOI:10.15347/wjm/2014.010. ISSN 20018762 </ref>]]

Severe OHSS requires hospital care in order for constant monitoring and treatment such as <ref name="WikiOHSS" />:

*Intravenous fluids with a crystalloid solution (100-150mL/hr)
*Intravenous Albumin is administered is IV fluids are insufficient (15-20mL/hr of 25% albumin for 4 hrs)
*In addition to Acetaminophen, ''Opioid analgesics'' can be administered for pain relief
*''Antiemetics'' can be used to subside nauseas and/or vomiting
*Woman administered to hospital of OHSS are considered at high risk of thromboembolic complications and are given low molecular weight ''heparin'', an anti-coagulant
*''Cabergoline''- lessens OHSS symptoms
*''GnRH agonist''- suppresses ovarian activity
**If at risk of OHSS, alternates include using a GnRH agonist instead of hCG however its effects on pregnancy rates are questionable. Using a GnRH agonist to replace the use of hCG for final oocyte stimulation will see a 6% decrease in delivery rate.
*Daily monitoring of creatine, urea, creatine clearance C-reactive protein (to rule out infection) are all required in combination with weekly tests such as liver and renal function tests and chest x-rays (to check for pleural effusion) <ref name="PMID12638783" />.

If there are serious complications then additional treatments are required:

*Surgery for a ruptured ovarian cyst
*Intensive care for the liver or lung complications

====Paracentesis====

For women with severe/grade 3 OHSS, paracentesis, the removal of fluid from the body using an aspiration needle, can be undertaken. It is a diagnostic and a therapeutic method that can be done trans-abdominally and trans-vaginally. It is used to relieve symptoms, improve haemodynamics e.g. Urinary output, and shorten the women's hospital stay. Complications of paracentesis include bleeding, infection and organ injury, however are note common <ref name="Paracentesis"> S. Monica Soni, HMS 3, Gillian Lieberman, MD [ http://eradiology.bidmc.harvard.edu/LearningLab/genito/Soni.pdf ], 'Ovarian Hyperstimulation Syndrome'</ref>.

{|
|-bgcolor="F8E0F1"
|
The most important aspect of treatment for any women with OHSS is close and constant '''monitoring''' with her healthcare professional. Counselling may also be provided to women and their partners or families in order to provide them with the best possible knowledge base to manage and treat their OHSS. It is important to note that there is '''no one cure or treatment''' for OHSS. Treatment involves managing and eliminating the symptoms until such time as the syndrome resolves itself <ref name="WikiOHSS" />.
|}

</div>

==Prevention==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

There are three key avenues through which the incidence of OHSS may be prevented. These include identifying risk factors to predict OHSS development, modifying treatment regimes on the basis of the identified risk factors and intervention to prevent progression to OHSS once the patient has undergone '''Controlled Ovarian Stimulation''' (COS).

=== Risk factors===

'''Primary risk factors'''

Pre-existing factors likely to exacerbate the ovarian stimulation response. Primary risk factors include <ref name="PMID26074966"><pubmed>26074966</pubmed></ref>:

*Young age
*Low body weight
*History of elevated response to gonadotropins
*Polycystic Ovary Syndrome (PCOS)
*Isolated PCOS characteristic
*Previous history of OHSS.
*High pretreatment basal Anti-Mullerian Hormone (AMH) concentration
*Large Antral Follicle Count (AFC)

'''Secondary risk factors'''

Secondary risk factors involve the monitoring of ovarian response parameters once COS has been initiated. These parameters are monitored for <ref name="PMID19007627"><pubmed>19007627</pubmed></ref>:

*rapidly rising E2 levels
*E2 concentration larger than 2500 pg/mL
*large number of developing follicles (10-14mm) on the day hCG is administered
*large number of oocytes retrieved

These factors in combination, act as a predictive tool to assess the likelihood of severe OHSS development, with a 83% sensitivity and 84% specificity. <ref name="PMID19007627"/>

=== Primary Prevention===
[[File:Severe OHSS Prevention.jpeg|right|thumbnail|400px|GnRH antagonists, embryo cryopreservation and cycle cancellation are key strategies in preventing OHSS progression within high-risk patients <ref name="PMID22938051"><pubmed>22938051</pubmed></ref>]]

Primary Prevention involves the modification of treatment regimens on the basis of OHSS risk classifications, in order to prevent OHSS occurrence.

'''Ovulation Induction'''

Unifollicular Ovulation Induction through Ovulation Induction (OI) is a primary means of avoiding OHSS in women with Polycystic Ovarian Syndrome, who are at an increased risk. In order to promote unifollicular development, the ovaries are stimulated with a low starting dose of FSH (75 IU).<ref name="PMID20416867"><pubmed>20416867</pubmed></ref> Studies suggests that a minimum gonadotropin dose lowers OHSS risk and thus a step-up regimen is utilised to achieve an ovarian response, whereby the FSH dosage is increased every 7 days until follicular development of greater than 10mm is noted.<ref name="PMID26074966" /> Alternatively, a step-down regimen may be followed, whereby a high initial FSH dosage is lowered according to the ovarian response. Another method to increase FSH levels during OI, is through '''Aromatase Inhibitors''' which promote folliculogenesis by increasing pituitary secretion of FSH, and downregulate oestrogen production through a negative feedback loop. However, Aromatase Inhibitors have not been shown to reduce OHSS incidence in comparison to other methods of OI.<ref name="PMID26074966" /> During OI, a key objective is to prevent early cycle cancellation due to premature luteinisation from pituitary secretion of LH. In order to downregulate LH secretion, '''Gonadotropin-releasing hormone agonists''' (GnRHa) are administered in addition to gonadotropins. Alternatively, '''GnRH antagonists''', which have a rapid onset of action, may be administered to downregulate endogenous LH secretion, with relative success as depicted in the diagram to the right.<ref name="PMID20416867" /> Comparative studies have shown that the GnRH antagonist protocol has a greater effect in lowering the incidence of mild to severe OHSS. However due to the rare nature of OHSS, and insufficient sample sizes, the difference was not found to be significant. <ref name="PMID21082508"><pubmed>21082508</pubmed></ref>. Generally, the duration of exposure to gonadotropins and subsequent risk of OHSS may be minimised through mild stimulation protocols which administer FSH only in the mid to late follicular phase.<ref name="PMID20416867" />

'''Adjuvant Metformin Therapy'''

Adjuvant Metformin Therapy has been found to lower the risk of OHSS by 63%.<ref name="PMID25406011"><pubmed>25406011</pubmed></ref> It involves the administration of metformin at a daily dosage of 1000 to 2000mg, 2 months prior to Controlled Ovarian Stimulation <ref name="PMID26074966"/>. Metformin lowers the elevated insulin levels in PCOS which consequently reduce intraovarian androgen levels. This leads to a reduced sensitivity and expression of granulosa cell-follicle stimulating hormone receptors which result in a less exaggerated response to gonadotropins. Furthermore, it is suggested that Metformin prevents OHSS by controlling vascular permeability through the inhibition of various vasoactive molecules, including VEGF.

'''Avoiding hCG during Luteal Phase Support

Following Controlled Ovarian Stimulation, the steroid levels of E2 and P4 are reduced during the luteal phase due to the negative feedback on the pituitary. This leads to low endogenous LH levels, which consequently reduce endometrial receptivity as well as the luteal phase duration itself. As a result, implantation and pregnancy rates are reduced and early pregnancy loss rates are increased.<ref name="PMID20416867" /> Luteal Phase Support (LPS) serves to combat these adverse events with the use of hCG. However, hCG has been found to increase the risk of OHSS. Alternatively, the use of progesterone has been found to not only halve the risk of OHSS, but also induce similar improvements in pregnancy and miscarriage rates as hCG.<ref name="PMID26148507"><pubmed>26148507</pubmed></ref>

===Secondary Prevention===

Secondary Prevention aims to prevent progression to OHSS once COS has been initiated and the patient has been found to mount an exaggerated response. <ref name="PMID20416867" />

'''Coasting'''

Coasting is a first-line secondary preventative strategy. It consists of the withdrawal of gonadotrophins when a critical number of follicles and/or E2 concentration is reached. hCG is administered once the E2 concentration reduces to a safe level, before the process of oocyte retrieval commences. This preventative strategy is conducted for a period of less than 3 days in order to avoid compromising IVF outcomes.<ref name="PMID26074966"/>

[[File:Cryopreservation of Porcine Embryos.jpeg|right|thumbnail|300px|Cryopreserved embryos of the swine model<ref name="PMID26309801"><pubmed>4497712</pubmed></ref>]]

'''Cryopreservation'''

Cryopreservation of embryos after oocyte retrieval is another avenue which may avert OHSS progression. The cryopreserved embryos are only reimplanted once the patient's hormone serum levels have normalised. Using oocyte vitrification, crystal formation within embryo tissue is avoided and so cryopreserved embryos have been found to produce better pregnancy rates with a 32% increase, than fresh embryo transfer.<ref name="PMID26074966"/> Recent studies suggest cryopreservation itself does not reduce OHSS rates, but must be followed by a GnRHa trigger to avert OHSS.<ref name="PMID24753847"><pubmed>24753847></ref>

'''Cycle cancellation'''

Cycle cancellation is a guaranteed method to prevent early OHSS whereby hCG is withheld. This is a last resort strategy as it carries the risk of significant psychological distress and financial loss for the patient. <ref name="PMID20416867"/>

</div>

==Effect on the Newborn==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

</div>
Women who develop OHSS while undergoing Assisted Reproductive Technologies (ART) treatment are not only more likely to achieve a pregnancy, but have a live birth as the pregnancy outcome. This live birth is also more likely to be a multiple birth of two, three or more children. <ref name="PMID19591989"><pubmed>19591989</pubmed></ref> It has been postulated that a multi-fetal pregnancy leads to a more rapid increase in hCG levels, resulting in an increased risk of OHSS. However, the causal nature between multi-fetal pregnancy and OHSS development is disputed and further research is required to distinguish correlation from causation. <ref name="PMID19573292"><pubmed>19573292</pubmed></ref>

OHSS development is also associated with an increased risk of adverse outcomes including '''stillbirth, premature birth and low birth weight'''.<ref name="PMID19591989" /> Although the cause for the increased risk in adverse pregnancy outcomes is unknown, it is suggested that as the incidence of OHSS is reduced through various prevention strategies, the risk of such outcomes may be also be reduced.

'''<span style="color:#FA58D0"> [http://pregnancyperfect.com/emilyley/ The following link is to a podcast of a woman describing her pregnancy in which she underwent IVF, had OHSS and gave birth to healthy twins]<ref name="Emily"> Pregnancy Perfect[ http://pregnancyperfect.com/emilyley/ ], 'TWINS, IVF, OHSS AND C-SECTION WITH EMILY LEY'</ref> </span>'''

==Genetics==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

Despite OHSS typically being of iatrogenic origin as a result of ovarian stimulation with gonadotropins, research has been conducted into the potential genetics behind OHSS as many sporadic and familial cases have been observed. '''Mutations''' in the receptor for hormones such as Follicle Simulating Hormone (FSH), Lutenizing Hormone (LH) and hCG have all been targets of OHSS genetics research. Interestingly, they too also arise from a common ancestral gene.

===Follicle Stimulating Hormome===

Dr. Botros Rizk, of the University of South Alabama College of Medicine <ref name="PMID19573286"><pubmed>19573286</pubmed></ref>, has written extensively regarding the genetics behind OHSS. In particular, he talks about '''FSH receptors''' (FSHR) and their role in the syndrome. He hypothesises that mutations in these receptors could be activating or inactivating, leading to an increased risk of developing OHSS or sterility respectively. Currently, 744 single nucleotide polymorphisms (a type of mutation) have been found in the gene encoding the FSHR, 8 of which are located in its exons (coding regions of the gene). How the ovary responds is resultant on the FSHR genotype. For example, Ser680Asn, a polymorphism in the FSHR gene has been shown to aid in predicting the severity of a woman's OHSS. Ordinarily FSH stimulates the growth of ovarian follicles, however, when mutated, it is stimulated by the hCG resulting in excessive follicle development.

Spontaneous OHSS, OHSS that arises and cannot be attributed to any form of ovarian stimulation or Assisted Reproductive Technology, has been linked to activating mutations in the FSHR <ref name="PMID23499866"><pubmed>23499866</pubmed></ref>. This familial disorder is an autosomal dominant one. In most cases the FSHR can be stimulated by the presence of Thyroid Stimulating Hormone (TSH) or hCG, in the absence of FSH (the ligand for FSHR).

[[File:FSHR Gene.jpg|centre|thumbnail|700px|This image depicts the location of the FSHR Gene on chromosome 2. It is located on the short arm between positions 21 and 16. Changed to the FSHR gene has been linked to OHSS. <ref name="Genetcis"> Genetics Home Reference [http://ghr.nlm.nih.gov/gene/FSHR'</ref>]]

===Lutenizing Hormome===

The '''Lutenizing Hormone Receptor''' (LHR) gene in humans is comprised of 11 exons. Animal studies have shown that many primates exhibit a similar gene which is comprised of only 10 exons, however a gene lacking the 10th exon has been identified and termed the type 2 LHR. Expression of the type 2 LHR has been seen in humans. The type 2 LHR, compared to the wild-type LHR appears to be repaired with regard to its function. Defects in the type 2 LHR include a decrease in efficiency of transport to the plasma membrane and irregularities in signal transduction. Inactivating mutations in the LHR have been seen to cause infertility in women as well as amenorrhoea. Activating LHR gene mutations are asymptomatic and are not associated with OHSS in women.

===Bone Morphogenic Protein===

An imporant growth factor, derived from oocytes called '''BMP-15''' (Bone Morphogenic Protein 15) is vital for female fertility. It belongs to the family of growth factors, Transforming Growth Factor β (TGF-β) and is heavily involved in folliculogenesis. It has been found that mutations in the BMP-15 gene caused infertility in female sheep. Conversely, it has also been indicated in enhanced fertility when BMP-15 is present is high amounts in follicular fluid <ref name="PMID19573286" />.

A case study done by Hanevik ''et. al.'' in 2013 <ref name="PMID21565556"><pubmed>21565556</pubmed></ref> found that a Single Nuclear Polymorphism (SNP) in the BMP-15 gene is responsible for a high response to ovarian hyper-stimulation. The aim of the study was to test the effect the SNP had on BMP-15 with regard to high and low responders buy taking blood from 53 high responders, 38 low responders and 100 non-responders (controls) and analysing 5 noted SNP's. Results from their study showed a correlation between a high response to ovarian hyper-stimulation and the BMP-15 9G allele. The article does state however, that further research is required into the molecular effects of SNP's on the function of BMP-15.

===Vascular Endothelial Growth Factor===

'''Vascular endothelial growth factor''' (VEGF) has been indicated as one of the key agents causing vascular permeability and subsequent ascites in OHSS. The gene, which is located on chromosome 12, is made up of 8 exons (coding regions), of which exons 6 and 7 do not always appear due to the exons being spliced out.The splicing of this gene allows for various isoforms of the gene to exist of which VEGF 121 and 165 appear to play a role in angiogenesis. There are two VEGF Receptors, VEGFR-1 and VEGFR-2 that belong to the tyrosine kinase family of receptors (for more information on VEGF see [[Pathophysiology]]). Because of its distinct role in OHSS, it has been targeted as an area for research for potential treatments. The idea is that if the genetic expression of VEGF and its receptors can be controlled, OHSS can be avoided or treated.<ref name="PMID19573286" />

A different study by Hanevik ''et. al.'' , <ref name="PMID22587628"><pubmed>22587628</pubmed></ref> done in 2012 involved analysing blood samples from 53 women with OHSS and 100 women without it (controls) and analysing 6 SNP's in the VEGFR2 gene to find any genetic variations. They found a correlation between women with the VEGF +405cc genotype and the development of OHSS indicating women that undergo controlled ovarian hyper-stimulation and posses his genotype, are at an increased risk of developing OHSS.

</div>

== Current Research on Animal Models==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

{|
|-bgcolor="FFF5FF"
|<span style="font-size:120%">'''Inhibition of Cyclooxygenase-2 (COX-2) by Meloxican decreasing the incidence of OHSS in Rat Model'''</span> <ref name="PMID18166186"><pubmed>18166186</pubmed></ref>

Reasearch was carried out to investigate the effects of selective inhibition of the enzyme COX-2 on the Ovarian Hyperstimulation Syndrome (OHSS) using Female Wistar rates as the subjects. The research aimed to find results by measuring the number of antral and luteinized follicles, ovarian weight, vascualr endothelial growth factors and COX-2 immunohistochemistry. The rats being tested were all 22 days old and were divided into four equal groups;

'''Group 1 (Control group)''' was subject to a 0.1 ml of Intraperitoneal Saline from days 22 ~ 26

'''Group 2 (Mildly-stimulated group)''' subject to 10IU of pregnant mare serum gonadotrophin (PMSG) on day 24 and then 10IU of Human Chorionic Gonadotrophin (hCG) on day 26

'''Group 3 (OHSS positive group)''' was subject to 10IU of PMSG from days 22 ~ 26 and then administered 30IU of hCG on day 26 to induce OHSS

'''Group 4 (OHSS positive variant group)''' received 15mg/ml of Meloxicam 2 hours prior to administration of 10IU PMSG from days 22 ~ 26

Results showed there was no difference in ovarian weight in samples from Group 1 and Group 2, however Group 3 showed signs of significant ovarian weight increase which in group 4 was suppressed by the introduction of Meloxicam. No differences were observed in the number of antral follicles amongst the four test groups. Results from Group 2 and Group 3 showed that the granulosa cells of preovulatory follicles and the stromal cells were highly VEGF immunoreactive, however the Meloxicam treated Group 4 showed less immunoreactivity than Group 2 and Group 3 which indicated the correlation between Meloxicam and the diminished VEGF expression. Group 3 presented an increased COS-2 immunoreactivity which was highly diminished than in Group 4.

The research concluded that in a rat model, the enzyme Meloxicam has a beneficial effect on OHSS by reducing the increase of ovarian weight and the expression of VEGF associated with OHSS, the effects of which may be mediated by the inhibitory capacity of COX-2 on Meloxicam
|}

{|
|-bgcolor="FFF5FF"
|<span style="font-size:120%">'''Inhibition of Ovarian VEGF secretion by activation of Dopamine Receptor 2'''</span> <ref name="PMID25217874"><pubmed>25217874</pubmed></ref>

This research was carried out to investigate a possibility in whether a Dopamine Receptor 2 agonist '''(D2-ag)''' can assist in the prevention of Ovarian Hyperstimulation Syndrome, using rat models, by decreasing the ovarian vascular endothelial growth factor '''(VEGF)''' production. Using Immature Wistar rats (22 days old) as their animal model, the rats were initially stimulated with Gonadotrophins to mimic the onset and effects of OHSS and then subjected to treatment with a D2-agonist and/or a D2-antagonist (D2-ant). The vascular permeability was measured at the endpoint after day 26 by measuring the peritoneal extravasion of a previously injected dye and ovaries from all subjects were collected to assess the effects of D2-ag and D2-ant on the production of Ovarian VEGF. The expression of VEGF mRNA was measured by quantitative real time PCR and the levels of VEGF proteins were measured by Western Blots.

Results showed that the D2-ag caused a large reduction in the vascular permeability which was in turn associated with the great decreased in VEGF protein production in the OHSS rat ovaries, whereas the introduction of D2-ant showed opposite results with a increase in the vascular permeability leading to the increase of VEGF protein production in the ovaries. Ovarian VEGF mRNA levels were found to be unaffected by the introduction of these drugs in OHSS rat subjects. Conclusions were drawn on the fact that Dopamine Receptor 2 agonists prevent the increase of vascular permeability in subjects with OHSS by decreasing the ovarian production of VEGF and also that due to the dose-dependent inhibitory effect of the D2-ag on ovarian VEGF, current OHSS therapies used in humans can benefit by increasing the intraovarian concentration of D2-ag.
|}

</div>

==Glossary==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

'''Aromatase Inhibitor''' - A drug that inhibits enzyme aromatase, which in turn suppresses estrogen synthesis.

'''Ascites''' - An accumulation of fluid in the peritoneal cavity with resultant abdominal swelling.

'''Cabergoline''' - A dopamine receptor agonist used to treat hormone imbalance.

'''Controlled Ovarian Stimulation''' - female infertility treatment using medications to stimulate the ovaries to develop follicles.

'''Cryopreservation''' - Cooling and storing biological material at extremely low temperatures.

'''E2''' - Estradiol - Potent estrogen sex hormone.

'''FSH''' - Follicle Stimulating Hormone

'''Gonadotropin''' - Any hormone that has a stimulating effect on the gonads.

'''GnRH agonist''' - Gonadotropin Releasing Hormone - A class of compounds that mimic the effect of the natural Gonadotropin Releasing Hormone.

'''GnRH antagonist''' - Gonadotropin Releasing Hormone - A class of compounds that are similar in terms of the structure of natural Gonadotropin Releasing Hormone but has a antagonistic effect.

'''hCG'''- Human Chorionic Gonadotropin

'''Hemoconcentration''' - An increase in the concentration of circulating red blood cells in response to a decrease in blood plasma volume.

'''Hypovolemic''' - A decrease in circulating blood volume.

'''Iatrogenic''' - Illness caused as a result of a medical examination or treatment.

'''Intravenous fluids''' - Is the infusion of liquid substances directly into a vein.

'''IVF''' - In-vitro Fertilization

'''LH''' - Luteinizing Hormone

'''Metformin''' - A biguanide, antidiabetic drug used as an adjuvant to modify the effect of other agents.

'''NSAID''' - Non-steroidal Anti-Inflammatory Drug e.g. Ibuprofen

'''Oocyte vitrification''' - technique for cryopreservation of oocytes.

'''OHSS''' - Ovarian Hyper-stimulation Syndrome

'''Oliguria'''- Decreased urine output/small amounts of urine produced.

'''P4''' - Progesterone - endogenous progestogen sex hormone.

'''PCOS''' - Polycystic Ovarian Syndrome. An endrocrine system disorder whereby the ovaries are enlarged with small collections of fluid.

</div>

==References==

File:Severe OHSS Prevention.jpeg

2015-10-23T16:18:48Z

Z3372824: /* Severe OHSS Regression */

==Severe OHSS Regression==

Flow chart describing the management approach for patients at high risk for developing OHSS. 10 patients did not develop severe OHSS and had embryo transfer cancellation due to the following reasons: failed fertilization n = 1, oocyte cryopreservation n = 2, no blastocyst formation n = 2, embryo cryopreservation due to Rokitansky syndrome n = 1, due to poor endometrium n = 1, absence of sperm on day of oocyte retrieval and use of donor sperm n = 3. Four patients with positive hCG following ET developed pregnancy-induced late OHSS and were admitted to the hospital (1.1%, 95% CI: 0.5 to 3.3).

(original figure legend, based on data by Lainas et al. PMID 22938051)

Example of Primary and Secondary Prevention strategies used to reduce severity of OHSS. Administration of GnRH antagonists, cryopreservation of embryos and cycle cancellation were all employed to prevent Ovarian Hyperstimulation Syndrome progression within patients.
===Reference===

<pubmed>22938051</pubmed>| [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3489837/]

====Copyright====
This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

1477-7827-10-69-1.jpeg

{{Template: Student Image}}

File:Severe OHSS Prevention.jpeg

2015-10-23T16:15:58Z

Z3372824:

==Severe OHSS Prevention==

Flow chart describing the management approach for patients at high risk for developing OHSS. 10 patients did not develop severe OHSS and had embryo transfer cancellation due to the following reasons: failed fertilization n = 1, oocyte cryopreservation n = 2, no blastocyst formation n = 2, embryo cryopreservation due to Rokitansky syndrome n = 1, due to poor endometrium n = 1, absence of sperm on day of oocyte retrieval and use of donor sperm n = 3. Four patients with positive hCG following ET developed pregnancy-induced late OHSS and were admitted to the hospital (1.1%, 95% CI: 0.5 to 3.3).
(original figure legend, based on data by Lainas et al. PMID 22938051)

Example of Primary and Secondary Prevention strategies used to avert the risk of Severe OHSS. Administration of GnRH antagonists, cryopreservation of embryos and cycle cancellation were all employed to prevent Ovarian Hyperstimulation Syndrome progression within patients.
===Reference===

<pubmed>22938051</pubmed>| [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3489837/]

====Copyright====
This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

1477-7827-10-69-1.jpeg

{{Template: Student Image}}

File:Severe OHSS Prevention.jpeg

2015-10-23T16:05:47Z

Z3372824: PMID 22938051

PMID 22938051

2015 Group Project 2

2015-10-23T15:17:13Z

Z3372824: /* Secondary Prevention */

{{ANAT2341Project2015header}}

==<span style="font-size:120%">'''Ovarian Hyper-stimulation Syndrome (OHSS)'''</span>==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

Ovarian Hyper stimulation Syndrome (OHSS) is an iatrogenic complication of '''Assisted Reproduction Technology''' (ART), in which women take medications to stimulate oocyte growth. It is generally identified by cystic enlargements of the ovaries and fluid accumulation in the peritoneal cavity due to the increased capillary permeability and ovarian neoangiogenesis <ref name="PMID22065820"><pubmed>22065820</pubmed></ref>. It is an occurrence which is dependent on the controlled stimulation of the ovaries in preparation for IVF i.e. administration of human Chorionic Gonadotropin (hCG).

OHSS was first described in 1943 as ''“syndrome d’hyperluteinisation massive des ovaries”''. It was during this time that gonadotropins were prepared from animals such as sheep to bring on ovulation in women. The first recorded death as a result of OHSS occurred in 1951 and was due to renal failure as a result of oligouria, a complication of the syndrome <ref name="OHSS"> Marie M. Budev, DO, MPH; Alejandro C. Arroliga, MD; Tommaso Falcone, MD, [ http://utilis.net/Morning%20Topics/REI/Ovarian%20Hyperstimulation.pdf ], 'Ovarian Hyperstimulation Syndrome'</ref> <ref name="PMID12638783"><pubmed>12638783</pubmed></ref>.

<span style="color:#FA58D0">'''This wikipage aims to provide clear information on various areas surrounding OHSS such as diagnosis, prevention and complications and will look into the genetics behind the disorder and the various animals models used to research it'''.</span>

<html5media height="350" width="450">https://www.youtube.com/watch?v=aXmjJw234a4</html5media>

'''Overview of Ovarian Hyperstimulation Syndrome''' <ref> Howcast (2013, August 27) Ovarian Hyperstimulation Syndrome | Infertility. Retrieved from https://www.youtube.com/watch?v=aXmjJw234a4</ref>

</div>

==Epidemiology==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

Ovarian Hyper-Stimulation Syndrome (OHSS) rarely occurs sporadically, and if it does, it is usually the result of an underlying genetic problem. The majority of OHSS is due to the ovaries being stimulated to mature and release an abundance of oocytes, in response to hormones Human Chorionic Gonadotropin (hCG) and Follicle Stimulating hormone (FSH), during IVF. Rarely, Clomifene Citrate therapy can cause OHSS.<ref name="WikiOHSS"> Wikipedia, [ https://en.wikipedia.org/wiki/Ovarian_hyperstimulation_syndrome ], 'Ovarian Hyperstimulation Syndrome'</ref>

OHSS only affects '''0.5-5%''' of women undergoing Ovarian Hyper-stimulation, but despite its small prevalence, it is a potentially fatal outcome of a non-vital procedure and remains a prevalent problem for fertility specialists <ref name="PMID12498425"><pubmed>12498425</pubmed></ref> <ref name="PMID12638783"><pubmed>12638783</pubmed></ref>. Age has been cited as a factor affecting those with OHSS, with younger women more at risk. Additionally, women with allergies were seen to have a higher incidence of OHSS. It is important to note that at this point in time, there is no positive correlation between gonadotropin dose and OHSS.

Of the 0.5-5% of women affected with OHSS mentioned above, 2% of those women will require hospitalisation. As of 2011, it has been reported that the incidence of OHSS was '''increasing''', resulting in approximately 3 deaths per 100,000 women undergoing ovarian stimulation per year <ref name="PMID21828116"><pubmed>21828116</pubmed></ref>. This is particularly worrying as in 2008, in the United States alone, there were around 150,000 IVF cycles undertaken.

{|
|-bgcolor="F8E0F1"
|
'''With the field of Assisted Reproductive Technologies expanding and more women partaking in IVF treatments, the threat of women developing OHSS is an ongoing and increasing one''' <ref name="PMID21828116" />.
|}
{| class="wikitable mw-collapsible mw-collapsed"
! colspan=4|Characteristics of women with OHSS by complication group <ref name="PMID19591989"><pubmed>19591989</pubmed></ref>
|-
! scope="col" width="100px" height="60px" style="text-align:center| '''Characteristic'''
! scope="col" width="100px" height="60px" style="text-align:center| '''No Complications
(N = 212,041)'''
! scope="col" width="100px" height="60px" style="text-align:center| '''Moderate OHSS
(N = 1,523)'''
! scope="col" width="100px" height="60px" style="text-align:center| '''Severe OHSS
(N = 655)'''
|-
|style="text-align:center; background: #FF99FF;"| '''Maternal Age (Mean ± SD)'''
|style="text-align:center; background: #F6CEEC;"| 35.6 ± 4.6
|style="text-align:center; background: #F6CEEC;"| 33.0 ± 4.3
|style="text-align:center; background: #F6CEEC;"| 33.1 ± 4.4
|-
|style="text-align:center; background: #FF99FF;"| '''Maternal Age (%)'''
|-
|style="text-align:left; background: #F6CEEC;"| <30 years
|style="text-align:center; background: #F6CEEC;"| 10 %
|style="text-align:center; background: #F6CEEC;"| 21.1 %
|style="text-align:center; background: #F6CEEC;"| 20.6 %
|-
|style="text-align:left; background: #F6CEEC;"| 30-34 years
|style="text-align:center; background: #F6CEEC;"| 30.4 %
|style="text-align:center; background: #F6CEEC;"| 43.2 %
|style="text-align:center; background: #F6CEEC;"| 40.5 %
|-
|style="text-align:left; background: #F6CEEC;"| 35-39 years
|style="text-align:center; background: #F6CEEC;"| 37.8 %
|style="text-align:center; background: #F6CEEC;"| 27.2 %
|style="text-align:center; background: #F6CEEC;"| 32.5 %
|-
|style="text-align:left; background: #F6CEEC;"| >40 years
|style="text-align:center; background: #F6CEEC;"| 21.8 %
|style="text-align:center; background: #F6CEEC;"| 8.4 %
|style="text-align:center; background: #F6CEEC;"| 6.4 %
|-
|style="text-align:center; background: #FF99FF;"| '''Nulligravida (%)'''
|style="text-align:center; background: #F6CEEC;"| 45.8 %
|style="text-align:center; background: #F6CEEC;"| 51.5 %
|style="text-align:center; background: #F6CEEC;"| 51.8 %
|-
|style="text-align:center; background: #FF99FF;"| '''Infertility Diagnosis (%)'''
|-
|style="text-align:left; background: #F6CEEC;"| Male factor
|style="text-align:center; background: #F6CEEC;"| 37.7 %
|style="text-align:center; background: #F6CEEC;"| 41.0 %
|style="text-align:center; background: #F6CEEC;"| 33.4 %
|-
|style="text-align:left; background: #F6CEEC;"| Endometriosis
|style="text-align:center; background: #F6CEEC;"| 13.5 %
|style="text-align:center; background: #F6CEEC;"| 13.5 %
|style="text-align:center; background: #F6CEEC;"| 10.7 %
|-
|style="text-align:left; background: #F6CEEC;"| Ovulation Disorders
|style="text-align:center; background: #F6CEEC;"| 14.0 %
|style="text-align:center; background: #F6CEEC;"| 29.5 %
|style="text-align:center; background: #F6CEEC;"| 22.4 %
|-
|style="text-align:left; background: #F6CEEC;"| Diminished ovarian reserve
|style="text-align:center; background: #F6CEEC;"| 16.9 %
|style="text-align:center; background: #F6CEEC;"| 3.2 %
|style="text-align:center; background: #F6CEEC;"| 2.4 %
|-
|style="text-align:left; background: #F6CEEC;"| Tubal factors
|style="text-align:center; background: #F6CEEC;"| 20.4 %
|style="text-align:center; background: #F6CEEC;"| 22.6 %
|style="text-align:center; background: #F6CEEC;"| 22.3 %
|-
|style="text-align:left; background: #F6CEEC;"| Uterine factors
|style="text-align:center; background: #F6CEEC;"| 5.1 %
|style="text-align:center; background: #F6CEEC;"| 4.3 %
|style="text-align:center; background: #F6CEEC;"| 3.1 %
|-
|style="text-align:left; background: #F6CEEC;"| Other factors
|style="text-align:center; background: #F6CEEC;"| 13.9 %
|style="text-align:center; background: #F6CEEC;"| 13.1 %
|style="text-align:center; background: #F6CEEC;"| 10.4 %
|-
|style="text-align:left; background: #F6CEEC;"| Unexplained factor
|style="text-align:center; background: #F6CEEC;"| 12.7 %
|style="text-align:center; background: #F6CEEC;"| 11.8 %
|style="text-align:center; background: #F6CEEC;"| 18.6 %
|-
|}
</div>

==Causative Agents==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

[[File:Follicular Development.jpeg|right|thumbnail|500px|Infertility treatments aim to facilitate follicular development and induce ovulation to improve chances of fertilisation <ref name="PMID24717179"><pubmed>24717179</pubmed></ref>]]

Normally a woman produces one egg per month from the ovaries, which travel down the Fallopian tube to be fertilized or be released from the body. In cases where women have difficulty falling pregnant, they are given medication which help them to produce and release eggs (as shown in the diagram to the right), further increasing their chances of fertilization and pregnancy <ref><pubmed>19573285</pubmed></ref>. Ovarian Hyper stimulation Syndrome generally occurs during infertility treatments when the ovaries are overstimulated by the fertility medication which causes the ovaries to swell and leak fluids into the belly and abdomen. The prevalence of OHSS onset is linked with excessive number of follicle development in response to the administration of injectable Follicle Stimulating Hormones (FSH) followed by the '''Human Chorionic Gonadotrophins''' (hCG) which triggers the release of the oocytes <ref><pubmed>26190539</pubmed></ref>.

'''Follicle Stimulating Hormones''' (FSH) <ref name="PMID9020850"><pubmed>9020850</pubmed></ref> are glycoprotein hormones that are produced and secreted from the Anterior Pituitary gland into the bloodstream, which regulate the developmental, growth, maturation and the reproductive processes within the body. In females, the Follicle Stimulating Hormones initiates the stages of growth and development of immature ovarian follicles within the ovaries before the release of an egg from a follicle at ovulation. When FSH is administered to a patient who is suffering from infertility, the increase FSH levels affect the rate of development and production, in turn increasing the amount of follicles which are ready to be released during ovulation.

</div>

==Symptoms==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

OHSS is classified based on a criteria from mild, moderate and severe <ref name="WikiOHSS" />:

'''Mild Symptoms'''- abdominal bloating, minimal weight gain, nausea, diarrhoea and a feeling of fullness.

'''Moderate Symptoms'''- Substantial weight gain (on average 2 or more pounds a day), increased abdominal girth, darkend urine and excessive thirst in addition to the mild symptoms.

'''Severe Symptoms'''- In addition to the symptoms associated with Mild and Moderate OHSS, in severe OHSS, you see shortness of breath, calf and chest pains and pleural effusion.

===<span style="font-size:100%">Classifications of Ovarian Hyper-stimulation Syndrome:</span> <ref name="PMID22065820"><pubmed>22065820</pubmed></ref>===

{| class="wikitable" style="text-align:center
|-
! scope="col" width="70px"| '''Classification'''
! scope="col" width="650px"| '''Symptoms'''
|-
|style="text-align:center; background: #F6CEEC;"| '''Mild'''
|style="height: 60px; background: #F6CEEC;"| '''Grade 1''' - Abdominal distention and discomfort
'''Grade 2''' - Abdominal distention, discomfort with nausea, vomiting and/or diarrhea and ovarian enlargement from 5~12cm
|-
|style="text-align:center; background: #F8E0F1;"| '''Moderate'''
|style="height: 60px; background: #F8E0F1;"| '''Grade 3''' - All features of Mild OHSS with ultrasonographic evidence of ascites
|-
|style="text-align:center; background: #F6CEEC;"| '''Severe'''
|style="height: 60px; background: #F6CEEC;"| '''Grade 4''' - All features of Moderate OHSS with the addition of clinical evidence of ascites and breathing difficulties present
'''Grade 5''' - All of the above symptoms along with a change in the blood volume, increased blood viscosity due to coagulation and diminished renal function
|}

</div>

==Diagnosis==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

Whilst symptoms of OHSS can occur as soon as 24 hours post hCG administration, they are usually seen in women 7-10 days post administration. Initially women with OHSS will present with abdominal bloating, as a result of fluid in the peritoneal cavity and an increase in ovary size. When women present with severe OHSS they are often dehydrated, due to increased vascular permeability, and have hemoconcentration. The above results in a decrease in intravascular volume, leading to '''oligouria''' <ref name="PMID22416285" />.

===History===

Initially a thorough history of the patient is taken during which the clinician looks for evidence of ovarian stimulation, followed by ovulation. During this history taking, the clinician will inquire into any weight gain noticed, urine output, and the woman's ability to maintain oral hydration. A key diagnostic tool for clinicians regarding women who are taking gonadotropins is to identify if they are at an increased risk of developing OHSS. Some risk factors include woman aged less than 30, women who have polycystic ovaries, woman with a previous history of OHSS and women who have had greater than 20 oocytes retrieved <ref name="PMID22416285" />.

===Physical Exam===
[[File:Vaginal_Ultrasonography_in_Sagittal_Plane.jpg|right|thumbnail|600px|Vaginal Ultrasonography in Sagittal plane <ref name="Wikiversity Journal of Medicine"> Häggström, Mikael. "Medical gallery of Mikael Häggström 2014". Wikiversity Journal of Medicine 1 (2). DOI:10.15347/wjm/2014.008. ISSN 20018762</ref>]]
After a history of the patient is taken, the next step is to perform a physical exam on the patient. Women who present with abdominal bloating will produce a shifting dullness upon abdominal percussion. Additionally the clinician will test the woman's vital signs, measure her abdominal girth, weight and will look for evidence of ascites or increase in calf size (usually unilateral)<ref name="PMID22416285" />.

===Investigations===

If the clinician further suspects a women of having OHSS, various investigations can be done such as an ultrasound.The intraperitoneal fluid is best imaged via vaginal ultrasound due to the enlarged ovaries making it difficult to image the pelvis using transabdominal ultrasound. The clinician can also order laboratory testing to look for urine specific gravity and and complete blood count to look for hemoconcentration with a hematocrit. Additionally, liver function tests can be ordered to look for elevated function. The clinician will also look for evidence of elevated D-dimers and fibrinogen and decreased levels of anti-thrombin 3 <ref name="SAHealth"> Government of South Australia Health [ http://www.sahealth.sa.gov.au/wps/wcm/connect/9b61ed004ee5348da663afd150ce4f37/Ovarian-hyperstimulation-syndrome-WCHN-PPG-17072012.pdf?MOD=AJPERES&CACHEID=9b61ed004ee5348da663afd150ce4f37 ], 'South Australian Paediatric Clinical Guidelines OHSS'</ref>.

====Ultrasound====

Typical appearances of the ultrasound include <ref name="Ultrasound"> Radiopaedia [ http://radiopaedia.org/articles/ovarian-hyperstimulation-syndrome-1 ], 'Ovarian Hyperstimulation Syndrome'</ref>:

*Bilaterally and symmetrically enlarged ovaries (>12cm)
* "Spoke-Wheel appearance" - presence of multiple cysts of varying size
*May also see ascites (fluid)

===Severity===

Once a clinician has deduced a women is suffering from OHSS, the severity of their condition needs to be established as either mild, moderate or severe. This is done by referring to the criteria under the sub-heading [[Symptoms]].The subsequent course of treatment for the woman will be based upon this evaluation.

{|
|-bgcolor="F6CEEC"
|
'''Further investigations''' can be done including a Chest X-ray to check for pleural effusions and oedema and USS with Doppler's to check for ascites or possible ovary torsion. <ref name="PMID22416285"><pubmed>22416285</pubmed></ref>
|}

===Differential Diagnosis===

Conditions presenting with similar symptoms or ultrasound images include <ref name="Ultrasound" />:

*Polycystic Ovaries (PO)
:: The difference is that with PO is that the cycts are typically smaller than OHSS cysts and there is no evidence of ascited or pleural effusion
*Mucinous Ovarian Malignancy
:: A type of Ovarian Epithelial tumour
*Ectopic Pregnancy <ref name="Casereport"> Australian Medical Student Journal [ http://www.amsj.org/wpcontent/uploads/files/articles/amsj_v2_i1/AMSJ_v2_i1_pg58-60.pdf ], 'Ovarian hyperstimulation syndrome'</ref>
::A pregnancy in which the foetus develops outside of the uterus e.g. in the fallopian tube

</div>

==Pathophysiology==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

The definition of Ovarian Stimulation is enlarged ovaries with many luteinized cysts, that can present with secondary complications. What distinguishes Ovarian Stimulation from OHSS is the presence of vascular hyper-permeability that results in fluids being redirected elsewhere in the body.

The key process to OHSS appears to be caused by '''Vascular Endothelial Growth Factor''' (VEGF), that is released along with other cytokines, estrogen and progesterone, due to the ovary undergoing luteinization as a result of stimulation by hCG. VEGF increases vascular permeability and as a result the capillaries become more "leaky" to the fluids in them. These fluids can then escape the capillaries and accumulate in the pleural and abdominal cavities as ascites. The woman then becomes hypovolemic and is at an increased risk of circulatory, renal and respiratory issues such as arterial thromboembolism due to the thickening of the blood. Note, the blood is thickened as fluid is leaving the capillaries, leaving behind red blood cells and other cellular components of the blood <ref name="WikiOHSS" />.

The increase in expression of VEGF and VEGF Receptor 2 (VEGFR2) is attributed to the greatly increased amount of their mRNA present in the body after stimulation with hCG <ref name="PMID21082502"><pubmed>21082502</pubmed></ref>. VEGF interacts with VEGF2 and VEGF Receptor 1 (VEGFR1) to create a strong angiogenic effect. Both VEGFR2 and VEGFR1 belong to a family of receptors called tyrosine kinases. VEGF2 is involved in the regulation of angiogenesis and vascular permeability whilst VEGF1 has a slightly contradictory role in that is is involved in the maintenance of the tight junctions between endothelial cells in blood vessels. A study by Gómez ''et. al.'' <ref name="PMID21082502" /> showed that women experiencing OHSS had substantially higher plasma levels of VEGF and lower levels of VEGFR1.

[[File:Pathogenesis_of_OHSS.png|600px|centre|thumb|Pathogenesis of OHSS <ref name="PMID20416867"><pubmed>20416867</pubmed></ref>]]

</div>

==Complications==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

Ovarian torsion or rupture, renal insufficiency and thrombophlebitis can all complicate OHSS. If a pregnancy occurs, symptoms may persist longer than the usual 1 to 2 weeks and become more severe, however, even with severe OHSS, they do not extend past the first trimester <ref name="WikiOHSS" />. [[File:Polycystic Ovaries.jpeg|right|thumbnail|360px|Comparison of Normal and Polycystic Ovary]]

<span style="color:#FA58D0"> '''1-2% of women who undergo ovarian stimulation develop a severe form of OHSS''' </span>. Complications from severe OHSS include:

*Fluid collection in the abdomen
*Electrolyte disturbances (sodium and potassium)
*Kidney failure
*Ovary twisting
*Rupture of a cyst in an ovary
*Breathing problems
*Blood clots in large vessels (most commonly the legs)
*Pregnancy loss from miscarriage or termination
*Rarely, death

A study by Nouri ''et. al.'' <ref name="PMID24996451"><pubmed>24996451</pubmed></ref> found that women with '''Polycystic Ovarian Syndrome''' (PCOS) and those that were induced with hCG experienced longer recovery times from severe OHSS than women who were not pregnant. They looked at a cohort of women hospitalised for the first time with severe OHSS and subject them to the same treatments. Based on a defined criteria, they established the recovery time of these women and compared the times between those that were pregnant to those that were not pregnant. They also found that whether a woman had PCOS or ovulation induction did not affect her risk of developing OHSS if she was not pregnant. It is only a risk factor for pregnant women.

===Thromboembolic events===

A frequent and deadly complication of OHSS are thromboembolic events due to increased blood clotting. This increase in blood clotting has been attributed to a variety of complications such as hemoconcentration (which thickens the blood), hypovolemia and an increase in the permeability of blood vessels as a result of increased vasoactive substances in the body of ovarian origin. Thromboembolic events include venous thromboses often in the upper extremities and arterial thromboses such as those in the cerebrovascular region. These events can lead to amputations of extremities, brain damage, miscarriage and death. To avoid this, anti-coagulants are given to pateitns with OHSS and they are fitted with compression stockings (see [[Treatment]]) <ref name="PMID23378404"><pubmed>23378404</pubmed></ref>.

{|
|-bgcolor="F8E0F1"
|
The risk of a woman developing OHSS is higher if she is having a '''twin pregnancy''', as she is exposed to higher concentration of hCG. <ref name="PMID9756273"><pubmed>9756273</pubmed></ref>
|}

</div>

==Treatment==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

'''General treatment
'''
*''Acetaminophen'' with or without a narcotic agent- used to treat abdominal discomfort
*Women are encouraged to drink 2-3 litres of water a day to prevent hemoconcentration
*Women are advised to avoid sexual intercourse and vigorous exercise at the risk of torsion or rupture of the ovaries
*NSAID's with anti-platelet properties should NOT be used as they may effect renal function in a women with OHSS
*Patients with significantly painful ascites or breathing problems may undergo ''Paracentesis'' (drainage of the ascites)
*''Culdocentesis'' (extraction of fluid from recto-uterine pouch) can be done to decrease the likelihood of a woman with moderate OHSS progressing to severe OHSS.<ref name="PMID22416285" />

===Mild to Moderate OHSS===

Mild OHSS can often resolve on its own, however, moderate OHSS may include treatments such as<ref name="WikiOHSS" />:

*Anti-nausea medication and prescription painkillers
*Regular physical examinations and ultrasounds
*Daily weigh-ins and waist measurements
*Measuring the amount of urine produced each day
*Frequent blood tests for monitoring dehydration and electrolyte imbalance
*Maintaining a high balance of fluids
*Drainage of excess abdominal fluid by inserting a needle in the abdominal cavity
*Wearing support stockings which help prevent blood clots/thrombosis

===Severe OHSS===

[[File:Abdominal Paracentesis.png|thumb|right|350px|Paracentesis is a common procedure done on women who have OHSS as it is used to drain the ascites in their abdomen. In this image you can see the puncture of the peritoneal cavity with a needle that then drains the fluid externally. <ref name="Wikiversity Journal of Medicine"> Blausen.com staff. "Blausen gallery 2014". Wikiversity Journal of Medicine. DOI:10.15347/wjm/2014.010. ISSN 20018762 </ref>]]

Severe OHSS requires hospital care in order for constant monitoring and treatment such as <ref name="WikiOHSS" />:

*Intravenous fluids with a crystalloid solution (100-150mL/hr)
*Intravenous Albumin is administered is IV fluids are insufficient (15-20mL/hr of 25% albumin for 4 hrs)
*In addition to Acetaminophen, ''Opioid analgesics'' can be administered for pain relief
*''Antiemetics'' can be used to subside nauseas and/or vomiting
*Woman administered to hospital of OHSS are considered at high risk of thromboembolic complications and are given low molecular weight ''heparin'', an anti-coagulant
*''Cabergoline''- lessens OHSS symptoms
*''GnRH agonist''- suppresses ovarian activity
**If at risk of OHSS, alternates include using a GnRH agonist instead of hCG however its effects on pregnancy rates are questionable. Using a GnRH agonist to replace the use of hCG for final oocyte stimulation will see a 6% decrease in delivery rate.
*Daily monitoring of creatine, urea, creatine clearance C-reactive protein (to rule out infection) are all required in combination with weekly tests such as liver and renal function tests and chest x-rays (to check for pleural effusion) <ref name="PMID12638783" />.

If there are serious complications then additional treatments are required:

*Surgery for a ruptured ovarian cyst
*Intensive care for the liver or lung complications

====Paracentesis====

For women with severe/grade 3 OHSS, paracentesis, the removal of fluid from the body using an aspiration needle, can be undertaken. It is a diagnostic and a therapeutic method that can be done trans-abdominally and trans-vaginally. It is used to relieve symptoms, improve haemodynamics e.g. Urinary output, and shorten the women's hospital stay. Complications of paracentesis include bleeding, infection and organ injury, however are note common <ref name="Paracentesis"> S. Monica Soni, HMS 3, Gillian Lieberman, MD [ http://eradiology.bidmc.harvard.edu/LearningLab/genito/Soni.pdf ], 'Ovarian Hyperstimulation Syndrome'</ref>.

{|
|-bgcolor="F8E0F1"
|
The most important aspect of treatment for any women with OHSS is close and constant '''monitoring''' with her healthcare professional. Counselling may also be provided to women and their partners or families in order to provide them with the best possible knowledge base to manage and treat their OHSS. It is important to note that there is '''no one cure or treatment''' for OHSS. Treatment involves managing and eliminating the symptoms until such time as the syndrome resolves itself <ref name="WikiOHSS" />.
|}

</div>

==Prevention==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

There are three key avenues through which the incidence of OHSS may be prevented. These include identifying risk factors to predict OHSS development, modifying treatment regimes on the basis of the identified risk factors and intervention to prevent progression to OHSS once the patient has undergone '''Controlled Ovarian Stimulation''' (COS).

=== Risk factors===

'''Primary risk factors'''

Pre-existing factors likely to exacerbate the ovarian stimulation response. Primary risk factors include <ref name="PMID26074966"><pubmed>26074966</pubmed></ref>:

*Young age
*Low body weight
*History of elevated response to gonadotropins
*Polycystic Ovary Syndrome (PCOS)
*Isolated PCOS characteristic
*Previous history of OHSS.
*High pretreatment basal Anti-Mullerian Hormone (AMH) concentration
*Large Antral Follicle Count (AFC)

'''Secondary risk factors'''

Secondary risk factors involve the monitoring of ovarian response parameters once COS has been initiated. These parameters are monitored for <ref name="PMID19007627"><pubmed>19007627</pubmed></ref>:

*rapidly rising E2 levels
*E2 concentration larger than 2500 pg/mL
*large number of developing follicles (10-14mm) on the day hCG is administered
*large number of oocytes retrieved

These factors in combination, act as a predictive tool to assess the likelihood of severe OHSS development, with a 83% sensitivity and 84% specificity. <ref name="PMID19007627"/>

=== Primary Prevention===

Primary Prevention involves the modification of treatment regimens on the basis of OHSS risk classifications, in order to prevent OHSS occurrence.

'''Ovulation Induction'''

Unifollicular Ovulation Induction through Ovulation Induction (OI) is a primary means of avoiding OHSS in women with Polycystic Ovarian Syndrome, who are at an increased risk. In order to promote unifollicular development, the ovaries are stimulated with a low starting dose of FSH (75 IU).<ref name="PMID20416867"><pubmed>20416867</pubmed></ref> Studies suggests that a minimum gonadotropin dose lowers OHSS risk and thus a step-up regimen is utilised to achieve an ovarian response, whereby the FSH dosage is increased every 7 days until follicular development of greater than 10mm is noted.<ref name="PMID26074966" /> Alternatively, a step-down regimen may be followed, whereby a high initial FSH dosage is lowered according to the ovarian response. Another method to increase FSH levels during OI, is through '''Aromatase Inhibitors''' which promote folliculogenesis by increasing pituitary secretion of FSH, and downregulate oestrogen production through a negative feedback loop. However, Aromatase Inhibitors have not been shown to reduce OHSS incidence in comparison to other methods of OI.<ref name="PMID26074966" /> During OI, a key objective is to prevent early cycle cancellation due to premature luteinisation from pituitary secretion of LH. In order to downregulate LH secretion, Gonadotropin-releasing hormone agonists '''GnRHa''' are administered in addition to gonadotropins. Alternatively, '''GnRH antagonists''', which have a rapid onset of action, may be administered to downregulate endogenous LH secretion..<ref name="PMID20416867" /> Comparative studies have shown that the GnRH antagonist protocol has a greater effect in lowering the incidence of mild to severe OHSS. However due to the rare nature of OHSS, and insufficient sample sizes, the difference was not found to be significant. <ref name="PMID21082508"><pubmed>21082508</pubmed></ref>. Generally, the duration of exposure to gonadotropins and subsequent risk of OHSS may be minimised through mild stimulation protocols which administer FSH only in the mid to late follicular phase.<ref name="PMID20416867" />

'''Adjuvant Metformin Therapy'''

Adjuvant Metformin Therapy has been found to lower the risk of OHSS by 63%.<ref name="PMID25406011"><pubmed>25406011</pubmed></ref> It involves the administration of metformin at a daily dosage of 1000 to 2000mg, 2 months prior to Controlled Ovarian Stimulation <ref name="PMID26074966"/>. Metformin lowers the elevated insulin levels in PCOS which consequently reduce intraovarian androgen levels. This leads to a reduced sensitivity and expression of granulosa cell-follicle stimulating hormone receptors which result in a less exaggerated response to gonadotropins. Furthermore, it is suggested that Metformin prevents OHSS by controlling vascular permeability through the inhibition of various vasoactive molecules, including VEGF.

'''Avoiding hCG during Luteal Phase Support

Following Controlled Ovarian Stimulation, the steroid levels of E2 and P4 are reduced during the luteal phase due to the negative feedback on the pituitary. This leads to low endogenous LH levels, which consequently reduce endometrial receptivity as well as the luteal phase duration itself. As a result, implantation and pregnancy rates are reduced and early pregnancy loss rates are increased.<ref name="PMID20416867" /> Luteal Phase Support (LPS) serves to combat these adverse events with the use of hCG. However, hCG has been found to increase the risk of OHSS. Alternatively, the use of progesterone has been found to not only halve the risk of OHSS, but also induce similar improvements in pregnancy and miscarriage rates as hCG.<ref name="PMID26148507"><pubmed>26148507</pubmed></ref>

===Secondary Prevention===

Secondary Prevention aims to prevent progression to OHSS once COS has been initiated and the patient has been found to mount an exaggerated response. <ref name="PMID20416867" />

'''Coasting'''

Coasting is a first-line secondary preventative strategy. It consists of the withdrawal of gonadotrophins when a critical number of follicles and/or E2 concentration is reached. hCG is administered once the E2 concentration reduces to a safe level, before the process of oocyte retrieval commences. This preventative strategy is conducted for a period of less than 3 days in order to avoid compromising IVF outcomes.<ref name="PMID26074966"/>

[[File:Cryopreservation of Porcine Embryos.jpeg|right|thumbnail|300px|Cryopreserved embryos of the swine model<ref name="PMID26309801"><pubmed>4497712</pubmed></ref>]]

'''Cryopreservation'''

Cryopreservation of embryos after oocyte retrieval is another avenue which may avert OHSS progression. The cryopreserved embryos are only reimplanted once the patient's hormone serum levels have normalised. Using oocyte vitrification, crystal formation within embryo tissue is avoided and so cryopreserved embryos have been found to produce better pregnancy rates with a 32% increase, than fresh embryo transfer.<ref name="PMID26074966"/> Recent studies suggest cryopreservation itself does not reduce OHSS rates, but must be followed by a GnRHa trigger to avert OHSS.<ref name="PMID24753847"><pubmed>24753847></ref>

'''Cycle cancellation'''

Cycle cancellation is a guaranteed method to prevent early OHSS whereby hCG is withheld. This is a last resort strategy as it carries the risk of significant psychological distress and financial loss for the patient. <ref name="PMID20416867"/>

</div>

==Effect on the Newborn==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

</div>
Women who develop OHSS while undergoing Assisted Reproductive Technologies (ART) treatment are not only more likely to achieve a pregnancy, but have a live birth as the pregnancy outcome. This live birth is also more likely to be a multiple birth of two, three or more children. <ref name="PMID19591989"><pubmed>19591989</pubmed></ref> It has been postulated that a multi-fetal pregnancy leads to a more rapid increase in hCG levels, resulting in an increased risk of OHSS. However, the causal nature between multi-fetal pregnancy and OHSS development is disputed and further research is required to distinguish correlation from causation. <ref name="PMID19573292"><pubmed>19573292</pubmed></ref>

OHSS development is also associated with an increased risk of adverse outcomes including '''stillbirth, premature birth and low birth weight'''.<ref name="PMID19591989" /> Although the cause for the increased risk in adverse pregnancy outcomes is unknown, it is suggested that as the incidence of OHSS is reduced through various prevention strategies, the risk of such outcomes may be also be reduced.

'''<span style="color:#FA58D0"> [http://pregnancyperfect.com/emilyley/ The following link is to a podcast of a woman describing her pregnancy in which she underwent IVF, had OHSS and gave birth to healthy twins]<ref name="Emily"> Pregnancy Perfect[ http://pregnancyperfect.com/emilyley/ ], 'TWINS, IVF, OHSS AND C-SECTION WITH EMILY LEY'</ref> </span>'''

==Genetics==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

Despite OHSS typically being of iatrogenic origin as a result of ovarian stimulation with gonadotropins, research has been conducted into the potential genetics behind OHSS as many sporadic and familial cases have been observed. '''Mutations''' in the receptor for hormones such as Follicle Simulating Hormone (FSH), Lutenizing Hormone (LH) and hCG have all been targets of OHSS genetics research. Interestingly, they too also arise from a common ancestral gene.

===Follicle Stimulating Hormome===

Dr. Botros Rizk, of the University of South Alabama College of Medicine <ref name="PMID19573286"><pubmed>19573286</pubmed></ref>, has written extensively regarding the genetics behind OHSS. In particular, he talks about '''FSH receptors''' (FSHR) and their role in the syndrome. He hypothesises that mutations in these receptors could be activating or inactivating, leading to an increased risk of developing OHSS or sterility respectively. Currently, 744 single nucleotide polymorphisms (a type of mutation) have been found in the gene encoding the FSHR, 8 of which are located in its exons (coding regions of the gene). How the ovary responds is resultant on the FSHR genotype. For example, Ser680Asn, a polymorphism in the FSHR gene has been shown to aid in predicting the severity of a woman's OHSS. Ordinarily FSH stimulates the growth of ovarian follicles, however, when mutated, it is stimulated by the hCG resulting in excessive follicle development.

Spontaneous OHSS, OHSS that arises and cannot be attributed to any form of ovarian stimulation or Assisted Reproductive Technology, has been linked to activating mutations in the FSHR <ref name="PMID23499866"><pubmed>23499866</pubmed></ref>. This familial disorder is an autosomal dominant one. In most cases the FSHR can be stimulated by the presence of Thyroid Stimulating Hormone (TSH) or hCG, in the absence of FSH (the ligand for FSHR).

[[File:FSHR Gene.jpg|centre|thumbnail|700px|This image depicts the location of the FSHR Gene on chromosome 2. It is located on the short arm between positions 21 and 16. Changed to the FSHR gene has been linked to OHSS. <ref name="Genetcis"> Genetics Home Reference [http://ghr.nlm.nih.gov/gene/FSHR'</ref>]]

===Lutenizing Hormome===

The '''Lutenizing Hormone Receptor''' (LHR) gene in humans is comprised of 11 exons. Animal studies have shown that many primates exhibit a similar gene which is comprised of only 10 exons, however a gene lacking the 10th exon has been identified and termed the type 2 LHR. Expression of the type 2 LHR has been seen in humans. The type 2 LHR, compared to the wild-type LHR appears to be repaired with regard to its function. Defects in the type 2 LHR include a decrease in efficiency of transport to the plasma membrane and irregularities in signal transduction. Inactivating mutations in the LHR have been seen to cause infertility in women as well as amenorrhoea. Activating LHR gene mutations are asymptomatic and are not associated with OHSS in women.

===Bone Morphogenic Protein===

An imporant growth factor, derived from oocytes called '''BMP-15''' (Bone Morphogenic Protein 15) is vital for female fertility. It belongs to the family of growth factors, Transforming Growth Factor β (TGF-β) and is heavily involved in folliculogenesis. It has been found that mutations in the BMP-15 gene caused infertility in female sheep. Conversely, it has also been indicated in enhanced fertility when BMP-15 is present is high amounts in follicular fluid <ref name="PMID19573286" />.

A case study done by Hanevik ''et. al.'' in 2013 <ref name="PMID21565556"><pubmed>21565556</pubmed></ref> found that a Single Nuclear Polymorphism (SNP) in the BMP-15 gene is responsible for a high response to ovarian hyper-stimulation. The aim of the study was to test the effect the SNP had on BMP-15 with regard to high and low responders buy taking blood from 53 high responders, 38 low responders and 100 non-responders (controls) and analysing 5 noted SNP's. Results from their study showed a correlation between a high response to ovarian hyper-stimulation and the BMP-15 9G allele. The article does state however, that further research is required into the molecular effects of SNP's on the function of BMP-15.

===Vascular Endothelial Growth Factor===

'''Vascular endothelial growth factor''' (VEGF) has been indicated as one of the key agents causing vascular permeability and subsequent ascites in OHSS. The gene, which is located on chromosome 12, is made up of 8 exons (coding regions), of which exons 6 and 7 do not always appear due to the exons being spliced out.The splicing of this gene allows for various isoforms of the gene to exist of which VEGF 121 and 165 appear to play a role in angiogenesis. There are two VEGF Receptors, VEGFR-1 and VEGFR-2 that belong to the tyrosine kinase family of receptors (for more information on VEGF see [[Pathophysiology]]). Because of its distinct role in OHSS, it has been targeted as an area for research for potential treatments. The idea is that if the genetic expression of VEGF and its receptors can be controlled, OHSS can be avoided or treated.<ref name="PMID19573286" />

A different study by Hanevik ''et. al.'' , <ref name="PMID22587628"><pubmed>22587628</pubmed></ref> done in 2012 involved analysing blood samples from 53 women with OHSS and 100 women without it (controls) and analysing 6 SNP's in the VEGFR2 gene to find any genetic variations. They found a correlation between women with the VEGF +405cc genotype and the development of OHSS indicating women that undergo controlled ovarian hyper-stimulation and posses his genotype, are at an increased risk of developing OHSS.

</div>

== Current Research on Animal Models==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

{|
|-bgcolor="FFF5FF"
|<span style="font-size:120%">'''Inhibition of Cyclooxygenase-2 (COX-2) by Meloxican decreasing the incidence of OHSS in Rat Model'''</span> <ref name="PMID18166186"><pubmed>18166186</pubmed></ref>

Reasearch was carried out to investigate the effects of selective inhibition of the enzyme COX-2 on the Ovarian Hyperstimulation Syndrome (OHSS) using Female Wistar rates as the subjects. The research aimed to find results by measuring the number of antral and luteinized follicles, ovarian weight, vascualr endothelial growth factors and COX-2 immunohistochemistry. The rats being tested were all 22 days old and were divided into four equal groups;

'''Group 1 (Control group)''' was subject to a 0.1 ml of Intraperitoneal Saline from days 22 ~ 26

'''Group 2 (Mildly-stimulated group)''' subject to 10IU of pregnant mare serum gonadotrophin (PMSG) on day 24 and then 10IU of Human Chorionic Gonadotrophin (hCG) on day 26

'''Group 3 (OHSS positive group)''' was subject to 10IU of PMSG from days 22 ~ 26 and then administered 30IU of hCG on day 26 to induce OHSS

'''Group 4 (OHSS positive variant group)''' received 15mg/ml of Meloxicam 2 hours prior to administration of 10IU PMSG from days 22 ~ 26

Results showed there was no difference in ovarian weight in samples from Group 1 and Group 2, however Group 3 showed signs of significant ovarian weight increase which in group 4 was suppressed by the introduction of Meloxicam. No differences were observed in the number of antral follicles amongst the four test groups. Results from Group 2 and Group 3 showed that the granulosa cells of preovulatory follicles and the stromal cells were highly VEGF immunoreactive, however the Meloxicam treated Group 4 showed less immunoreactivity than Group 2 and Group 3 which indicated the correlation between Meloxicam and the diminished VEGF expression. Group 3 presented an increased COS-2 immunoreactivity which was highly diminished than in Group 4.

The research concluded that in a rat model, the enzyme Meloxicam has a beneficial effect on OHSS by reducing the increase of ovarian weight and the expression of VEGF associated with OHSS, the effects of which may be mediated by the inhibitory capacity of COX-2 on Meloxicam
|}

{|
|-bgcolor="FFF5FF"
|<span style="font-size:120%">'''Inhibition of Ovarian VEGF secretion by activation of Dopamine Receptor 2'''</span> <ref name="PMID25217874"><pubmed>25217874</pubmed></ref>

This research was carried out to investigate a possibility in whether a Dopamine Receptor 2 agonist '''(D2-ag)''' can assist in the prevention of Ovarian Hyperstimulation Syndrome, using rat models, by decreasing the ovarian vascular endothelial growth factor '''(VEGF)''' production. Using Immature Wistar rats (22 days old) as their animal model, the rats were initially stimulated with Gonadotrophins to mimic the onset and effects of OHSS and then subjected to treatment with a D2-agonist and/or a D2-antagonist (D2-ant). The vascular permeability was measured at the endpoint after day 26 by measuring the peritoneal extravasion of a previously injected dye and ovaries from all subjects were collected to assess the effects of D2-ag and D2-ant on the production of Ovarian VEGF. The expression of VEGF mRNA was measured by quantitative real time PCR and the levels of VEGF proteins were measured by Western Blots.

Results showed that the D2-ag caused a large reduction in the vascular permeability which was in turn associated with the great decreased in VEGF protein production in the OHSS rat ovaries, whereas the introduction of D2-ant showed opposite results with a increase in the vascular permeability leading to the increase of VEGF protein production in the ovaries. Ovarian VEGF mRNA levels were found to be unaffected by the introduction of these drugs in OHSS rat subjects. Conclusions were drawn on the fact that Dopamine Receptor 2 agonists prevent the increase of vascular permeability in subjects with OHSS by decreasing the ovarian production of VEGF and also that due to the dose-dependent inhibitory effect of the D2-ag on ovarian VEGF, current OHSS therapies used in humans can benefit by increasing the intraovarian concentration of D2-ag.
|}

</div>

==Glossary==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

'''Aromatase Inhibitor''' - A drug that inhibits enzyme aromatase, which in turn suppresses estrogen synthesis.

'''Ascites''' - An accumulation of fluid in the peritoneal cavity with resultant abdominal swelling.

'''Cabergoline''' - A dopamine receptor agonist used to treat hormone imbalance.

'''Controlled Ovarian Stimulation''' - female infertility treatment using medications to stimulate the ovaries to develop follicles.

'''Cryopreservation''' - Cooling and storing biological material at extremely low temperatures.

'''E2''' - Estradiol - Potent estrogen sex hormone.

'''FSH''' - Follicle Stimulating Hormone

'''Gonadotropin''' - Any hormone that has a stimulating effect on the gonads.

'''GnRH agonist''' - Gonadotropin Releasing Hormone - A class of compounds that mimic the effect of the natural Gonadotropin Releasing Hormone.

'''GnRH antagonist''' - Gonadotropin Releasing Hormone - A class of compounds that are similar in terms of the structure of natural Gonadotropin Releasing Hormone but has a antagonistic effect.

'''hCG'''- Human Chorionic Gonadotropin

'''Hemoconcentration''' - An increase in the concentration of circulating red blood cells in response to a decrease in blood plasma volume.

'''Hypovolemic''' - A decrease in circulating blood volume.

'''Iatrogenic''' - Illness caused as a result of a medical examination or treatment.

'''Intravenous fluids''' - Is the infusion of liquid substances directly into a vein.

'''IVF''' - In-vitro Fertilization

'''LH''' - Luteinizing Hormone

'''Metformin''' - A biguanide, antidiabetic drug used as an adjuvant to modify the effect of other agents.

'''NSAID''' - Non-steroidal Anti-Inflammatory Drug e.g. Ibuprofen

'''Oocyte vitrification''' - technique for cryopreservation of oocytes.

'''OHSS''' - Ovarian Hyper-stimulation Syndrome

'''Oliguria'''- Decreased urine output/small amounts of urine produced.

'''P4''' - Progesterone - endogenous progestogen sex hormone.

'''PCOS''' - Polycystic Ovarian Syndrome. An endrocrine system disorder whereby the ovaries are enlarged with small collections of fluid.

</div>

==References==

File:Cryopreservation of Porcine Embryos.jpeg

2015-10-23T15:14:09Z

Z3372824: /* Cryopreservation of Porcine embryos */

==Cryopreservation of Porcine embryos==

(Derived from original figure legend, based on article by Men et al. PMID 26309801)

Representative image of cryopreserved embryos of the swine model: a) mature oocyte b) day 1 embryo c) day 4 embryo d) blastocyst from cryopreserved day 1 embryo with an intact zona pellucida excluding the lipid droplet. Scale bars=20 μm.

Cryopreservation of embryos allows for embryos to be preserved at sub-zero temperatures. The embryo may be implanted when patient serum levels have normalised and the risk of OHSS progression is reduced.

===References===

<pubmed>26309801</pubmed>| [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4497712/]

====Copyright====

© Hongsheng Men et al. 2015; Published by Mary Ann Liebert, Inc.
This Open Access article is distributed under the terms of the Creative Commons License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited.

fig-2.jpeg

{{Template:Student Image}}

File:Cryopreservation of Porcine Embryos.jpeg

2015-10-23T15:08:34Z

Z3372824: /* Cryopreservation of Porcine embryos */

==Cryopreservation of Porcine embryos==

(Derived from original legend)

Representative image of cryopreserved embryos of the swine model: a) mature oocyte b) day 1 embryo c) day 4 embryo d) blastocyst from cryopreserved day 1 embryo with an intact zona pellucida excluding the lipid droplet. Scale bars=20 μm.

Cryopreservation of embryos allows for embryos to be preserved at sub-zero temperatures. The embryo may be implanted when patient serum levels have normalised and the risk of OHSS progression is reduced.

===References===

<pubmed>4497712</pubmed>| [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4497712/]

====Copyright====

© Hongsheng Men et al. 2015; Published by Mary Ann Liebert, Inc.
This Open Access article is distributed under the terms of the Creative Commons License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited.

fig-2.jpeg

{{Template:Student Image}}

2015 Group Project 2

2015-10-23T15:07:29Z

Z3372824: /* Prevention */

{{ANAT2341Project2015header}}

==<span style="font-size:120%">'''Ovarian Hyper-stimulation Syndrome (OHSS)'''</span>==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

Ovarian Hyper stimulation Syndrome (OHSS) is an iatrogenic complication of '''Assisted Reproduction Technology''' (ART), in which women take medications to stimulate oocyte growth. It is generally identified by cystic enlargements of the ovaries and fluid accumulation in the peritoneal cavity due to the increased capillary permeability and ovarian neoangiogenesis <ref name="PMID22065820"><pubmed>22065820</pubmed></ref>. It is an occurrence which is dependent on the controlled stimulation of the ovaries in preparation for IVF i.e. administration of human Chorionic Gonadotropin (hCG).

OHSS was first described in 1943 as ''“syndrome d’hyperluteinisation massive des ovaries”''. It was during this time that gonadotropins were prepared from animals such as sheep to bring on ovulation in women. The first recorded death as a result of OHSS occurred in 1951 and was due to renal failure as a result of oligouria, a complication of the syndrome <ref name="OHSS"> Marie M. Budev, DO, MPH; Alejandro C. Arroliga, MD; Tommaso Falcone, MD, [ http://utilis.net/Morning%20Topics/REI/Ovarian%20Hyperstimulation.pdf ], 'Ovarian Hyperstimulation Syndrome'</ref> <ref name="PMID12638783"><pubmed>12638783</pubmed></ref>.

<span style="color:#FA58D0">'''This wikipage aims to provide clear information on various areas surrounding OHSS such as diagnosis, prevention and complications and will look into the genetics behind the disorder and the various animals models used to research it'''.</span>

<html5media height="350" width="450">https://www.youtube.com/watch?v=aXmjJw234a4</html5media>

'''Overview of Ovarian Hyperstimulation Syndrome''' <ref> Howcast (2013, August 27) Ovarian Hyperstimulation Syndrome | Infertility. Retrieved from https://www.youtube.com/watch?v=aXmjJw234a4</ref>

</div>

==Epidemiology==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

Ovarian Hyper-Stimulation Syndrome (OHSS) rarely occurs sporadically, and if it does, it is usually the result of an underlying genetic problem. The majority of OHSS is due to the ovaries being stimulated to mature and release an abundance of oocytes, in response to hormones Human Chorionic Gonadotropin (hCG) and Follicle Stimulating hormone (FSH), during IVF. Rarely, Clomifene Citrate therapy can cause OHSS.<ref name="WikiOHSS"> Wikipedia, [ https://en.wikipedia.org/wiki/Ovarian_hyperstimulation_syndrome ], 'Ovarian Hyperstimulation Syndrome'</ref>

OHSS only affects '''0.5-5%''' of women undergoing Ovarian Hyper-stimulation, but despite its small prevalence, it is a potentially fatal outcome of a non-vital procedure and remains a prevalent problem for fertility specialists <ref name="PMID12498425"><pubmed>12498425</pubmed></ref> <ref name="PMID12638783"><pubmed>12638783</pubmed></ref>. Age has been cited as a factor affecting those with OHSS, with younger women more at risk. Additionally, women with allergies were seen to have a higher incidence of OHSS. It is important to note that at this point in time, there is no positive correlation between gonadotropin dose and OHSS.

Of the 0.5-5% of women affected with OHSS mentioned above, 2% of those women will require hospitalisation. As of 2011, it has been reported that the incidence of OHSS was '''increasing''', resulting in approximately 3 deaths per 100,000 women undergoing ovarian stimulation per year <ref name="PMID21828116"><pubmed>21828116</pubmed></ref>. This is particularly worrying as in 2008, in the United States alone, there were around 150,000 IVF cycles undertaken.

{|
|-bgcolor="F8E0F1"
|
'''With the field of Assisted Reproductive Technologies expanding and more women partaking in IVF treatments, the threat of women developing OHSS is an ongoing and increasing one''' <ref name="PMID21828116" />.
|}
{| class="wikitable mw-collapsible mw-collapsed"
! colspan=4|Characteristics of women with OHSS by complication group <ref name="PMID19591989"><pubmed>19591989</pubmed></ref>
|-
! scope="col" width="100px" height="60px" style="text-align:center| '''Characteristic'''
! scope="col" width="100px" height="60px" style="text-align:center| '''No Complications
(N = 212,041)'''
! scope="col" width="100px" height="60px" style="text-align:center| '''Moderate OHSS
(N = 1,523)'''
! scope="col" width="100px" height="60px" style="text-align:center| '''Severe OHSS
(N = 655)'''
|-
|style="text-align:center; background: #FF99FF;"| '''Maternal Age (Mean ± SD)'''
|style="text-align:center; background: #F6CEEC;"| 35.6 ± 4.6
|style="text-align:center; background: #F6CEEC;"| 33.0 ± 4.3
|style="text-align:center; background: #F6CEEC;"| 33.1 ± 4.4
|-
|style="text-align:center; background: #FF99FF;"| '''Maternal Age (%)'''
|-
|style="text-align:left; background: #F6CEEC;"| <30 years
|style="text-align:center; background: #F6CEEC;"| 10 %
|style="text-align:center; background: #F6CEEC;"| 21.1 %
|style="text-align:center; background: #F6CEEC;"| 20.6 %
|-
|style="text-align:left; background: #F6CEEC;"| 30-34 years
|style="text-align:center; background: #F6CEEC;"| 30.4 %
|style="text-align:center; background: #F6CEEC;"| 43.2 %
|style="text-align:center; background: #F6CEEC;"| 40.5 %
|-
|style="text-align:left; background: #F6CEEC;"| 35-39 years
|style="text-align:center; background: #F6CEEC;"| 37.8 %
|style="text-align:center; background: #F6CEEC;"| 27.2 %
|style="text-align:center; background: #F6CEEC;"| 32.5 %
|-
|style="text-align:left; background: #F6CEEC;"| >40 years
|style="text-align:center; background: #F6CEEC;"| 21.8 %
|style="text-align:center; background: #F6CEEC;"| 8.4 %
|style="text-align:center; background: #F6CEEC;"| 6.4 %
|-
|style="text-align:center; background: #FF99FF;"| '''Nulligravida (%)'''
|style="text-align:center; background: #F6CEEC;"| 45.8 %
|style="text-align:center; background: #F6CEEC;"| 51.5 %
|style="text-align:center; background: #F6CEEC;"| 51.8 %
|-
|style="text-align:center; background: #FF99FF;"| '''Infertility Diagnosis (%)'''
|-
|style="text-align:left; background: #F6CEEC;"| Male factor
|style="text-align:center; background: #F6CEEC;"| 37.7 %
|style="text-align:center; background: #F6CEEC;"| 41.0 %
|style="text-align:center; background: #F6CEEC;"| 33.4 %
|-
|style="text-align:left; background: #F6CEEC;"| Endometriosis
|style="text-align:center; background: #F6CEEC;"| 13.5 %
|style="text-align:center; background: #F6CEEC;"| 13.5 %
|style="text-align:center; background: #F6CEEC;"| 10.7 %
|-
|style="text-align:left; background: #F6CEEC;"| Ovulation Disorders
|style="text-align:center; background: #F6CEEC;"| 14.0 %
|style="text-align:center; background: #F6CEEC;"| 29.5 %
|style="text-align:center; background: #F6CEEC;"| 22.4 %
|-
|style="text-align:left; background: #F6CEEC;"| Diminished ovarian reserve
|style="text-align:center; background: #F6CEEC;"| 16.9 %
|style="text-align:center; background: #F6CEEC;"| 3.2 %
|style="text-align:center; background: #F6CEEC;"| 2.4 %
|-
|style="text-align:left; background: #F6CEEC;"| Tubal factors
|style="text-align:center; background: #F6CEEC;"| 20.4 %
|style="text-align:center; background: #F6CEEC;"| 22.6 %
|style="text-align:center; background: #F6CEEC;"| 22.3 %
|-
|style="text-align:left; background: #F6CEEC;"| Uterine factors
|style="text-align:center; background: #F6CEEC;"| 5.1 %
|style="text-align:center; background: #F6CEEC;"| 4.3 %
|style="text-align:center; background: #F6CEEC;"| 3.1 %
|-
|style="text-align:left; background: #F6CEEC;"| Other factors
|style="text-align:center; background: #F6CEEC;"| 13.9 %
|style="text-align:center; background: #F6CEEC;"| 13.1 %
|style="text-align:center; background: #F6CEEC;"| 10.4 %
|-
|style="text-align:left; background: #F6CEEC;"| Unexplained factor
|style="text-align:center; background: #F6CEEC;"| 12.7 %
|style="text-align:center; background: #F6CEEC;"| 11.8 %
|style="text-align:center; background: #F6CEEC;"| 18.6 %
|-
|}
</div>

==Causative Agents==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

[[File:Follicular Development.jpeg|right|thumbnail|500px|Infertility treatments aim to facilitate follicular development and induce ovulation to improve chances of fertilisation <ref name="PMID24717179"><pubmed>24717179</pubmed></ref>]]

Normally a woman produces one egg per month from the ovaries, which travel down the Fallopian tube to be fertilized or be released from the body. In cases where women have difficulty falling pregnant, they are given medication which help them to produce and release eggs (as shown in the diagram to the right), further increasing their chances of fertilization and pregnancy <ref><pubmed>19573285</pubmed></ref>. Ovarian Hyper stimulation Syndrome generally occurs during infertility treatments when the ovaries are overstimulated by the fertility medication which causes the ovaries to swell and leak fluids into the belly and abdomen. The prevalence of OHSS onset is linked with excessive number of follicle development in response to the administration of injectable Follicle Stimulating Hormones (FSH) followed by the '''Human Chorionic Gonadotrophins''' (hCG) which triggers the release of the oocytes <ref><pubmed>26190539</pubmed></ref>.

'''Follicle Stimulating Hormones''' (FSH) <ref name="PMID9020850"><pubmed>9020850</pubmed></ref> are glycoprotein hormones that are produced and secreted from the Anterior Pituitary gland into the bloodstream, which regulate the developmental, growth, maturation and the reproductive processes within the body. In females, the Follicle Stimulating Hormones initiates the stages of growth and development of immature ovarian follicles within the ovaries before the release of an egg from a follicle at ovulation. When FSH is administered to a patient who is suffering from infertility, the increase FSH levels affect the rate of development and production, in turn increasing the amount of follicles which are ready to be released during ovulation.

</div>

==Symptoms==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

OHSS is classified based on a criteria from mild, moderate and severe <ref name="WikiOHSS" />:

'''Mild Symptoms'''- abdominal bloating, minimal weight gain, nausea, diarrhoea and a feeling of fullness.

'''Moderate Symptoms'''- Substantial weight gain (on average 2 or more pounds a day), increased abdominal girth, darkend urine and excessive thirst in addition to the mild symptoms.

'''Severe Symptoms'''- In addition to the symptoms associated with Mild and Moderate OHSS, in severe OHSS, you see shortness of breath, calf and chest pains and pleural effusion.

===<span style="font-size:100%">Classifications of Ovarian Hyper-stimulation Syndrome:</span> <ref name="PMID22065820"><pubmed>22065820</pubmed></ref>===

{| class="wikitable" style="text-align:center
|-
! scope="col" width="70px"| '''Classification'''
! scope="col" width="650px"| '''Symptoms'''
|-
|style="text-align:center; background: #F6CEEC;"| '''Mild'''
|style="height: 60px; background: #F6CEEC;"| '''Grade 1''' - Abdominal distention and discomfort
'''Grade 2''' - Abdominal distention, discomfort with nausea, vomiting and/or diarrhea and ovarian enlargement from 5~12cm
|-
|style="text-align:center; background: #F8E0F1;"| '''Moderate'''
|style="height: 60px; background: #F8E0F1;"| '''Grade 3''' - All features of Mild OHSS with ultrasonographic evidence of ascites
|-
|style="text-align:center; background: #F6CEEC;"| '''Severe'''
|style="height: 60px; background: #F6CEEC;"| '''Grade 4''' - All features of Moderate OHSS with the addition of clinical evidence of ascites and breathing difficulties present
'''Grade 5''' - All of the above symptoms along with a change in the blood volume, increased blood viscosity due to coagulation and diminished renal function
|}

</div>

==Diagnosis==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

Whilst symptoms of OHSS can occur as soon as 24 hours post hCG administration, they are usually seen in women 7-10 days post administration. Initially women with OHSS will present with abdominal bloating, as a result of fluid in the peritoneal cavity and an increase in ovary size. When women present with severe OHSS they are often dehydrated, due to increased vascular permeability, and have hemoconcentration. The above results in a decrease in intravascular volume, leading to '''oligouria''' <ref name="PMID22416285" />.

===History===

Initially a thorough history of the patient is taken during which the clinician looks for evidence of ovarian stimulation, followed by ovulation. During this history taking, the clinician will inquire into any weight gain noticed, urine output, and the woman's ability to maintain oral hydration. A key diagnostic tool for clinicians regarding women who are taking gonadotropins is to identify if they are at an increased risk of developing OHSS. Some risk factors include woman aged less than 30, women who have polycystic ovaries, woman with a previous history of OHSS and women who have had greater than 20 oocytes retrieved <ref name="PMID22416285" />.

===Physical Exam===
[[File:Vaginal_Ultrasonography_in_Sagittal_Plane.jpg|right|thumbnail|600px|Vaginal Ultrasonography in Sagittal plane <ref name="Wikiversity Journal of Medicine"> Häggström, Mikael. "Medical gallery of Mikael Häggström 2014". Wikiversity Journal of Medicine 1 (2). DOI:10.15347/wjm/2014.008. ISSN 20018762</ref>]]
After a history of the patient is taken, the next step is to perform a physical exam on the patient. Women who present with abdominal bloating will produce a shifting dullness upon abdominal percussion. Additionally the clinician will test the woman's vital signs, measure her abdominal girth, weight and will look for evidence of ascites or increase in calf size (usually unilateral)<ref name="PMID22416285" />.

===Investigations===

If the clinician further suspects a women of having OHSS, various investigations can be done such as an ultrasound.The intraperitoneal fluid is best imaged via vaginal ultrasound due to the enlarged ovaries making it difficult to image the pelvis using transabdominal ultrasound. The clinician can also order laboratory testing to look for urine specific gravity and and complete blood count to look for hemoconcentration with a hematocrit. Additionally, liver function tests can be ordered to look for elevated function. The clinician will also look for evidence of elevated D-dimers and fibrinogen and decreased levels of anti-thrombin 3 <ref name="SAHealth"> Government of South Australia Health [ http://www.sahealth.sa.gov.au/wps/wcm/connect/9b61ed004ee5348da663afd150ce4f37/Ovarian-hyperstimulation-syndrome-WCHN-PPG-17072012.pdf?MOD=AJPERES&CACHEID=9b61ed004ee5348da663afd150ce4f37 ], 'South Australian Paediatric Clinical Guidelines OHSS'</ref>.

====Ultrasound====

Typical appearances of the ultrasound include <ref name="Ultrasound"> Radiopaedia [ http://radiopaedia.org/articles/ovarian-hyperstimulation-syndrome-1 ], 'Ovarian Hyperstimulation Syndrome'</ref>:

*Bilaterally and symmetrically enlarged ovaries (>12cm)
* "Spoke-Wheel appearance" - presence of multiple cysts of varying size
*May also see ascites (fluid)

===Severity===

Once a clinician has deduced a women is suffering from OHSS, the severity of their condition needs to be established as either mild, moderate or severe. This is done by referring to the criteria under the sub-heading [[Symptoms]].The subsequent course of treatment for the woman will be based upon this evaluation.

{|
|-bgcolor="F6CEEC"
|
'''Further investigations''' can be done including a Chest X-ray to check for pleural effusions and oedema and USS with Doppler's to check for ascites or possible ovary torsion. <ref name="PMID22416285"><pubmed>22416285</pubmed></ref>
|}

===Differential Diagnosis===

Conditions presenting with similar symptoms or ultrasound images include <ref name="Ultrasound" />:

*Polycystic Ovaries (PO)
:: The difference is that with PO is that the cycts are typically smaller than OHSS cysts and there is no evidence of ascited or pleural effusion
*Mucinous Ovarian Malignancy
:: A type of Ovarian Epithelial tumour
*Ectopic Pregnancy <ref name="Casereport"> Australian Medical Student Journal [ http://www.amsj.org/wpcontent/uploads/files/articles/amsj_v2_i1/AMSJ_v2_i1_pg58-60.pdf ], 'Ovarian hyperstimulation syndrome'</ref>
::A pregnancy in which the foetus develops outside of the uterus e.g. in the fallopian tube

</div>

==Pathophysiology==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

The definition of Ovarian Stimulation is enlarged ovaries with many luteinized cysts, that can present with secondary complications. What distinguishes Ovarian Stimulation from OHSS is the presence of vascular hyper-permeability that results in fluids being redirected elsewhere in the body.

The key process to OHSS appears to be caused by '''Vascular Endothelial Growth Factor''' (VEGF), that is released along with other cytokines, estrogen and progesterone, due to the ovary undergoing luteinization as a result of stimulation by hCG. VEGF increases vascular permeability and as a result the capillaries become more "leaky" to the fluids in them. These fluids can then escape the capillaries and accumulate in the pleural and abdominal cavities as ascites. The woman then becomes hypovolemic and is at an increased risk of circulatory, renal and respiratory issues such as arterial thromboembolism due to the thickening of the blood. Note, the blood is thickened as fluid is leaving the capillaries, leaving behind red blood cells and other cellular components of the blood <ref name="WikiOHSS" />.

The increase in expression of VEGF and VEGF Receptor 2 (VEGFR2) is attributed to the greatly increased amount of their mRNA present in the body after stimulation with hCG <ref name="PMID21082502"><pubmed>21082502</pubmed></ref>. VEGF interacts with VEGF2 and VEGF Receptor 1 (VEGFR1) to create a strong angiogenic effect. Both VEGFR2 and VEGFR1 belong to a family of receptors called tyrosine kinases. VEGF2 is involved in the regulation of angiogenesis and vascular permeability whilst VEGF1 has a slightly contradictory role in that is is involved in the maintenance of the tight junctions between endothelial cells in blood vessels. A study by Gómez ''et. al.'' <ref name="PMID21082502" /> showed that women experiencing OHSS had substantially higher plasma levels of VEGF and lower levels of VEGFR1.

[[File:Pathogenesis_of_OHSS.png|600px|centre|thumb|Pathogenesis of OHSS <ref name="PMID20416867"><pubmed>20416867</pubmed></ref>]]

</div>

==Complications==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

Ovarian torsion or rupture, renal insufficiency and thrombophlebitis can all complicate OHSS. If a pregnancy occurs, symptoms may persist longer than the usual 1 to 2 weeks and become more severe, however, even with severe OHSS, they do not extend past the first trimester <ref name="WikiOHSS" />. [[File:Polycystic Ovaries.jpeg|right|thumbnail|360px|Comparison of Normal and Polycystic Ovary]]

<span style="color:#FA58D0"> '''1-2% of women who undergo ovarian stimulation develop a severe form of OHSS''' </span>. Complications from severe OHSS include:

*Fluid collection in the abdomen
*Electrolyte disturbances (sodium and potassium)
*Kidney failure
*Ovary twisting
*Rupture of a cyst in an ovary
*Breathing problems
*Blood clots in large vessels (most commonly the legs)
*Pregnancy loss from miscarriage or termination
*Rarely, death

A study by Nouri ''et. al.'' <ref name="PMID24996451"><pubmed>24996451</pubmed></ref> found that women with '''Polycystic Ovarian Syndrome''' (PCOS) and those that were induced with hCG experienced longer recovery times from severe OHSS than women who were not pregnant. They looked at a cohort of women hospitalised for the first time with severe OHSS and subject them to the same treatments. Based on a defined criteria, they established the recovery time of these women and compared the times between those that were pregnant to those that were not pregnant. They also found that whether a woman had PCOS or ovulation induction did not affect her risk of developing OHSS if she was not pregnant. It is only a risk factor for pregnant women.

===Thromboembolic events===

A frequent and deadly complication of OHSS are thromboembolic events due to increased blood clotting. This increase in blood clotting has been attributed to a variety of complications such as hemoconcentration (which thickens the blood), hypovolemia and an increase in the permeability of blood vessels as a result of increased vasoactive substances in the body of ovarian origin. Thromboembolic events include venous thromboses often in the upper extremities and arterial thromboses such as those in the cerebrovascular region. These events can lead to amputations of extremities, brain damage, miscarriage and death. To avoid this, anti-coagulants are given to pateitns with OHSS and they are fitted with compression stockings (see [[Treatment]]) <ref name="PMID23378404"><pubmed>23378404</pubmed></ref>.

{|
|-bgcolor="F8E0F1"
|
The risk of a woman developing OHSS is higher if she is having a '''twin pregnancy''', as she is exposed to higher concentration of hCG. <ref name="PMID9756273"><pubmed>9756273</pubmed></ref>
|}

</div>

==Treatment==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

'''General treatment
'''
*''Acetaminophen'' with or without a narcotic agent- used to treat abdominal discomfort
*Women are encouraged to drink 2-3 litres of water a day to prevent hemoconcentration
*Women are advised to avoid sexual intercourse and vigorous exercise at the risk of torsion or rupture of the ovaries
*NSAID's with anti-platelet properties should NOT be used as they may effect renal function in a women with OHSS
*Patients with significantly painful ascites or breathing problems may undergo ''Paracentesis'' (drainage of the ascites)
*''Culdocentesis'' (extraction of fluid from recto-uterine pouch) can be done to decrease the likelihood of a woman with moderate OHSS progressing to severe OHSS.<ref name="PMID22416285" />

===Mild to Moderate OHSS===

Mild OHSS can often resolve on its own, however, moderate OHSS may include treatments such as<ref name="WikiOHSS" />:

*Anti-nausea medication and prescription painkillers
*Regular physical examinations and ultrasounds
*Daily weigh-ins and waist measurements
*Measuring the amount of urine produced each day
*Frequent blood tests for monitoring dehydration and electrolyte imbalance
*Maintaining a high balance of fluids
*Drainage of excess abdominal fluid by inserting a needle in the abdominal cavity
*Wearing support stockings which help prevent blood clots/thrombosis

===Severe OHSS===

[[File:Abdominal Paracentesis.png|thumb|right|350px|Paracentesis is a common procedure done on women who have OHSS as it is used to drain the ascites in their abdomen. In this image you can see the puncture of the peritoneal cavity with a needle that then drains the fluid externally. <ref name="Wikiversity Journal of Medicine"> Blausen.com staff. "Blausen gallery 2014". Wikiversity Journal of Medicine. DOI:10.15347/wjm/2014.010. ISSN 20018762 </ref>]]

Severe OHSS requires hospital care in order for constant monitoring and treatment such as <ref name="WikiOHSS" />:

*Intravenous fluids with a crystalloid solution (100-150mL/hr)
*Intravenous Albumin is administered is IV fluids are insufficient (15-20mL/hr of 25% albumin for 4 hrs)
*In addition to Acetaminophen, ''Opioid analgesics'' can be administered for pain relief
*''Antiemetics'' can be used to subside nauseas and/or vomiting
*Woman administered to hospital of OHSS are considered at high risk of thromboembolic complications and are given low molecular weight ''heparin'', an anti-coagulant
*''Cabergoline''- lessens OHSS symptoms
*''GnRH agonist''- suppresses ovarian activity
**If at risk of OHSS, alternates include using a GnRH agonist instead of hCG however its effects on pregnancy rates are questionable. Using a GnRH agonist to replace the use of hCG for final oocyte stimulation will see a 6% decrease in delivery rate.
*Daily monitoring of creatine, urea, creatine clearance C-reactive protein (to rule out infection) are all required in combination with weekly tests such as liver and renal function tests and chest x-rays (to check for pleural effusion) <ref name="PMID12638783" />.

If there are serious complications then additional treatments are required:

*Surgery for a ruptured ovarian cyst
*Intensive care for the liver or lung complications

====Paracentesis====

For women with severe/grade 3 OHSS, paracentesis, the removal of fluid from the body using an aspiration needle, can be undertaken. It is a diagnostic and a therapeutic method that can be done trans-abdominally and trans-vaginally. It is used to relieve symptoms, improve haemodynamics e.g. Urinary output, and shorten the women's hospital stay. Complications of paracentesis include bleeding, infection and organ injury, however are note common <ref name="Paracentesis"> S. Monica Soni, HMS 3, Gillian Lieberman, MD [ http://eradiology.bidmc.harvard.edu/LearningLab/genito/Soni.pdf ], 'Ovarian Hyperstimulation Syndrome'</ref>.

{|
|-bgcolor="F8E0F1"
|
The most important aspect of treatment for any women with OHSS is close and constant '''monitoring''' with her healthcare professional. Counselling may also be provided to women and their partners or families in order to provide them with the best possible knowledge base to manage and treat their OHSS. It is important to note that there is '''no one cure or treatment''' for OHSS. Treatment involves managing and eliminating the symptoms until such time as the syndrome resolves itself <ref name="WikiOHSS" />.
|}

</div>

==Prevention==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

There are three key avenues through which the incidence of OHSS may be prevented. These include identifying risk factors to predict OHSS development, modifying treatment regimes on the basis of the identified risk factors and intervention to prevent progression to OHSS once the patient has undergone '''Controlled Ovarian Stimulation''' (COS).

=== Risk factors===

'''Primary risk factors'''

Pre-existing factors likely to exacerbate the ovarian stimulation response. Primary risk factors include <ref name="PMID26074966"><pubmed>26074966</pubmed></ref>:

*Young age
*Low body weight
*History of elevated response to gonadotropins
*Polycystic Ovary Syndrome (PCOS)
*Isolated PCOS characteristic
*Previous history of OHSS.
*High pretreatment basal Anti-Mullerian Hormone (AMH) concentration
*Large Antral Follicle Count (AFC)

'''Secondary risk factors'''

Secondary risk factors involve the monitoring of ovarian response parameters once COS has been initiated. These parameters are monitored for <ref name="PMID19007627"><pubmed>19007627</pubmed></ref>:

*rapidly rising E2 levels
*E2 concentration larger than 2500 pg/mL
*large number of developing follicles (10-14mm) on the day hCG is administered
*large number of oocytes retrieved

These factors in combination, act as a predictive tool to assess the likelihood of severe OHSS development, with a 83% sensitivity and 84% specificity. <ref name="PMID19007627"/>

=== Primary Prevention===

Primary Prevention involves the modification of treatment regimens on the basis of OHSS risk classifications, in order to prevent OHSS occurrence.

'''Ovulation Induction'''

Unifollicular Ovulation Induction through Ovulation Induction (OI) is a primary means of avoiding OHSS in women with Polycystic Ovarian Syndrome, who are at an increased risk. In order to promote unifollicular development, the ovaries are stimulated with a low starting dose of FSH (75 IU).<ref name="PMID20416867"><pubmed>20416867</pubmed></ref> Studies suggests that a minimum gonadotropin dose lowers OHSS risk and thus a step-up regimen is utilised to achieve an ovarian response, whereby the FSH dosage is increased every 7 days until follicular development of greater than 10mm is noted.<ref name="PMID26074966" /> Alternatively, a step-down regimen may be followed, whereby a high initial FSH dosage is lowered according to the ovarian response. Another method to increase FSH levels during OI, is through '''Aromatase Inhibitors''' which promote folliculogenesis by increasing pituitary secretion of FSH, and downregulate oestrogen production through a negative feedback loop. However, Aromatase Inhibitors have not been shown to reduce OHSS incidence in comparison to other methods of OI.<ref name="PMID26074966" /> During OI, a key objective is to prevent early cycle cancellation due to premature luteinisation from pituitary secretion of LH. In order to downregulate LH secretion, Gonadotropin-releasing hormone agonists '''GnRHa''' are administered in addition to gonadotropins. Alternatively, '''GnRH antagonists''', which have a rapid onset of action, may be administered to downregulate endogenous LH secretion..<ref name="PMID20416867" /> Comparative studies have shown that the GnRH antagonist protocol has a greater effect in lowering the incidence of mild to severe OHSS. However due to the rare nature of OHSS, and insufficient sample sizes, the difference was not found to be significant. <ref name="PMID21082508"><pubmed>21082508</pubmed></ref>. Generally, the duration of exposure to gonadotropins and subsequent risk of OHSS may be minimised through mild stimulation protocols which administer FSH only in the mid to late follicular phase.<ref name="PMID20416867" />

'''Adjuvant Metformin Therapy'''

Adjuvant Metformin Therapy has been found to lower the risk of OHSS by 63%.<ref name="PMID25406011"><pubmed>25406011</pubmed></ref> It involves the administration of metformin at a daily dosage of 1000 to 2000mg, 2 months prior to Controlled Ovarian Stimulation <ref name="PMID26074966"/>. Metformin lowers the elevated insulin levels in PCOS which consequently reduce intraovarian androgen levels. This leads to a reduced sensitivity and expression of granulosa cell-follicle stimulating hormone receptors which result in a less exaggerated response to gonadotropins. Furthermore, it is suggested that Metformin prevents OHSS by controlling vascular permeability through the inhibition of various vasoactive molecules, including VEGF.

'''Avoiding hCG during Luteal Phase Support

Following Controlled Ovarian Stimulation, the steroid levels of E2 and P4 are reduced during the luteal phase due to the negative feedback on the pituitary. This leads to low endogenous LH levels, which consequently reduce endometrial receptivity as well as the luteal phase duration itself. As a result, implantation and pregnancy rates are reduced and early pregnancy loss rates are increased.<ref name="PMID20416867" /> Luteal Phase Support (LPS) serves to combat these adverse events with the use of hCG. However, hCG has been found to increase the risk of OHSS. Alternatively, the use of progesterone has been found to not only halve the risk of OHSS, but also induce similar improvements in pregnancy and miscarriage rates as hCG.<ref name="PMID26148507"><pubmed>26148507</pubmed></ref>

===Secondary Prevention===

Secondary Prevention aims to prevent progression to OHSS once COS has been initiated and the patient has been found to mount an exaggerated response. <ref name="PMID20416867" />

'''Coasting'''

Coasting is a first-line secondary preventative strategy. It consists of the withdrawal of gonadotrophins when a critical number of follicles and/or E2 concentration is reached. hCG is administered once the E2 concentration reduces to a safe level, before the process of oocyte retrieval commences. This preventative strategy is conducted for a period of less than 3 days in order to avoid compromising IVF outcomes.<ref name="PMID26074966"/>

[[File:Cryopreservation of Porcine Embryos.jpeg|right|thumbnail|300px|Cryopreserved embryos of the swine model<ref name="PMID4497712"><pubmed>4497712</pubmed></ref>]]

'''Cryopreservation'''

Cryopreservation of embryos after oocyte retrieval is another avenue which may avert OHSS progression. The cryopreserved embryos are only reimplanted once the patient's hormone serum levels have normalised. Using oocyte vitrification, crystal formation within embryo tissue is avoided and so cryopreserved embryos have been found to produce better pregnancy rates with a 32% increase, than fresh embryo transfer.<ref name="PMID26074966"/> Recent studies suggest cryopreservation itself does not reduce OHSS rates, but must be followed by a GnRHa trigger to avert OHSS.<ref name="PMID24753847"><pubmed>24753847></ref>

'''Cycle cancellation'''

Cycle cancellation is a guaranteed method to prevent early OHSS whereby hCG is withheld. This is a last resort strategy as it carries the risk of significant psychological distress and financial loss for the patient. <ref name="PMID20416867"/>

</div>

==Effect on the Newborn==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

</div>
Women who develop OHSS while undergoing Assisted Reproductive Technologies (ART) treatment are not only more likely to achieve a pregnancy, but have a live birth as the pregnancy outcome. This live birth is also more likely to be a multiple birth of two, three or more children. <ref name="PMID19591989"><pubmed>19591989</pubmed></ref> It has been postulated that a multi-fetal pregnancy leads to a more rapid increase in hCG levels, resulting in an increased risk of OHSS. However, the causal nature between multi-fetal pregnancy and OHSS development is disputed and further research is required to distinguish correlation from causation. <ref name="PMID19573292"><pubmed>19573292</pubmed></ref>

OHSS development is also associated with an increased risk of adverse outcomes including '''stillbirth, premature birth and low birth weight'''.<ref name="PMID19591989" /> Although the cause for the increased risk in adverse pregnancy outcomes is unknown, it is suggested that as the incidence of OHSS is reduced through various prevention strategies, the risk of such outcomes may be also be reduced.

'''<span style="color:#FA58D0"> [http://pregnancyperfect.com/emilyley/ The following link is to a podcast of a woman describing her pregnancy in which she underwent IVF, had OHSS and gave birth to healthy twins]<ref name="Emily"> Pregnancy Perfect[ http://pregnancyperfect.com/emilyley/ ], 'TWINS, IVF, OHSS AND C-SECTION WITH EMILY LEY'</ref> </span>'''

==Genetics==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

Despite OHSS typically being of iatrogenic origin as a result of ovarian stimulation with gonadotropins, research has been conducted into the potential genetics behind OHSS as many sporadic and familial cases have been observed. '''Mutations''' in the receptor for hormones such as Follicle Simulating Hormone (FSH), Lutenizing Hormone (LH) and hCG have all been targets of OHSS genetics research. Interestingly, they too also arise from a common ancestral gene.

===Follicle Stimulating Hormome===

Dr. Botros Rizk, of the University of South Alabama College of Medicine <ref name="PMID19573286"><pubmed>19573286</pubmed></ref>, has written extensively regarding the genetics behind OHSS. In particular, he talks about '''FSH receptors''' (FSHR) and their role in the syndrome. He hypothesises that mutations in these receptors could be activating or inactivating, leading to an increased risk of developing OHSS or sterility respectively. Currently, 744 single nucleotide polymorphisms (a type of mutation) have been found in the gene encoding the FSHR, 8 of which are located in its exons (coding regions of the gene). How the ovary responds is resultant on the FSHR genotype. For example, Ser680Asn, a polymorphism in the FSHR gene has been shown to aid in predicting the severity of a woman's OHSS. Ordinarily FSH stimulates the growth of ovarian follicles, however, when mutated, it is stimulated by the hCG resulting in excessive follicle development.

Spontaneous OHSS, OHSS that arises and cannot be attributed to any form of ovarian stimulation or Assisted Reproductive Technology, has been linked to activating mutations in the FSHR <ref name="PMID23499866"><pubmed>23499866</pubmed></ref>. This familial disorder is an autosomal dominant one. In most cases the FSHR can be stimulated by the presence of Thyroid Stimulating Hormone (TSH) or hCG, in the absence of FSH (the ligand for FSHR).

[[File:FSHR Gene.jpg|centre|thumbnail|700px|This image depicts the location of the FSHR Gene on chromosome 2. It is located on the short arm between positions 21 and 16. Changed to the FSHR gene has been linked to OHSS. <ref name="Genetcis"> Genetics Home Reference [http://ghr.nlm.nih.gov/gene/FSHR'</ref>]]

===Lutenizing Hormome===

The '''Lutenizing Hormone Receptor''' (LHR) gene in humans is comprised of 11 exons. Animal studies have shown that many primates exhibit a similar gene which is comprised of only 10 exons, however a gene lacking the 10th exon has been identified and termed the type 2 LHR. Expression of the type 2 LHR has been seen in humans. The type 2 LHR, compared to the wild-type LHR appears to be repaired with regard to its function. Defects in the type 2 LHR include a decrease in efficiency of transport to the plasma membrane and irregularities in signal transduction. Inactivating mutations in the LHR have been seen to cause infertility in women as well as amenorrhoea. Activating LHR gene mutations are asymptomatic and are not associated with OHSS in women.

===Bone Morphogenic Protein===

An imporant growth factor, derived from oocytes called '''BMP-15''' (Bone Morphogenic Protein 15) is vital for female fertility. It belongs to the family of growth factors, Transforming Growth Factor β (TGF-β) and is heavily involved in folliculogenesis. It has been found that mutations in the BMP-15 gene caused infertility in female sheep. Conversely, it has also been indicated in enhanced fertility when BMP-15 is present is high amounts in follicular fluid <ref name="PMID19573286" />.

A case study done by Hanevik ''et. al.'' in 2013 <ref name="PMID21565556"><pubmed>21565556</pubmed></ref> found that a Single Nuclear Polymorphism (SNP) in the BMP-15 gene is responsible for a high response to ovarian hyper-stimulation. The aim of the study was to test the effect the SNP had on BMP-15 with regard to high and low responders buy taking blood from 53 high responders, 38 low responders and 100 non-responders (controls) and analysing 5 noted SNP's. Results from their study showed a correlation between a high response to ovarian hyper-stimulation and the BMP-15 9G allele. The article does state however, that further research is required into the molecular effects of SNP's on the function of BMP-15.

===Vascular Endothelial Growth Factor===

'''Vascular endothelial growth factor''' (VEGF) has been indicated as one of the key agents causing vascular permeability and subsequent ascites in OHSS. The gene, which is located on chromosome 12, is made up of 8 exons (coding regions), of which exons 6 and 7 do not always appear due to the exons being spliced out.The splicing of this gene allows for various isoforms of the gene to exist of which VEGF 121 and 165 appear to play a role in angiogenesis. There are two VEGF Receptors, VEGFR-1 and VEGFR-2 that belong to the tyrosine kinase family of receptors (for more information on VEGF see [[Pathophysiology]]). Because of its distinct role in OHSS, it has been targeted as an area for research for potential treatments. The idea is that if the genetic expression of VEGF and its receptors can be controlled, OHSS can be avoided or treated.<ref name="PMID19573286" />

A different study by Hanevik ''et. al.'' , <ref name="PMID22587628"><pubmed>22587628</pubmed></ref> done in 2012 involved analysing blood samples from 53 women with OHSS and 100 women without it (controls) and analysing 6 SNP's in the VEGFR2 gene to find any genetic variations. They found a correlation between women with the VEGF +405cc genotype and the development of OHSS indicating women that undergo controlled ovarian hyper-stimulation and posses his genotype, are at an increased risk of developing OHSS.

</div>

== Current Research on Animal Models==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

{|
|-bgcolor="FFF5FF"
|<span style="font-size:120%">'''Inhibition of Cyclooxygenase-2 (COX-2) by Meloxican decreasing the incidence of OHSS in Rat Model'''</span> <ref name="PMID18166186"><pubmed>18166186</pubmed></ref>

Reasearch was carried out to investigate the effects of selective inhibition of the enzyme COX-2 on the Ovarian Hyperstimulation Syndrome (OHSS) using Female Wistar rates as the subjects. The research aimed to find results by measuring the number of antral and luteinized follicles, ovarian weight, vascualr endothelial growth factors and COX-2 immunohistochemistry. The rats being tested were all 22 days old and were divided into four equal groups;

'''Group 1 (Control group)''' was subject to a 0.1 ml of Intraperitoneal Saline from days 22 ~ 26

'''Group 2 (Mildly-stimulated group)''' subject to 10IU of pregnant mare serum gonadotrophin (PMSG) on day 24 and then 10IU of Human Chorionic Gonadotrophin (hCG) on day 26

'''Group 3 (OHSS positive group)''' was subject to 10IU of PMSG from days 22 ~ 26 and then administered 30IU of hCG on day 26 to induce OHSS

'''Group 4 (OHSS positive variant group)''' received 15mg/ml of Meloxicam 2 hours prior to administration of 10IU PMSG from days 22 ~ 26

Results showed there was no difference in ovarian weight in samples from Group 1 and Group 2, however Group 3 showed signs of significant ovarian weight increase which in group 4 was suppressed by the introduction of Meloxicam. No differences were observed in the number of antral follicles amongst the four test groups. Results from Group 2 and Group 3 showed that the granulosa cells of preovulatory follicles and the stromal cells were highly VEGF immunoreactive, however the Meloxicam treated Group 4 showed less immunoreactivity than Group 2 and Group 3 which indicated the correlation between Meloxicam and the diminished VEGF expression. Group 3 presented an increased COS-2 immunoreactivity which was highly diminished than in Group 4.

The research concluded that in a rat model, the enzyme Meloxicam has a beneficial effect on OHSS by reducing the increase of ovarian weight and the expression of VEGF associated with OHSS, the effects of which may be mediated by the inhibitory capacity of COX-2 on Meloxicam
|}

{|
|-bgcolor="FFF5FF"
|<span style="font-size:120%">'''Inhibition of Ovarian VEGF secretion by activation of Dopamine Receptor 2'''</span> <ref name="PMID25217874"><pubmed>25217874</pubmed></ref>

This research was carried out to investigate a possibility in whether a Dopamine Receptor 2 agonist '''(D2-ag)''' can assist in the prevention of Ovarian Hyperstimulation Syndrome, using rat models, by decreasing the ovarian vascular endothelial growth factor '''(VEGF)''' production. Using Immature Wistar rats (22 days old) as their animal model, the rats were initially stimulated with Gonadotrophins to mimic the onset and effects of OHSS and then subjected to treatment with a D2-agonist and/or a D2-antagonist (D2-ant). The vascular permeability was measured at the endpoint after day 26 by measuring the peritoneal extravasion of a previously injected dye and ovaries from all subjects were collected to assess the effects of D2-ag and D2-ant on the production of Ovarian VEGF. The expression of VEGF mRNA was measured by quantitative real time PCR and the levels of VEGF proteins were measured by Western Blots.

Results showed that the D2-ag caused a large reduction in the vascular permeability which was in turn associated with the great decreased in VEGF protein production in the OHSS rat ovaries, whereas the introduction of D2-ant showed opposite results with a increase in the vascular permeability leading to the increase of VEGF protein production in the ovaries. Ovarian VEGF mRNA levels were found to be unaffected by the introduction of these drugs in OHSS rat subjects. Conclusions were drawn on the fact that Dopamine Receptor 2 agonists prevent the increase of vascular permeability in subjects with OHSS by decreasing the ovarian production of VEGF and also that due to the dose-dependent inhibitory effect of the D2-ag on ovarian VEGF, current OHSS therapies used in humans can benefit by increasing the intraovarian concentration of D2-ag.
|}

</div>

==Glossary==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

'''Aromatase Inhibitor''' - A drug that inhibits enzyme aromatase, which in turn suppresses estrogen synthesis.

'''Ascites''' - An accumulation of fluid in the peritoneal cavity with resultant abdominal swelling.

'''Cabergoline''' - A dopamine receptor agonist used to treat hormone imbalance.

'''Controlled Ovarian Stimulation''' - female infertility treatment using medications to stimulate the ovaries to develop follicles.

'''Cryopreservation''' - Cooling and storing biological material at extremely low temperatures.

'''E2''' - Estradiol - Potent estrogen sex hormone.

'''FSH''' - Follicle Stimulating Hormone

'''Gonadotropin''' - Any hormone that has a stimulating effect on the gonads.

'''GnRH agonist''' - Gonadotropin Releasing Hormone - A class of compounds that mimic the effect of the natural Gonadotropin Releasing Hormone.

'''GnRH antagonist''' - Gonadotropin Releasing Hormone - A class of compounds that are similar in terms of the structure of natural Gonadotropin Releasing Hormone but has a antagonistic effect.

'''hCG'''- Human Chorionic Gonadotropin

'''Hemoconcentration''' - An increase in the concentration of circulating red blood cells in response to a decrease in blood plasma volume.

'''Hypovolemic''' - A decrease in circulating blood volume.

'''Iatrogenic''' - Illness caused as a result of a medical examination or treatment.

'''Intravenous fluids''' - Is the infusion of liquid substances directly into a vein.

'''IVF''' - In-vitro Fertilization

'''LH''' - Luteinizing Hormone

'''Metformin''' - A biguanide, antidiabetic drug used as an adjuvant to modify the effect of other agents.

'''NSAID''' - Non-steroidal Anti-Inflammatory Drug e.g. Ibuprofen

'''Oocyte vitrification''' - technique for cryopreservation of oocytes.

'''OHSS''' - Ovarian Hyper-stimulation Syndrome

'''Oliguria'''- Decreased urine output/small amounts of urine produced.

'''P4''' - Progesterone - endogenous progestogen sex hormone.

'''PCOS''' - Polycystic Ovarian Syndrome. An endrocrine system disorder whereby the ovaries are enlarged with small collections of fluid.

</div>

==References==

2015 Group Project 2

2015-10-23T15:05:01Z

Z3372824:

{{ANAT2341Project2015header}}

==<span style="font-size:120%">'''Ovarian Hyper-stimulation Syndrome (OHSS)'''</span>==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

Ovarian Hyper stimulation Syndrome (OHSS) is an iatrogenic complication of '''Assisted Reproduction Technology''' (ART), in which women take medications to stimulate oocyte growth. It is generally identified by cystic enlargements of the ovaries and fluid accumulation in the peritoneal cavity due to the increased capillary permeability and ovarian neoangiogenesis <ref name="PMID22065820"><pubmed>22065820</pubmed></ref>. It is an occurrence which is dependent on the controlled stimulation of the ovaries in preparation for IVF i.e. administration of human Chorionic Gonadotropin (hCG).

OHSS was first described in 1943 as ''“syndrome d’hyperluteinisation massive des ovaries”''. It was during this time that gonadotropins were prepared from animals such as sheep to bring on ovulation in women. The first recorded death as a result of OHSS occurred in 1951 and was due to renal failure as a result of oligouria, a complication of the syndrome <ref name="OHSS"> Marie M. Budev, DO, MPH; Alejandro C. Arroliga, MD; Tommaso Falcone, MD, [ http://utilis.net/Morning%20Topics/REI/Ovarian%20Hyperstimulation.pdf ], 'Ovarian Hyperstimulation Syndrome'</ref> <ref name="PMID12638783"><pubmed>12638783</pubmed></ref>.

<span style="color:#FA58D0">'''This wikipage aims to provide clear information on various areas surrounding OHSS such as diagnosis, prevention and complications and will look into the genetics behind the disorder and the various animals models used to research it'''.</span>

<html5media height="350" width="450">https://www.youtube.com/watch?v=aXmjJw234a4</html5media>

'''Overview of Ovarian Hyperstimulation Syndrome''' <ref> Howcast (2013, August 27) Ovarian Hyperstimulation Syndrome | Infertility. Retrieved from https://www.youtube.com/watch?v=aXmjJw234a4</ref>

</div>

==Epidemiology==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

Ovarian Hyper-Stimulation Syndrome (OHSS) rarely occurs sporadically, and if it does, it is usually the result of an underlying genetic problem. The majority of OHSS is due to the ovaries being stimulated to mature and release an abundance of oocytes, in response to hormones Human Chorionic Gonadotropin (hCG) and Follicle Stimulating hormone (FSH), during IVF. Rarely, Clomifene Citrate therapy can cause OHSS.<ref name="WikiOHSS"> Wikipedia, [ https://en.wikipedia.org/wiki/Ovarian_hyperstimulation_syndrome ], 'Ovarian Hyperstimulation Syndrome'</ref>

OHSS only affects '''0.5-5%''' of women undergoing Ovarian Hyper-stimulation, but despite its small prevalence, it is a potentially fatal outcome of a non-vital procedure and remains a prevalent problem for fertility specialists <ref name="PMID12498425"><pubmed>12498425</pubmed></ref> <ref name="PMID12638783"><pubmed>12638783</pubmed></ref>. Age has been cited as a factor affecting those with OHSS, with younger women more at risk. Additionally, women with allergies were seen to have a higher incidence of OHSS. It is important to note that at this point in time, there is no positive correlation between gonadotropin dose and OHSS.

Of the 0.5-5% of women affected with OHSS mentioned above, 2% of those women will require hospitalisation. As of 2011, it has been reported that the incidence of OHSS was '''increasing''', resulting in approximately 3 deaths per 100,000 women undergoing ovarian stimulation per year <ref name="PMID21828116"><pubmed>21828116</pubmed></ref>. This is particularly worrying as in 2008, in the United States alone, there were around 150,000 IVF cycles undertaken.

{|
|-bgcolor="F8E0F1"
|
'''With the field of Assisted Reproductive Technologies expanding and more women partaking in IVF treatments, the threat of women developing OHSS is an ongoing and increasing one''' <ref name="PMID21828116" />.
|}
{| class="wikitable mw-collapsible mw-collapsed"
! colspan=4|Characteristics of women with OHSS by complication group <ref name="PMID19591989"><pubmed>19591989</pubmed></ref>
|-
! scope="col" width="100px" height="60px" style="text-align:center| '''Characteristic'''
! scope="col" width="100px" height="60px" style="text-align:center| '''No Complications
(N = 212,041)'''
! scope="col" width="100px" height="60px" style="text-align:center| '''Moderate OHSS
(N = 1,523)'''
! scope="col" width="100px" height="60px" style="text-align:center| '''Severe OHSS
(N = 655)'''
|-
|style="text-align:center; background: #FF99FF;"| '''Maternal Age (Mean ± SD)'''
|style="text-align:center; background: #F6CEEC;"| 35.6 ± 4.6
|style="text-align:center; background: #F6CEEC;"| 33.0 ± 4.3
|style="text-align:center; background: #F6CEEC;"| 33.1 ± 4.4
|-
|style="text-align:center; background: #FF99FF;"| '''Maternal Age (%)'''
|-
|style="text-align:left; background: #F6CEEC;"| <30 years
|style="text-align:center; background: #F6CEEC;"| 10 %
|style="text-align:center; background: #F6CEEC;"| 21.1 %
|style="text-align:center; background: #F6CEEC;"| 20.6 %
|-
|style="text-align:left; background: #F6CEEC;"| 30-34 years
|style="text-align:center; background: #F6CEEC;"| 30.4 %
|style="text-align:center; background: #F6CEEC;"| 43.2 %
|style="text-align:center; background: #F6CEEC;"| 40.5 %
|-
|style="text-align:left; background: #F6CEEC;"| 35-39 years
|style="text-align:center; background: #F6CEEC;"| 37.8 %
|style="text-align:center; background: #F6CEEC;"| 27.2 %
|style="text-align:center; background: #F6CEEC;"| 32.5 %
|-
|style="text-align:left; background: #F6CEEC;"| >40 years
|style="text-align:center; background: #F6CEEC;"| 21.8 %
|style="text-align:center; background: #F6CEEC;"| 8.4 %
|style="text-align:center; background: #F6CEEC;"| 6.4 %
|-
|style="text-align:center; background: #FF99FF;"| '''Nulligravida (%)'''
|style="text-align:center; background: #F6CEEC;"| 45.8 %
|style="text-align:center; background: #F6CEEC;"| 51.5 %
|style="text-align:center; background: #F6CEEC;"| 51.8 %
|-
|style="text-align:center; background: #FF99FF;"| '''Infertility Diagnosis (%)'''
|-
|style="text-align:left; background: #F6CEEC;"| Male factor
|style="text-align:center; background: #F6CEEC;"| 37.7 %
|style="text-align:center; background: #F6CEEC;"| 41.0 %
|style="text-align:center; background: #F6CEEC;"| 33.4 %
|-
|style="text-align:left; background: #F6CEEC;"| Endometriosis
|style="text-align:center; background: #F6CEEC;"| 13.5 %
|style="text-align:center; background: #F6CEEC;"| 13.5 %
|style="text-align:center; background: #F6CEEC;"| 10.7 %
|-
|style="text-align:left; background: #F6CEEC;"| Ovulation Disorders
|style="text-align:center; background: #F6CEEC;"| 14.0 %
|style="text-align:center; background: #F6CEEC;"| 29.5 %
|style="text-align:center; background: #F6CEEC;"| 22.4 %
|-
|style="text-align:left; background: #F6CEEC;"| Diminished ovarian reserve
|style="text-align:center; background: #F6CEEC;"| 16.9 %
|style="text-align:center; background: #F6CEEC;"| 3.2 %
|style="text-align:center; background: #F6CEEC;"| 2.4 %
|-
|style="text-align:left; background: #F6CEEC;"| Tubal factors
|style="text-align:center; background: #F6CEEC;"| 20.4 %
|style="text-align:center; background: #F6CEEC;"| 22.6 %
|style="text-align:center; background: #F6CEEC;"| 22.3 %
|-
|style="text-align:left; background: #F6CEEC;"| Uterine factors
|style="text-align:center; background: #F6CEEC;"| 5.1 %
|style="text-align:center; background: #F6CEEC;"| 4.3 %
|style="text-align:center; background: #F6CEEC;"| 3.1 %
|-
|style="text-align:left; background: #F6CEEC;"| Other factors
|style="text-align:center; background: #F6CEEC;"| 13.9 %
|style="text-align:center; background: #F6CEEC;"| 13.1 %
|style="text-align:center; background: #F6CEEC;"| 10.4 %
|-
|style="text-align:left; background: #F6CEEC;"| Unexplained factor
|style="text-align:center; background: #F6CEEC;"| 12.7 %
|style="text-align:center; background: #F6CEEC;"| 11.8 %
|style="text-align:center; background: #F6CEEC;"| 18.6 %
|-
|}
</div>

==Causative Agents==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

[[File:Follicular Development.jpeg|right|thumbnail|500px|Infertility treatments aim to facilitate follicular development and induce ovulation to improve chances of fertilisation <ref name="PMID24717179"><pubmed>24717179</pubmed></ref>]]

Normally a woman produces one egg per month from the ovaries, which travel down the Fallopian tube to be fertilized or be released from the body. In cases where women have difficulty falling pregnant, they are given medication which help them to produce and release eggs (as shown in the diagram to the right), further increasing their chances of fertilization and pregnancy <ref><pubmed>19573285</pubmed></ref>. Ovarian Hyper stimulation Syndrome generally occurs during infertility treatments when the ovaries are overstimulated by the fertility medication which causes the ovaries to swell and leak fluids into the belly and abdomen. The prevalence of OHSS onset is linked with excessive number of follicle development in response to the administration of injectable Follicle Stimulating Hormones (FSH) followed by the '''Human Chorionic Gonadotrophins''' (hCG) which triggers the release of the oocytes <ref><pubmed>26190539</pubmed></ref>.

'''Follicle Stimulating Hormones''' (FSH) <ref name="PMID9020850"><pubmed>9020850</pubmed></ref> are glycoprotein hormones that are produced and secreted from the Anterior Pituitary gland into the bloodstream, which regulate the developmental, growth, maturation and the reproductive processes within the body. In females, the Follicle Stimulating Hormones initiates the stages of growth and development of immature ovarian follicles within the ovaries before the release of an egg from a follicle at ovulation. When FSH is administered to a patient who is suffering from infertility, the increase FSH levels affect the rate of development and production, in turn increasing the amount of follicles which are ready to be released during ovulation.

</div>

==Symptoms==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

OHSS is classified based on a criteria from mild, moderate and severe <ref name="WikiOHSS" />:

'''Mild Symptoms'''- abdominal bloating, minimal weight gain, nausea, diarrhoea and a feeling of fullness.

'''Moderate Symptoms'''- Substantial weight gain (on average 2 or more pounds a day), increased abdominal girth, darkend urine and excessive thirst in addition to the mild symptoms.

'''Severe Symptoms'''- In addition to the symptoms associated with Mild and Moderate OHSS, in severe OHSS, you see shortness of breath, calf and chest pains and pleural effusion.

===<span style="font-size:100%">Classifications of Ovarian Hyper-stimulation Syndrome:</span> <ref name="PMID22065820"><pubmed>22065820</pubmed></ref>===

{| class="wikitable" style="text-align:center
|-
! scope="col" width="70px"| '''Classification'''
! scope="col" width="650px"| '''Symptoms'''
|-
|style="text-align:center; background: #F6CEEC;"| '''Mild'''
|style="height: 60px; background: #F6CEEC;"| '''Grade 1''' - Abdominal distention and discomfort
'''Grade 2''' - Abdominal distention, discomfort with nausea, vomiting and/or diarrhea and ovarian enlargement from 5~12cm
|-
|style="text-align:center; background: #F8E0F1;"| '''Moderate'''
|style="height: 60px; background: #F8E0F1;"| '''Grade 3''' - All features of Mild OHSS with ultrasonographic evidence of ascites
|-
|style="text-align:center; background: #F6CEEC;"| '''Severe'''
|style="height: 60px; background: #F6CEEC;"| '''Grade 4''' - All features of Moderate OHSS with the addition of clinical evidence of ascites and breathing difficulties present
'''Grade 5''' - All of the above symptoms along with a change in the blood volume, increased blood viscosity due to coagulation and diminished renal function
|}

</div>

==Diagnosis==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

Whilst symptoms of OHSS can occur as soon as 24 hours post hCG administration, they are usually seen in women 7-10 days post administration. Initially women with OHSS will present with abdominal bloating, as a result of fluid in the peritoneal cavity and an increase in ovary size. When women present with severe OHSS they are often dehydrated, due to increased vascular permeability, and have hemoconcentration. The above results in a decrease in intravascular volume, leading to '''oligouria''' <ref name="PMID22416285" />.

===History===

Initially a thorough history of the patient is taken during which the clinician looks for evidence of ovarian stimulation, followed by ovulation. During this history taking, the clinician will inquire into any weight gain noticed, urine output, and the woman's ability to maintain oral hydration. A key diagnostic tool for clinicians regarding women who are taking gonadotropins is to identify if they are at an increased risk of developing OHSS. Some risk factors include woman aged less than 30, women who have polycystic ovaries, woman with a previous history of OHSS and women who have had greater than 20 oocytes retrieved <ref name="PMID22416285" />.

===Physical Exam===
[[File:Vaginal_Ultrasonography_in_Sagittal_Plane.jpg|right|thumbnail|600px|Vaginal Ultrasonography in Sagittal plane <ref name="Wikiversity Journal of Medicine"> Häggström, Mikael. "Medical gallery of Mikael Häggström 2014". Wikiversity Journal of Medicine 1 (2). DOI:10.15347/wjm/2014.008. ISSN 20018762</ref>]]
After a history of the patient is taken, the next step is to perform a physical exam on the patient. Women who present with abdominal bloating will produce a shifting dullness upon abdominal percussion. Additionally the clinician will test the woman's vital signs, measure her abdominal girth, weight and will look for evidence of ascites or increase in calf size (usually unilateral)<ref name="PMID22416285" />.

===Investigations===

If the clinician further suspects a women of having OHSS, various investigations can be done such as an ultrasound.The intraperitoneal fluid is best imaged via vaginal ultrasound due to the enlarged ovaries making it difficult to image the pelvis using transabdominal ultrasound. The clinician can also order laboratory testing to look for urine specific gravity and and complete blood count to look for hemoconcentration with a hematocrit. Additionally, liver function tests can be ordered to look for elevated function. The clinician will also look for evidence of elevated D-dimers and fibrinogen and decreased levels of anti-thrombin 3 <ref name="SAHealth"> Government of South Australia Health [ http://www.sahealth.sa.gov.au/wps/wcm/connect/9b61ed004ee5348da663afd150ce4f37/Ovarian-hyperstimulation-syndrome-WCHN-PPG-17072012.pdf?MOD=AJPERES&CACHEID=9b61ed004ee5348da663afd150ce4f37 ], 'South Australian Paediatric Clinical Guidelines OHSS'</ref>.

====Ultrasound====

Typical appearances of the ultrasound include <ref name="Ultrasound"> Radiopaedia [ http://radiopaedia.org/articles/ovarian-hyperstimulation-syndrome-1 ], 'Ovarian Hyperstimulation Syndrome'</ref>:

*Bilaterally and symmetrically enlarged ovaries (>12cm)
* "Spoke-Wheel appearance" - presence of multiple cysts of varying size
*May also see ascites (fluid)

===Severity===

Once a clinician has deduced a women is suffering from OHSS, the severity of their condition needs to be established as either mild, moderate or severe. This is done by referring to the criteria under the sub-heading [[Symptoms]].The subsequent course of treatment for the woman will be based upon this evaluation.

{|
|-bgcolor="F6CEEC"
|
'''Further investigations''' can be done including a Chest X-ray to check for pleural effusions and oedema and USS with Doppler's to check for ascites or possible ovary torsion. <ref name="PMID22416285"><pubmed>22416285</pubmed></ref>
|}

===Differential Diagnosis===

Conditions presenting with similar symptoms or ultrasound images include <ref name="Ultrasound" />:

*Polycystic Ovaries (PO)
:: The difference is that with PO is that the cycts are typically smaller than OHSS cysts and there is no evidence of ascited or pleural effusion
*Mucinous Ovarian Malignancy
:: A type of Ovarian Epithelial tumour
*Ectopic Pregnancy <ref name="Casereport"> Australian Medical Student Journal [ http://www.amsj.org/wpcontent/uploads/files/articles/amsj_v2_i1/AMSJ_v2_i1_pg58-60.pdf ], 'Ovarian hyperstimulation syndrome'</ref>
::A pregnancy in which the foetus develops outside of the uterus e.g. in the fallopian tube

</div>

==Pathophysiology==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

The definition of Ovarian Stimulation is enlarged ovaries with many luteinized cysts, that can present with secondary complications. What distinguishes Ovarian Stimulation from OHSS is the presence of vascular hyper-permeability that results in fluids being redirected elsewhere in the body.

The key process to OHSS appears to be caused by '''Vascular Endothelial Growth Factor''' (VEGF), that is released along with other cytokines, estrogen and progesterone, due to the ovary undergoing luteinization as a result of stimulation by hCG. VEGF increases vascular permeability and as a result the capillaries become more "leaky" to the fluids in them. These fluids can then escape the capillaries and accumulate in the pleural and abdominal cavities as ascites. The woman then becomes hypovolemic and is at an increased risk of circulatory, renal and respiratory issues such as arterial thromboembolism due to the thickening of the blood. Note, the blood is thickened as fluid is leaving the capillaries, leaving behind red blood cells and other cellular components of the blood <ref name="WikiOHSS" />.

The increase in expression of VEGF and VEGF Receptor 2 (VEGFR2) is attributed to the greatly increased amount of their mRNA present in the body after stimulation with hCG <ref name="PMID21082502"><pubmed>21082502</pubmed></ref>. VEGF interacts with VEGF2 and VEGF Receptor 1 (VEGFR1) to create a strong angiogenic effect. Both VEGFR2 and VEGFR1 belong to a family of receptors called tyrosine kinases. VEGF2 is involved in the regulation of angiogenesis and vascular permeability whilst VEGF1 has a slightly contradictory role in that is is involved in the maintenance of the tight junctions between endothelial cells in blood vessels. A study by Gómez ''et. al.'' <ref name="PMID21082502" /> showed that women experiencing OHSS had substantially higher plasma levels of VEGF and lower levels of VEGFR1.

[[File:Pathogenesis_of_OHSS.png|600px|centre|thumb|Pathogenesis of OHSS <ref name="PMID20416867"><pubmed>20416867</pubmed></ref>]]

</div>

==Complications==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

Ovarian torsion or rupture, renal insufficiency and thrombophlebitis can all complicate OHSS. If a pregnancy occurs, symptoms may persist longer than the usual 1 to 2 weeks and become more severe, however, even with severe OHSS, they do not extend past the first trimester <ref name="WikiOHSS" />. [[File:Polycystic Ovaries.jpeg|right|thumbnail|360px|Comparison of Normal and Polycystic Ovary]]

<span style="color:#FA58D0"> '''1-2% of women who undergo ovarian stimulation develop a severe form of OHSS''' </span>. Complications from severe OHSS include:

*Fluid collection in the abdomen
*Electrolyte disturbances (sodium and potassium)
*Kidney failure
*Ovary twisting
*Rupture of a cyst in an ovary
*Breathing problems
*Blood clots in large vessels (most commonly the legs)
*Pregnancy loss from miscarriage or termination
*Rarely, death

A study by Nouri ''et. al.'' <ref name="PMID24996451"><pubmed>24996451</pubmed></ref> found that women with '''Polycystic Ovarian Syndrome''' (PCOS) and those that were induced with hCG experienced longer recovery times from severe OHSS than women who were not pregnant. They looked at a cohort of women hospitalised for the first time with severe OHSS and subject them to the same treatments. Based on a defined criteria, they established the recovery time of these women and compared the times between those that were pregnant to those that were not pregnant. They also found that whether a woman had PCOS or ovulation induction did not affect her risk of developing OHSS if she was not pregnant. It is only a risk factor for pregnant women.

===Thromboembolic events===

A frequent and deadly complication of OHSS are thromboembolic events due to increased blood clotting. This increase in blood clotting has been attributed to a variety of complications such as hemoconcentration (which thickens the blood), hypovolemia and an increase in the permeability of blood vessels as a result of increased vasoactive substances in the body of ovarian origin. Thromboembolic events include venous thromboses often in the upper extremities and arterial thromboses such as those in the cerebrovascular region. These events can lead to amputations of extremities, brain damage, miscarriage and death. To avoid this, anti-coagulants are given to pateitns with OHSS and they are fitted with compression stockings (see [[Treatment]]) <ref name="PMID23378404"><pubmed>23378404</pubmed></ref>.

{|
|-bgcolor="F8E0F1"
|
The risk of a woman developing OHSS is higher if she is having a '''twin pregnancy''', as she is exposed to higher concentration of hCG. <ref name="PMID9756273"><pubmed>9756273</pubmed></ref>
|}

</div>

==Treatment==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

'''General treatment
'''
*''Acetaminophen'' with or without a narcotic agent- used to treat abdominal discomfort
*Women are encouraged to drink 2-3 litres of water a day to prevent hemoconcentration
*Women are advised to avoid sexual intercourse and vigorous exercise at the risk of torsion or rupture of the ovaries
*NSAID's with anti-platelet properties should NOT be used as they may effect renal function in a women with OHSS
*Patients with significantly painful ascites or breathing problems may undergo ''Paracentesis'' (drainage of the ascites)
*''Culdocentesis'' (extraction of fluid from recto-uterine pouch) can be done to decrease the likelihood of a woman with moderate OHSS progressing to severe OHSS.<ref name="PMID22416285" />

===Mild to Moderate OHSS===

Mild OHSS can often resolve on its own, however, moderate OHSS may include treatments such as<ref name="WikiOHSS" />:

*Anti-nausea medication and prescription painkillers
*Regular physical examinations and ultrasounds
*Daily weigh-ins and waist measurements
*Measuring the amount of urine produced each day
*Frequent blood tests for monitoring dehydration and electrolyte imbalance
*Maintaining a high balance of fluids
*Drainage of excess abdominal fluid by inserting a needle in the abdominal cavity
*Wearing support stockings which help prevent blood clots/thrombosis

===Severe OHSS===

[[File:Abdominal Paracentesis.png|thumb|right|350px|Paracentesis is a common procedure done on women who have OHSS as it is used to drain the ascites in their abdomen. In this image you can see the puncture of the peritoneal cavity with a needle that then drains the fluid externally. <ref name="Wikiversity Journal of Medicine"> Blausen.com staff. "Blausen gallery 2014". Wikiversity Journal of Medicine. DOI:10.15347/wjm/2014.010. ISSN 20018762 </ref>]]

Severe OHSS requires hospital care in order for constant monitoring and treatment such as <ref name="WikiOHSS" />:

*Intravenous fluids with a crystalloid solution (100-150mL/hr)
*Intravenous Albumin is administered is IV fluids are insufficient (15-20mL/hr of 25% albumin for 4 hrs)
*In addition to Acetaminophen, ''Opioid analgesics'' can be administered for pain relief
*''Antiemetics'' can be used to subside nauseas and/or vomiting
*Woman administered to hospital of OHSS are considered at high risk of thromboembolic complications and are given low molecular weight ''heparin'', an anti-coagulant
*''Cabergoline''- lessens OHSS symptoms
*''GnRH agonist''- suppresses ovarian activity
**If at risk of OHSS, alternates include using a GnRH agonist instead of hCG however its effects on pregnancy rates are questionable. Using a GnRH agonist to replace the use of hCG for final oocyte stimulation will see a 6% decrease in delivery rate.
*Daily monitoring of creatine, urea, creatine clearance C-reactive protein (to rule out infection) are all required in combination with weekly tests such as liver and renal function tests and chest x-rays (to check for pleural effusion) <ref name="PMID12638783" />.

If there are serious complications then additional treatments are required:

*Surgery for a ruptured ovarian cyst
*Intensive care for the liver or lung complications

====Paracentesis====

For women with severe/grade 3 OHSS, paracentesis, the removal of fluid from the body using an aspiration needle, can be undertaken. It is a diagnostic and a therapeutic method that can be done trans-abdominally and trans-vaginally. It is used to relieve symptoms, improve haemodynamics e.g. Urinary output, and shorten the women's hospital stay. Complications of paracentesis include bleeding, infection and organ injury, however are note common <ref name="Paracentesis"> S. Monica Soni, HMS 3, Gillian Lieberman, MD [ http://eradiology.bidmc.harvard.edu/LearningLab/genito/Soni.pdf ], 'Ovarian Hyperstimulation Syndrome'</ref>.

{|
|-bgcolor="F8E0F1"
|
The most important aspect of treatment for any women with OHSS is close and constant '''monitoring''' with her healthcare professional. Counselling may also be provided to women and their partners or families in order to provide them with the best possible knowledge base to manage and treat their OHSS. It is important to note that there is '''no one cure or treatment''' for OHSS. Treatment involves managing and eliminating the symptoms until such time as the syndrome resolves itself <ref name="WikiOHSS" />.
|}

</div>

==Prevention==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

There are three key avenues through which the incidence of OHSS may be prevented. These include identifying risk factors to predict OHSS development, modifying treatment regimes on the basis of the identified risk factors and intervention to prevent progression to OHSS once the patient has undergone '''Controlled Ovarian Stimulation''' (COS).

=== Risk factors===

'''Primary risk factors'''

Pre-existing factors likely to exacerbate the ovarian stimulation response. Primary risk factors include <ref name="PMID26074966"><pubmed>26074966</pubmed></ref>:

*Young age
*Low body weight
*History of elevated response to gonadotropins
*Polycystic Ovary Syndrome (PCOS)
*Isolated PCOS characteristic
*Previous history of OHSS.
*High pretreatment basal Anti-Mullerian Hormone (AMH) concentration
*Large Antral Follicle Count (AFC)

'''Secondary risk factors'''

Secondary risk factors involve the monitoring of ovarian response parameters once COS has been initiated. These parameters are monitored for <ref name="PMID19007627"><pubmed>19007627</pubmed></ref>:

*rapidly rising E2 levels
*E2 concentration larger than 2500 pg/mL
*large number of developing follicles (10-14mm) on the day hCG is administered
*large number of oocytes retrieved

These factors in combination, act as a predictive tool to assess the likelihood of severe OHSS development, with a 83% sensitivity and 84% specificity. <ref name="PMID19007627"/>

=== Primary Prevention===

Primary Prevention involves the modification of treatment regimens on the basis of OHSS risk classifications, in order to prevent OHSS occurrence.

'''Ovulation Induction'''

Unifollicular Ovulation Induction through Ovulation Induction (OI) is a primary means of avoiding OHSS in women with Polycystic Ovarian Syndrome, who are at an increased risk. In order to promote unifollicular development, the ovaries are stimulated with a low starting dose of FSH (75 IU).<ref name="PMID20416867"><pubmed>20416867</pubmed></ref> Studies suggests that a minimum gonadotropin dose lowers OHSS risk and thus a step-up regimen is utilised to achieve an ovarian response, whereby the FSH dosage is increased every 7 days until follicular development of greater than 10mm is noted.<ref name="PMID26074966" /> Alternatively, a step-down regimen may be followed, whereby a high initial FSH dosage is lowered according to the ovarian response. Another method to increase FSH levels during OI, is through '''Aromatase Inhibitors''' which promote folliculogenesis by increasing pituitary secretion of FSH, and downregulate oestrogen production through a negative feedback loop. However, Aromatase Inhibitors have not been shown to reduce OHSS incidence in comparison to other methods of OI.<ref name="PMID26074966" /> During OI, a key objective is to prevent early cycle cancellation due to premature luteinisation from pituitary secretion of LH. In order to downregulate LH secretion, Gonadotropin-releasing hormone agonists '''GnRHa''' are administered in addition to gonadotropins. Alternatively, '''GnRH antagonists''', which have a rapid onset of action, may be administered to downregulate endogenous LH secretion..<ref name="PMID20416867" /> Comparative studies have shown that the GnRH antagonist protocol has a greater effect in lowering the incidence of mild to severe OHSS. However due to the rare nature of OHSS, and insufficient sample sizes, the difference was not found to be significant. <ref name="PMID21082508"><pubmed>21082508</pubmed></ref>. Generally, the duration of exposure to gonadotropins and subsequent risk of OHSS may be minimised through mild stimulation protocols which administer FSH only in the mid to late follicular phase.<ref name="PMID20416867" />

'''Adjuvant Metformin Therapy'''

Adjuvant Metformin Therapy has been found to lower the risk of OHSS by 63%.<ref name="PMID25406011"><pubmed>25406011</pubmed></ref> It involves the administration of metformin at a daily dosage of 1000 to 2000mg, 2 months prior to Controlled Ovarian Stimulation <ref name="PMID26074966"/>. Metformin lowers the elevated insulin levels in PCOS which consequently reduce intraovarian androgen levels. This leads to a reduced sensitivity and expression of granulosa cell-follicle stimulating hormone receptors which result in a less exaggerated response to gonadotropins. Furthermore, it is suggested that Metformin prevents OHSS by controlling vascular permeability through the inhibition of various vasoactive molecules, including VEGF.

'''Avoiding hCG during Luteal Phase Support

Following Controlled Ovarian Stimulation, the steroid levels of E2 and P4 are reduced during the luteal phase due to the negative feedback on the pituitary. This leads to low endogenous LH levels, which consequently reduce endometrial receptivity as well as the luteal phase duration itself. As a result, implantation and pregnancy rates are reduced and early pregnancy loss rates are increased.<ref name="PMID20416867" /> Luteal Phase Support (LPS) serves to combat these adverse events with the use of hCG. However, hCG has been found to increase the risk of OHSS. Alternatively, the use of progesterone has been found to not only halve the risk of OHSS, but also induce similar improvements in pregnancy and miscarriage rates as hCG.<ref name="PMID26148507"><pubmed>26148507</pubmed></ref>

===Secondary Prevention===

Secondary Prevention aims to prevent progression to OHSS once COS has been initiated and the patient has been found to mount an exaggerated response. <ref name="PMID20416867" />

'''Coasting'''

Coasting is a first-line secondary preventative strategy. It consists of the withdrawal of gonadotrophins when a critical number of follicles and/or E2 concentration is reached. hCG is administered once the E2 concentration reduces to a safe level, before the process of oocyte retrieval commences. This preventative strategy is conducted for a period of less than 3 days in order to avoid compromising IVF outcomes.

[[File:Cryopreservation of Porcine Embryos.jpeg|right|thumbnail|300px|Cryopreserved embryos of the swine model<ref name="PMID4497712"><pubmed>4497712</pubmed></ref>]]

'''Cryopreservation'''

Cryopreservation of embryos after oocyte retrieval is another avenue which may avert OHSS progression. The cryopreserved embryos are only reimplanted once the patient's hormone serum levels have normalised. Using oocyte vitrification, crystal formation within embryo tissue is avoided and so cryopreserved embryos have been found to produce better pregnancy rates with a 32% increase, than fresh embryo transfer.<ref name="PMID26074966"/> Recent studies suggest cryopreservation itself does not reduce OHSS rates, but must be followed by a GnRHa trigger to avert OHSS.<ref name="PMID24753847"><pubmed>24753847></ref>

'''Cycle cancellation'''

Cycle cancellation is a guaranteed method to prevent early OHSS whereby hCG is withheld. This is a last resort strategy as it carries the risk of significant psychological distress and financial loss for the patient. <ref name="PMID20416867"/>

</div>

==Effect on the Newborn==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

</div>
Women who develop OHSS while undergoing Assisted Reproductive Technologies (ART) treatment are not only more likely to achieve a pregnancy, but have a live birth as the pregnancy outcome. This live birth is also more likely to be a multiple birth of two, three or more children. <ref name="PMID19591989"><pubmed>19591989</pubmed></ref> It has been postulated that a multi-fetal pregnancy leads to a more rapid increase in hCG levels, resulting in an increased risk of OHSS. However, the causal nature between multi-fetal pregnancy and OHSS development is disputed and further research is required to distinguish correlation from causation. <ref name="PMID19573292"><pubmed>19573292</pubmed></ref>

OHSS development is also associated with an increased risk of adverse outcomes including '''stillbirth, premature birth and low birth weight'''.<ref name="PMID19591989" /> Although the cause for the increased risk in adverse pregnancy outcomes is unknown, it is suggested that as the incidence of OHSS is reduced through various prevention strategies, the risk of such outcomes may be also be reduced.

'''<span style="color:#FA58D0"> [http://pregnancyperfect.com/emilyley/ The following link is to a podcast of a woman describing her pregnancy in which she underwent IVF, had OHSS and gave birth to healthy twins]<ref name="Emily"> Pregnancy Perfect[ http://pregnancyperfect.com/emilyley/ ], 'TWINS, IVF, OHSS AND C-SECTION WITH EMILY LEY'</ref> </span>'''

==Genetics==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

Despite OHSS typically being of iatrogenic origin as a result of ovarian stimulation with gonadotropins, research has been conducted into the potential genetics behind OHSS as many sporadic and familial cases have been observed. '''Mutations''' in the receptor for hormones such as Follicle Simulating Hormone (FSH), Lutenizing Hormone (LH) and hCG have all been targets of OHSS genetics research. Interestingly, they too also arise from a common ancestral gene.

===Follicle Stimulating Hormome===

Dr. Botros Rizk, of the University of South Alabama College of Medicine <ref name="PMID19573286"><pubmed>19573286</pubmed></ref>, has written extensively regarding the genetics behind OHSS. In particular, he talks about '''FSH receptors''' (FSHR) and their role in the syndrome. He hypothesises that mutations in these receptors could be activating or inactivating, leading to an increased risk of developing OHSS or sterility respectively. Currently, 744 single nucleotide polymorphisms (a type of mutation) have been found in the gene encoding the FSHR, 8 of which are located in its exons (coding regions of the gene). How the ovary responds is resultant on the FSHR genotype. For example, Ser680Asn, a polymorphism in the FSHR gene has been shown to aid in predicting the severity of a woman's OHSS. Ordinarily FSH stimulates the growth of ovarian follicles, however, when mutated, it is stimulated by the hCG resulting in excessive follicle development.

Spontaneous OHSS, OHSS that arises and cannot be attributed to any form of ovarian stimulation or Assisted Reproductive Technology, has been linked to activating mutations in the FSHR <ref name="PMID23499866"><pubmed>23499866</pubmed></ref>. This familial disorder is an autosomal dominant one. In most cases the FSHR can be stimulated by the presence of Thyroid Stimulating Hormone (TSH) or hCG, in the absence of FSH (the ligand for FSHR).

[[File:FSHR Gene.jpg|centre|thumbnail|700px|This image depicts the location of the FSHR Gene on chromosome 2. It is located on the short arm between positions 21 and 16. Changed to the FSHR gene has been linked to OHSS. <ref name="Genetcis"> Genetics Home Reference [http://ghr.nlm.nih.gov/gene/FSHR'</ref>]]

===Lutenizing Hormome===

The '''Lutenizing Hormone Receptor''' (LHR) gene in humans is comprised of 11 exons. Animal studies have shown that many primates exhibit a similar gene which is comprised of only 10 exons, however a gene lacking the 10th exon has been identified and termed the type 2 LHR. Expression of the type 2 LHR has been seen in humans. The type 2 LHR, compared to the wild-type LHR appears to be repaired with regard to its function. Defects in the type 2 LHR include a decrease in efficiency of transport to the plasma membrane and irregularities in signal transduction. Inactivating mutations in the LHR have been seen to cause infertility in women as well as amenorrhoea. Activating LHR gene mutations are asymptomatic and are not associated with OHSS in women.

===Bone Morphogenic Protein===

An imporant growth factor, derived from oocytes called '''BMP-15''' (Bone Morphogenic Protein 15) is vital for female fertility. It belongs to the family of growth factors, Transforming Growth Factor β (TGF-β) and is heavily involved in folliculogenesis. It has been found that mutations in the BMP-15 gene caused infertility in female sheep. Conversely, it has also been indicated in enhanced fertility when BMP-15 is present is high amounts in follicular fluid <ref name="PMID19573286" />.

A case study done by Hanevik ''et. al.'' in 2013 <ref name="PMID21565556"><pubmed>21565556</pubmed></ref> found that a Single Nuclear Polymorphism (SNP) in the BMP-15 gene is responsible for a high response to ovarian hyper-stimulation. The aim of the study was to test the effect the SNP had on BMP-15 with regard to high and low responders buy taking blood from 53 high responders, 38 low responders and 100 non-responders (controls) and analysing 5 noted SNP's. Results from their study showed a correlation between a high response to ovarian hyper-stimulation and the BMP-15 9G allele. The article does state however, that further research is required into the molecular effects of SNP's on the function of BMP-15.

===Vascular Endothelial Growth Factor===

'''Vascular endothelial growth factor''' (VEGF) has been indicated as one of the key agents causing vascular permeability and subsequent ascites in OHSS. The gene, which is located on chromosome 12, is made up of 8 exons (coding regions), of which exons 6 and 7 do not always appear due to the exons being spliced out.The splicing of this gene allows for various isoforms of the gene to exist of which VEGF 121 and 165 appear to play a role in angiogenesis. There are two VEGF Receptors, VEGFR-1 and VEGFR-2 that belong to the tyrosine kinase family of receptors (for more information on VEGF see [[Pathophysiology]]). Because of its distinct role in OHSS, it has been targeted as an area for research for potential treatments. The idea is that if the genetic expression of VEGF and its receptors can be controlled, OHSS can be avoided or treated.<ref name="PMID19573286" />

A different study by Hanevik ''et. al.'' , <ref name="PMID22587628"><pubmed>22587628</pubmed></ref> done in 2012 involved analysing blood samples from 53 women with OHSS and 100 women without it (controls) and analysing 6 SNP's in the VEGFR2 gene to find any genetic variations. They found a correlation between women with the VEGF +405cc genotype and the development of OHSS indicating women that undergo controlled ovarian hyper-stimulation and posses his genotype, are at an increased risk of developing OHSS.

</div>

== Current Research on Animal Models==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

{|
|-bgcolor="FFF5FF"
|<span style="font-size:120%">'''Inhibition of Cyclooxygenase-2 (COX-2) by Meloxican decreasing the incidence of OHSS in Rat Model'''</span> <ref name="PMID18166186"><pubmed>18166186</pubmed></ref>

Reasearch was carried out to investigate the effects of selective inhibition of the enzyme COX-2 on the Ovarian Hyperstimulation Syndrome (OHSS) using Female Wistar rates as the subjects. The research aimed to find results by measuring the number of antral and luteinized follicles, ovarian weight, vascualr endothelial growth factors and COX-2 immunohistochemistry. The rats being tested were all 22 days old and were divided into four equal groups;

'''Group 1 (Control group)''' was subject to a 0.1 ml of Intraperitoneal Saline from days 22 ~ 26

'''Group 2 (Mildly-stimulated group)''' subject to 10IU of pregnant mare serum gonadotrophin (PMSG) on day 24 and then 10IU of Human Chorionic Gonadotrophin (hCG) on day 26

'''Group 3 (OHSS positive group)''' was subject to 10IU of PMSG from days 22 ~ 26 and then administered 30IU of hCG on day 26 to induce OHSS

'''Group 4 (OHSS positive variant group)''' received 15mg/ml of Meloxicam 2 hours prior to administration of 10IU PMSG from days 22 ~ 26

Results showed there was no difference in ovarian weight in samples from Group 1 and Group 2, however Group 3 showed signs of significant ovarian weight increase which in group 4 was suppressed by the introduction of Meloxicam. No differences were observed in the number of antral follicles amongst the four test groups. Results from Group 2 and Group 3 showed that the granulosa cells of preovulatory follicles and the stromal cells were highly VEGF immunoreactive, however the Meloxicam treated Group 4 showed less immunoreactivity than Group 2 and Group 3 which indicated the correlation between Meloxicam and the diminished VEGF expression. Group 3 presented an increased COS-2 immunoreactivity which was highly diminished than in Group 4.

The research concluded that in a rat model, the enzyme Meloxicam has a beneficial effect on OHSS by reducing the increase of ovarian weight and the expression of VEGF associated with OHSS, the effects of which may be mediated by the inhibitory capacity of COX-2 on Meloxicam
|}

{|
|-bgcolor="FFF5FF"
|<span style="font-size:120%">'''Inhibition of Ovarian VEGF secretion by activation of Dopamine Receptor 2'''</span> <ref name="PMID25217874"><pubmed>25217874</pubmed></ref>

This research was carried out to investigate a possibility in whether a Dopamine Receptor 2 agonist '''(D2-ag)''' can assist in the prevention of Ovarian Hyperstimulation Syndrome, using rat models, by decreasing the ovarian vascular endothelial growth factor '''(VEGF)''' production. Using Immature Wistar rats (22 days old) as their animal model, the rats were initially stimulated with Gonadotrophins to mimic the onset and effects of OHSS and then subjected to treatment with a D2-agonist and/or a D2-antagonist (D2-ant). The vascular permeability was measured at the endpoint after day 26 by measuring the peritoneal extravasion of a previously injected dye and ovaries from all subjects were collected to assess the effects of D2-ag and D2-ant on the production of Ovarian VEGF. The expression of VEGF mRNA was measured by quantitative real time PCR and the levels of VEGF proteins were measured by Western Blots.

Results showed that the D2-ag caused a large reduction in the vascular permeability which was in turn associated with the great decreased in VEGF protein production in the OHSS rat ovaries, whereas the introduction of D2-ant showed opposite results with a increase in the vascular permeability leading to the increase of VEGF protein production in the ovaries. Ovarian VEGF mRNA levels were found to be unaffected by the introduction of these drugs in OHSS rat subjects. Conclusions were drawn on the fact that Dopamine Receptor 2 agonists prevent the increase of vascular permeability in subjects with OHSS by decreasing the ovarian production of VEGF and also that due to the dose-dependent inhibitory effect of the D2-ag on ovarian VEGF, current OHSS therapies used in humans can benefit by increasing the intraovarian concentration of D2-ag.
|}

</div>

==Glossary==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

'''Aromatase Inhibitor''' - A drug that inhibits enzyme aromatase, which in turn suppresses estrogen synthesis.

'''Ascites''' - An accumulation of fluid in the peritoneal cavity with resultant abdominal swelling.

'''Cabergoline''' - A dopamine receptor agonist used to treat hormone imbalance.

'''Controlled Ovarian Stimulation''' - female infertility treatment using medications to stimulate the ovaries to develop follicles.

'''Cryopreservation''' - Cooling and storing biological material at extremely low temperatures.

'''E2''' - Estradiol - Potent estrogen sex hormone.

'''FSH''' - Follicle Stimulating Hormone

'''Gonadotropin''' - Any hormone that has a stimulating effect on the gonads.

'''GnRH agonist''' - Gonadotropin Releasing Hormone - A class of compounds that mimic the effect of the natural Gonadotropin Releasing Hormone.

'''GnRH antagonist''' - Gonadotropin Releasing Hormone - A class of compounds that are similar in terms of the structure of natural Gonadotropin Releasing Hormone but has a antagonistic effect.

'''hCG'''- Human Chorionic Gonadotropin

'''Hemoconcentration''' - An increase in the concentration of circulating red blood cells in response to a decrease in blood plasma volume.

'''Hypovolemic''' - A decrease in circulating blood volume.

'''Iatrogenic''' - Illness caused as a result of a medical examination or treatment.

'''Intravenous fluids''' - Is the infusion of liquid substances directly into a vein.

'''IVF''' - In-vitro Fertilization

'''LH''' - Luteinizing Hormone

'''Metformin''' - A biguanide, antidiabetic drug used as an adjuvant to modify the effect of other agents.

'''NSAID''' - Non-steroidal Anti-Inflammatory Drug e.g. Ibuprofen

'''Oocyte vitrification''' - technique for cryopreservation of oocytes.

'''OHSS''' - Ovarian Hyper-stimulation Syndrome

'''Oliguria'''- Decreased urine output/small amounts of urine produced.

'''P4''' - Progesterone - endogenous progestogen sex hormone.

'''PCOS''' - Polycystic Ovarian Syndrome. An endrocrine system disorder whereby the ovaries are enlarged with small collections of fluid.

</div>

==References==

File:Cryopreservation of Porcine Embryos.jpeg

2015-10-23T14:44:08Z

Z3372824:

==Cryopreservation of Porcine embryos==

(Derived from original legend)
Representative image of cryopreserved embryos of the swine model: a) mature oocyte b) day 1 embryo c) day 4 embryo d) blastocyst from cryopreserved day 1 embryo with an intact zona pellucida excluding the lipid droplet. Scale bars= 20 μm.

Cryopreservation of embryos allows for embryos to be preserved at sub-zero temperatures. The embryo may be implanted when patient serum levels have normalised and the risk of OHSS progression is reduced.

===References===

<pubmed>4497712</pubmed>| [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4497712/]

====Copyright====

© Hongsheng Men et al. 2015; Published by Mary Ann Liebert, Inc.
This Open Access article is distributed under the terms of the Creative Commons License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited.

fig-2.jpeg

{{Template:Student Image}}

File:Cryopreservation of Porcine Embryos.jpeg

2015-10-23T02:42:35Z

Z3372824: PMID 26309801

PMID 26309801

Talk:2015 Group Project 2

2015-10-23T02:32:40Z

Z3372824:

{{ANAT2341Project2015discussionheader}}

http://www.womenshealth.gov/publications/our-publications/fact-sheet/polycystic-ovary-syndrome.html

https://en.wikipedia.org/wiki/Paracentesis#/media/File:Blausen_0004_AbdominalParacentesis.png

--[[User:Z5016784|Z5016784]] ([[User talk:Z5016784|talk]]) 14:42, 13 October 2015 (AEDT) Just regarding the peer reviewing of other group projects, do we have to be assessing all 5 other projects?

--[[User:Z8600021|Mark Hill]] ([[User talk:Z8600021|talk]]) 11:16, 25 September 2015 (AEST) Hmm still a little thin. There should be some animal model info, histology images, physiological data, drug info, and genetic information.

--[[User:Z3374116|Z3374116]] ([[User talk:Z3374116|talk]]) 17:15, 18 August 2015 (AEST) Hello there

--[[User:Z3415911|Z3415911]] ([[User talk:Z3415911|talk]]) 16:12, 24 August 2015 (AEST) Hey guys! So I've gone and added a few subheadings that may be useful to start researching. For this weeks assessment we need to choose one each and find 3 articles to go with it etc. So if we all choose one and start researching it, that would be good :)

--[[User:Z3415911|Z3415911]] ([[User talk:Z3415911|talk]]) 11:02, 26 August 2015 (AEST) Good article for treatment http://humupd.oxfordjournals.org/content/16/5/459.abstract?etoc

--[[User:Z3374116|Z3374116]] ([[User talk:Z3374116|talk]]) 19:20, 26 August 2015 (AEST) Sweet, Thanks for putting up those headings to get things going. Lets all put up related documents by Thursday so we have can discuss things at the Lab this Friday!

--[[User:Z3374116|Z3374116]] ([[User talk:Z3374116|talk]]) 19:29, 26 August 2015 (AEST) I've put up some interesting pubmed documents on our main page, Have a read through them (I haven't read them all yet)

=== <span style="font-size:75%">'''Classifications of Ovarian Hyper-stimulation Syndrome'''</span> ===
{| class="wikitable" style="text-align:center
|-
! scope="col" width="70px"| '''Classification'''
! scope="col" width="650px"| '''Symptoms'''
|-
|style="text-align:center; background: #CCEEEE;"| '''Mild'''
|style="height: 75px; background: #CCEEEE;"| '''Grade 1''' - Abdominal distention and discomfort
'''Grade 2''' - Abdominal distention, discomfort with nausea, vomiting and/or diarrhea and ovarian enlargement from 5~12cm
|-
|style="text-align:center; background: #EEEEEE;"| '''Moderate'''
|style="height: 75px; background: #EEEEEE;"| '''Grade 3''' - All features of Mild OHSS with ultrasonographic evidence of ascites
|-
|style="text-align:center; background: #CCEEEE;"| '''Severe'''
|style="height: 75px; background: #CCEEEE;"| '''Grade 4''' - All features of Moderate OHSS with the addition of clinical evidence of ascites and breathing difficulties present
'''Grade 5''' - All of the above symptoms along with a change in the blood volume, increased blood viscosity due to coagulation and diminished renal function
|}

--[[User:Z3374116|Z3374116]] ([[User talk:Z3374116|talk]]) 11:40, 28 August 2015 (AEST) I wont be able to make it to uni today for the lab and the meetup after it. Got to take my cousin to the ER

--[[User:Z3374116|Z3374116]] ([[User talk:Z3374116|talk]]) 12:07, 28 August 2015 (AEST) I was thinking to include the risk factors in the 'causative' subheading

--[[User:Z3374116|Z3374116]] ([[User talk:Z3374116|talk]]) 13:22, 28 August 2015 (AEST) So basically in the Causative subheading, I was planning
1) Identify the different causes (including primary and secondary risk factors)
2) What difference occurs from a normal cycle (e.g. level of hCG normally)

--[[User:Z3415911|Z3415911]] ([[User talk:Z3415911|talk]]) 13:36, 28 August 2015 (AEST) No problem! I hope your cousin is okay. Whoever added a sub heading called: Tests and Diagnosis, there already is the same kind of subheading, Symptoms and Diagnosis so we need to merge the two. It also needs to be in chronological order

--[[User:Z3372824|Z3372824]] ([[User talk:Z3372824|talk]]) 13:46, 28 August 2015 (AEST)Hope he gets well! Talking about sections, I'll try and work on Prevention, and get the research summaries done for that section by next week.

--[[User:Z3372824|Z3372824]] ([[User talk:Z3372824|talk]]) 14:00, 28 August 2015 (AEST) J and I had a little discussion about how we're going to go about completing this. We can all work on each others sections and collaborate that way. Let's focus on finding research articles, collating them, referencing them i.e. get to the meat of the matter. Once we've done that we can cut to the point and make it more easy-to-read/user-friendly. We also think that our 1 wiki page reference should be the OHSS Wiki page. Also, when writing about your section, always compare/refer to the Controlled Ovarian Stimulation case. Bring those picture/youtube suggestions in!

--[[User:Z3374116|Z3374116]] ([[User talk:Z3374116|talk]]) 00:12, 29 August 2015 (AEST) Sweet, thanks for the info. Will be on the lookout for youtube clips and pictures. Is the OHSS wikipage you are referring to https://en.wikipedia.org/wiki/Ovarian_hyperstimulation_syndrome
this one?? And I agree on helping each other with respective sections and then cutting it down to the fine details

--[[User:Z3415911|Z3415911]] ([[User talk:Z3415911|talk]]) 21:49, 1 September 2015 (AEST) Yes, that's the wiki page :) I have already started taking down information from it in each section so when you see '''[OHSS Wiki]''', that's where the information is from. I just don't know how to reference something that is not pubmed yet haha

--[[User:Z3415911|Z3415911]] ([[User talk:Z3415911|talk]]) 22:11, 1 September 2015 (AEST) Also guys please note, I have not used any info. from wiki in regards to TREATMENT and PREVENTION as it appears someone is already working on those subheadings and I don't want to interfere, so yea, that info. is still out there for you guys to use.

--[[User:Z3415911|Z3415911]] ([[User talk:Z3415911|talk]]) 11:51, 13 September 2015 (AEST) Hey guys, can everyone please send me an email with your full names so I can add you on fb and make group. I feel like we need a better way of communicating. Thanks, z3415911@student.unsw.edu.au.

--[[User:Z5016784|Z5016784]] ([[User talk:Z5016784|talk]]) 16:25, 13 October 2015 (AEDT) Hey guys, i am working on a few sections, mark said not to add to the project until the peer assessments are done, so i was thinking of bringing my information to class on Friday so yous can have a look and see if it is useful enough, i will place the link to one article, it has two tables in there that i think can be used, what are your thoughts about them?
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2842872/

I have found a few articles on the effect on a newborn
http://www.ncbi.nlm.nih.gov/pubmed/19573292
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2604472/ (Are pregnancy rates comprised following embryo freezing to prevent OHSS, also contains a few tables based on the results)
http://www.ncbi.nlm.nih.gov/pubmed/11756371 (Increased early pregnancy loss in IVF patients with severe OHSS)
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4036081/
http://www.ncbi.nlm.nih.gov/pubmed/15618246 (Outcome of complicated pregnancies by severe OHSS)

Animal models
http://www.ncbi.nlm.nih.gov/pubmed/25864291 (Is a small experiment, with not a lot of information)
http://www.ncbi.nlm.nih.gov/pubmed/20423279
http://www.ncbi.nlm.nih.gov/pubmed/25990477

--[[User:Z5016784|Z5016784]] ([[User talk:Z5016784|talk]]) 13:35, 22 October 2015 (AEDT) So what is happening with the articles and other sections?

Video that J found!
http://www.howcast.com/videos/511910-ovarian-hyperstimulation-syndrome-infertility/

--[[User:Z3372824|Z3372824]] ([[User talk:Z3372824|talk]]) 13:32, 23 October 2015 (AEDT) So the FSH receptor/follicular development image comes from PMID 19573286

==Peer Review==

This wikipage is very well put together. Your choice of headings, subheadings and tables and images is remarkable, it definitely makes the whole page flow very well. I particularly like the hand-drawn image which does a great job at simplifying the process of the pathogenesis of OHSS.

The introduction very concisely explains the contents of the page and I liked how it was finished off with a statement about the aim of the page. I thought it really brought the introduction together nicely. I can’t say much about the content except that it is very engaging and very well written so well done guys! Keep up the good work!

Some suggestions I have that could improve your page include adding more images. It would be nice to have some graphs to complement the statistical date from the epidemiology. Also, in some of the paragraphs e.g. in the last paragraph of ‘Epidemiology’ there isn’t a citation that accounts for the information at the end of the paragraph so that should be fixed.

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This page clearly and efficiently explains the topic of choice. It covers all relevant matters well and the text is descriptive and informative. After reading the page, I felt as though I had a greater understanding of the topic. The subheadings used are good, and are placed appropriately in order - providing an element of cohesiveness between the page and the topic in general. Good use of linking statements – connecting all the elements discussed on the page.

There is however an excessive amount of text used. Although the information is relevant and informative, the page is dense and reading all at once is tiresome. Reducing/sifting through the amount of text on the page – and also adding a great deal more media files will help to break up the denseness of the page. There is only 1 image on the whole page – greater attention needs to be paid to alternative media files and sources to help break up the page. Additional media files will also add to increasing the understanding of readers.
The diagram drawn is neat and cited correctly. --[[User:Z5015534|Z5015534]] ([[User talk:Z5015534|talk]]) 15:07, 13 October 2015 (AEDT)

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This Wiki covers the topic well. The content is very well written and easy to understand. Images and texts are correctly cited and referenced. In some of the sections, eg, ‘Ovulation Induction’, ‘Avoiding hCG during Luteal Phase Support’, more in-text reference will need to be added.

It is a great idea to have some bold texts in lines, which highlight the main points of paragraphs, and help readers to understand when skimming.

The hand-draw diagram of ‘pathogenesis of OHSS’ is excellent. It is well structured, and easy to understand and memorize. It will be great if more images, diagrams, videos can be added to the other sections.

Overall, the project page is very well developed. Some of the sections need to have more work on though. It would be nice if more graphs and tables can be added to balance the texts.

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So far your wiki page gives a very good coverage of Ovarian Hyper-Stimulation Syndrome. The progression of your subheadings progresses logically from one topic to another. It's good to see that you've included an excellent hand-drawn image which is well suited to the 'pathophysiology' subheading. The amount of textual information you have under each heading is vast and gives a comprehensive description of OHSS. Furthermore, you have an excellent range of sources to support your discussion.

I feel however that asides from your hand-drawn image, your use of images and other source of media is definitely lacking. As is, your page is largely text with little to no breaks, making it quite difficult to read. The use of images would not only help break up the monotony of the text, but also help reinforce some of your ideas. I feel that the inclusion of images in the 'symptoms' and 'complications' subheadings would be suitable.

It may also be worthwhile to include subheadings concerning current research, to inform readers about contemporary developments regarding OHSS. Furthermore, 'future research' could also be another potential subheading and could illuminate potential areas that are beginning to be or could be investigated in coming years.

Overall, a very impressive page so far, that could be enhanced with the addition of relevant images and other media.

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Great work, it looks like your group has a clear mindset and direction to where your group project is going, even if it is not there yet. Also great introduction! Your entire page's contents were introduced well and simple. However, all Text and no images were included except one image. Not a good look to go through. The information here is good but is also very dense and hard to follow without any images. It would be great if you could break it up a bit with more images, tables, diagrams and hand drawn pictures. This style of writing is very professional and would be perfect for a report or essay; however as a wiki page it is too hard to follow. Breaking up the information into tables and short videos would allow you to guide the reader through your topic. Well done on the use of bullet points make it easy to follow. Only one hand drawn image as well as one table uploaded onto the page contains adequate information explaining them, which is good.

Well done on use of “Glossary” section. It is indeed necessary and important.

There has clearly been a lot of research and work put into this project and that is very commendable and I do appreciate it. However on a whole as I mentioned, there is too much information without having any interactive techniques such as tables, diagrams and etc. One of my suggestions is to make a table for “Prevention” or “Genetics” section or even both. I also suggest adding another subheading for “current research findings” or “Future research” which requires more time and research. Therefore you can include more journal articles in this section .In this section pictures would also be good to help understand and engage readers. Overall, well done on your written information for each section. They’re very relevant to the topic and to the project as well.

Some sections like “Effect on the Newborn” or “Animal Models” seem to be untouched. I’m assuming you are still in the process of adding content. Please be aware of the deadline. Moreover, in text citation is crucial which are missing in some paragraphs. Citations should be carried through the entire page to know exactly where you have got your information from. Good job on referencing at the end of the page. All research articles seem to be relevant to all sections.

Overall, it is a really good project with the potential to be excellent because of the amount of effort you have put into the research. Keep up the good work, but just edit and add those things I mentioned to the project and finish the sections you need to. Very well done so far and good luck with finishing the project off.

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I found your topic very intriguing! It appears as though you have put a lot of time into researching your area and ensuring that your have addressed the main concepts.

'''COMMENDATIONS'''

• Fantastic introduction! It gave me a clear overview of what your group’s topic is, and it was easy to understand.

• Great overview of the symptoms. Your table added some colour to the page and the information was succinct.

• You are to be commended on your hand drawn image - very clear and neat. Good job!

• Clear reference list and good in text citations.

'''RECOMMENDATIONS'''

• A map in the Epidemiology section would put your text into perspective for the reader.

• Some words have been typed in bold (particularly in the Diagnosis section). The selected words seem to be a bit random. Maybe you could highlight phrases rather than words, or organise the information under subheadings.

• More images would break up the information and aid the reader’s understanding of the given concepts. Subheadings would also help organise the information to place ease on reading and comprehension.

• Your page features large chunks of text for the most part. I would recommend reading through your text and removing excessive bits of information; try and be a bit more succinct. You could use more tables and diagrams to communicate certain concepts as well (e.g. Treatment and Diagnosis).

• Information is absent under “Animal Models” and “Effect on the Newborn.”

With this said, your group has covered all the key concepts and it is evident that you have done a lot of in depth research. You are definitely on the right track.

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Collectively, this page is well structured and shows you have a well-rounded understanding of this topic. The introduction encapsulates the whole topic extremely well and provides a good framework for the rest of the page. The headings are relevant and follow the structure to discuss a disease, thus being very easy for the reader to grasp the key concepts of the syndrome. Perhaps consider using bullet points in your “Causative Agents” section and “Prevention” heading. You can also utilize numerical steps to describe the pathogenesis of OHSS to accompany the well-structured diagram, and to break up the text in your page.

I have also noticed that the page is lacking subheadings in a few sections, thus it prevents the reader from knowing the key points that are being discussed and explained. Together with the subheadings that are already present, they can also be used under “Diagnosis” for each diagnostic tool, “Genetics” for VEGF, LHR and BMP-15, and possibly in the “Animal Models” section. The content under each of these headings however, is very interesting and has been written well, showing you have gained a thorough understanding of OHSS. I am certain the content you add for the untouched headings will also be of a high standard. On that note, further explanation about treatments and complications of OHSS could be added. These sections are currently lists therefore they can be further expanded with more research and videos to explain things like surgery procedures.

The glossary provided is extremely beneficial however; more diagrams, tables, and videos should be incorporated to further enhance the reader’s understanding. At the moment it is quite content heavy and needs visual aids to make the page more interesting and easy to read.

This page also demonstrates that you have thoroughly researched each aspect of OHSS, and have used recent studies to support the content added. The resources have all been cited correctly, but perhaps search for more literature to further support your claims and theory regarding OHSS.

I am really impressed with your page so far. Using more references, visual aids, and adjusting the format of this page will guarantee a successful mark. Well done!

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I’d like to start by commending you on an exceptional choice of key points which you have chosen to research and elaborate on. They provide a good overview of the subject for your readers. They are clearly explained and taught at a peer level without dragging on with irrelevant points. Your introduction is well written, I especially like that you have included the aim of you wikipage in the introduction and the key points you will be focusing on to orient your reader. Including epidemiology was also a good choice as it shows the relevance and impact of Ovarian-stimulation syndrome in society. I also find that including prevention and treatment is great for visitors without an embryology background who are looking for general information on the topic, especially for women who can learn to better reduce their risk since this page is accessible to the public.

Other great aspects of your page include the inclusion of a glossary for readers to refer to when they are unclear on the terminology and that you have used relevant sources. The table used to organize the symptoms makes its easy to read and understand. I particularly liked your section on the pathophysiology. Not only is it explained well but you have included a great hand drawn diagram that is clearly drawn, complements the adjacent paragraphs well and includes a statement with permission to other visitors to reuse it.

Going forward your main focus’ should be conducting further research to complete your remaining key points on the effects on the Newborn and animal models (very relevant for embryology peers). Also, focus on including more supporting diagrams and figures since so far you only have one. A histological image of the ovaries would be very appropriate to your topic. Make sure you read over your page to edit your grammar and wording for example in the phrase “they are given to assistive medication”. Your citing is well done, but make sure when you are referencing websites that you include the retrieval date such as in reference 11.

Overall your page is well written, with my main concern being is it sounds more like a report than a peer teaching page. You can fix this by adding more images, diagrams, figures and tables to break up the text and help to explain your content. Adding a video would also be engaging. Otherwise, great progress so far!

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Everyone seems to have already commented on your introduction, but it will not deter me from giving you another amazing high five! That introduction is so well thought out and structured that it has set up the entire page in an easy to read and easy to understand way- amazing work!! The page as a whole was fantastically structured and I found it very easy to follow which made the experience of reading and learning about the topic. Furthermore the topic was outstandingly researched with a wide variety of sources and really demonstrated the time and effort that you guys have put into it so great job; however, one thing that lets you down here is that there are some citations missing or large chunks of writing that are not cited which is a shame because it is evident that you have put in the time and effort. The language that has been used through out the page, although very formal, was appropriate and made it easy to understand the information. This was further aided by the inclusion of the glossary which is a necessity and was very well planned. I also really enjoyed the inclusion of the section "Epidemiology" as it provided a comprehensive snap shot and scope of the disease.

Some aspects that you could improve on include the inclusion of more images, videos, graphs and tables. Again, everyone seems to have commented on this, there is too much writing and it makes it difficult to follow and stay concentrated on the information. Another point to improve on would be further explanations about the treatment and prevention, this would be highly beneficial as it not only would provide information to students but also relevant and useful information to the public as the site is public facing. Lastly, the information missing below the “Effect on the Newborn” and “Animal Models” section will add another layer of detail and ultimately complete the page.

Overall, you guys have done an amazing job- the main area of improvement is the inclusion of more interactive and visual elements that can break up the chunks of texts and make the page more well-rounded. Awesome work and I look forward to seeing the end result!!

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This Wikipage is very well structured, the headings and subheadings are all very appropriate; the introduction presents the entire topic very well. This really grabs the attention of the audience as the structure of the page is very easy to navigate. “Epidemiology” was very easy to understand as you introduced all the jargon with its shortened name; good idea to add the glossary at the bottom defining all the scientific terms. It is very beneficial for those audience who have not been introduced to these scientific terms. “Causative Agents” was explained perfectly, which makes it easier for the audience to read. I also suggest using some bullet points and tables. It’s great to see the use of tables in “Symptoms”, it simplifies the content and makes it easier to categorise the different severity of the symptoms. As for “Diagnosis”, I suggest adding some subheading to separate the different ways of diagnosis (History, physical examination, ultrasound, further investigations etc). Make sure you add more subheading throughout the page, it highlights the key points for each heading for the audience. “Complications”, “Treatment” and “Prevention” has good use to subheadings, it is well structured and interesting to read. This shows that you have conducted adequate literature searches and have a deep understanding of OHSS. I suggest to add more information into complication, case studies or examples could be used.

I am impressed to see that you guys have drawn your own detailed diagram. However, I suggest that you add more diagrams, videos and tables; this can enhance the audience’s understanding towards OHSS. There is a lot content at this point which is great to see all the research you guys have conducted however, it need visual aids to make the page easier and more interesting to read. All the resources have been cited correctly but I think more research to support the page and enhance the validity of your information.

Overall, I am very happy with this page. Remember, more visual aids (diagrams, videos, tables and flowcharts). Great work!

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The contents of the website about OHSS appear to be very well researched and the key points of the topic are clearly described. The headings and subheadings are in a logical and complete order. However, it might be useful to add a new heading labelled “Current Research” about e.g. the pathophysiology, treatments, diagnosis, etc. It might be that this will be included in the “animal models” section, which is still incomplete. Upon completion of the last sections it might be useful to round the website off with a conclusion.

The website so far has only one image. However, the image is self-drawn and very clear. The image is useful, readable, and makes the understanding of the pathophysiological processes easier. It might be good to consider adding more graphs and images to the website. Useful images could display the involved anatomical structures, the symptoms, and the diagnostic procedures (Ultra-sound showing OHSS).

The used references are all very recent, which strengthens the credibility of the website. However, sometimes sentences or paragraphs are not cited at all. Thus, lacking citations should be added. The glossary is a nice addition to the website but still needs to be completed (VEGF, LHR, BMP-15, etc.)

It might be beneficial if the link to ART were explained more clearly. As the general frame of the project is ART, including OHSS’ implications on the procedure, causative role, etc. would elucidate that link.

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The structure of your page is very effective in allowing us to easily understand the topic. The introduction is brilliant as it focuses on the main points of the topic while touching on a bit of its history and then finally stating the purpose of the page.

The hand drawn image is outstanding and presents the information in a very appealing way. As there is only one image so far, it would be great if you could include more images, especially for sections such as epidemiology and causative agents. For diagnosis, you could include an image of an ultrasound or X-ray which would give us a better understanding of the physical changes that are seen as a result of this problem.

I love the use of bold text to highlight the important features of some sections. It would be great if this is used in the other sections too as it really helps to focus on the main points.

The use of a table to present the symptoms is a great idea. It would be great if this was also done for treatments which is also divided into sections of mild, moderate and severe.

It's evident that a lot of research has been done to finding the information on this topic, however I feel that for some sections, there might be a bit too much information, particularly for Prevention and Genetics. If possible, try and make these sections more concise by focusing on the main points. For genetics, it might be helpful to have a sub-sub heading for each new growth factor or receptor discussed.

Overall, I think you guys have done an amazing job with this page. Apart from the minor changes here and there, there is not much more to be done. Great job!

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First of all, I’d like to say this is a fantastic wiki page. The key points for polycystic ovarian syndrome are well described. The page is well structured and the layout is clear and easy to follow. Making each section expandable is a good idea. The bold texts in lines highlight help readers catching the main points easier. One of the highlights of this page is the introductory. It is well written and the aim of the page gives reader an overview and a general idea of this page. The table and image used are relative to the topic. The background color of the table is pretty nice and the content in the table is still easy to read. The glossary at the end of page helps those without background knowledge understanding the topic easier. The references and citations are appropriate as well as the text citations. Some recommendations I will give will be:

1. More images and videos may be used so that the page is easier to read.

2. Recent research may be included in your page.

Overall, you have done a fantastic job. Thanks for your effort.

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Great project so far, it is well structured and easy to read. the headings make sense and flow easily form one to the next. You introduction is really nice and the stated purpose at the bottom as well as a brief historical context really and depth and context to the assignment. your have also used of dot points and bold to highlight key points within the text which is very effective. Your hand drawn image is clear and concise, it is also correctly cited as well good job!

There is not much more that I would recommend for this web page, as the content is very relevant. I recommend trying to use some more references, they are valid and useful but most of the other groups have nearly double the resources and references that you guys do, perhaps a good target would be more than 1 citation per paragraph.

Also more images could be used as you page is very content heavy, but you could use more images, a video and perhaps even a Graph to break up the information. under the Causative agent subheading perhaps you could make reference to pituitary action as well as the anterior pituitary and provide a flow chart of diagram, there are many excellent diagrams displaying this process that could be incorporated here- look into text books.
The animal models would be as awesome addition to you webpage and there will be a huge range of awesome images that you will be able to use and maybe incorporate current research in the field subheading and find some information of current studies being conducted ect. Great use of the glossary but more terms need to be added to the list. Also you have a lot of physiology and pathology content - which is fantastic perhaps you may try to relate it back to ART and IVF more as well as maybe including abnormalities and effects of the development and birth of the child.

On the whole, this is an awesome project, and there isn't much more to do to complete it. Great Job guys
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Great stuff guys,
Good layout, nice flow of topics and comprehensive. Language is easy to follow. Well research and supported. There are couple of parts that need some references WIKI original recommends that if you make a statement of fact or something that can be disputed you should add a reference ie. last statement of epidemiology . But, work in progress, i understand.
You could hyperlink some of the more unfamiliar words to the UNSW embryology glossary and other pages to get the wiki "click through" effect. I hate to recommend it because i really like how clean and "wiki" like your page is but we have to add images so perhaps a map of the genes and mutations, show the promoters and such?
The symptoms section has some repetition to its structure i think you should condense it all into the table then write a lead in paragraph to the table. Lead in could have a bit about when the symptoms usually come on in life? I would recommend moving diagnosis to above treatment and after pathology to help with flow. This would also semi-separate the page into theory and clinical.
For the pathology image if you make a one by one table and put the image into it, it should sit in alignment on the page. Its just my browser but on a smaller screen it cuts out to the left. Not a big deal. try to have the images on a line to them selves or at the end of paragraphs rather then word wrapping the text. Makes it look neater no matter how big you have the window.
That's all i can think of. Other wise looks like it going to be one of the best of the class. Very professional.

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The topic of OHSS was outlined very well, with very good choice of headings, separating the different key points and areas that you’ve discussed on your page. It’s evident you’ve done extensive research on your topic, and all your information is very concise and very readable. You’ve also extended your topic beyond the general symptoms, diagnosis, causes etc like “animal models” “effect on the newborn”, it is very extensive!
<b>Pros</b>
*Extensive research evident, a lot of information is provided
*Introduction is short and concise, but also extremely informative, highlighting the aim of the page as well!
*Statistics of the disease is also given, numerical data is always good
*Good use of a table in “Symptoms”, making it very readable and engaging
*The presence and position of the drawing in “Pathophysiology” is prenominal, you’ve gone out of your way to draw a diagram to illustrate the topic
*Good use of bullet points in “Treatment”, very concise and readable and there isn’t a jumble of words
<b>Cons</b>
*A photo or video in your introduction could be used to illustrate what the topic is better
*There’s a lot of technical jargon already in your introduction, words like neoangiogenesis and iatrogenic. Readers who come to your page may not necessarily understand those words. These words can be defined in your glossary, but readers read in logical flow, they won’t scroll all the way to the bottom of your page because they didn’t understand the word to find the meaning then come back to the introduction to continue. These words don’t have to be replaced, but an explanation might ease your cause
*A graph or table or pie chart representing epidemiology will make the heading more informative
*Photos showing symptoms will substantially help, especially when they’re separated into mild, moderate, and sever.
*Diagnosis needs to be expanded more. The bold type words should be made into subheadings so you can expand on each more, defining how and why they are performed
*Headings of “effect on the newborn” and “animal models” need to be completed
*You have a lot of information on your page but only a few are referenced, a lot more in text referencing and references are needed for the amount of information you have

User:Z3372824

2015-10-23T02:08:00Z

Z3372824:

==Lab Attendance==

--[[User:Z3372824|Z3372824]] ([[User talk:Z3372824|talk]]) 13:46, 7 August 2015 (AEST)

--[[User:Z3372824|Z3372824]] ([[User talk:Z3372824|talk]]) 13:38, 14 August 2015 (AEST)

--[[User:Z3372824|Z3372824]] ([[User talk:Z3372824|talk]]) 15:14, 21 August 2015 (AEST)

--[[User:Z3372824|Z3372824]] ([[User talk:Z3372824|talk]]) 12:12, 28 August 2015 (AEST)

--[[User:Z3372824|Z3372824]] ([[User talk:Z3372824|talk]]) 12:14, 4 September 2015 (AEST)

--[[User:Z3372824|Z3372824]] ([[User talk:Z3372824|talk]]) 12:57, 25 September 2015 (AEST)

--[[User:Z3372824|Z3372824]] ([[User talk:Z3372824|talk]]) 12:48, 9 October 2015 (AEDT)

--[[User:Z3372824|Z3372824]] ([[User talk:Z3372824|talk]]) 13:37, 16 October 2015 (AEDT)

--[[User:Z3372824|Z3372824]] ([[User talk:Z3372824|talk]]) 13:07, 23 October 2015 (AEDT)

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{{StudentPage2015}}

[[Test student 2015]]

==Week 1 Assessment==

1) PMID 18603501

Increased Progesterone/Estradiol Ration on the Day of hCG Administration Adversely Affects Success of In Vitro Fertilisation-Embryo Transfer in Patients Stimulated with Gonadotropin-releasing Hormone Agonist and Recombinant Follicle-stimulating Hormone

This study examines the influence of premature luteinisation, with respect to ovarian response, during IVF. This was done using gonadotropin-releasing hormone agonist (GnRHa) and recombinant follicle-stimulating hormone (rFSH).The study defined premature luteinisation as a ratio between progesterone and estradiol of greater than one, the day hCG was administered. The experimental group of prematurely luteinised was then compared to the non-prematurely luteinised groups.

The study was performed on 311 infertile couples, in which a total of 339 cycles of ovarian hyperstimulation with GnRHa and rFSH. The females studied were aged from 20 to 40 years, and did not undergo cycles incorporating hMG, nor did they receive oocyte donations. The patients underwent ovarian stimulation, a long stimulation protocol of GnRHa therapy, rFSH administration as well as transvaginal oocyte retrieval, respectively. hCG was administered after adequate follicular maturation and oocytes were obtained 35-37 hours after hCG administration using transvaginal aspiration with ultrasound assistance. The follicular fluids and follicular washes were examined using a dissecting stereomicroscope that was incubated at 37 degrees with 5%CO2. Sperm insemination procedures were also performed, after which the oocytes were inseminated with spermatozoa. The oocytes were removed after 2 hour exposures to the spermatozoa and cultured in fresh IVF medium. The control group underwent ICSI procedures, while the experimental group underwent IVF procedures. The oocytes were then cultured and assessed for pronuclei presence 16-18 hours incubation in order to determine fertilisation (presence of 2 pronuclei). Embryos were then cultured and classified, as were the blastocysts.

The study found 137 out of the 339 cycles to have premature luteinisation. Poor ovarian response was more common in the experimental group. It was also found the the experimental group had a higher progesterone level and lower E2 level on the hCG administration day. However the mean luteinising hormone on day 6 of stimulation was similar in both control and study groups but higher in the control group on hCG administeration day. The experimental group demonstrated a lower number of oocytes obtained, and lower number of mature oocytes recovered. It should be noted that fertilisation rates were similar in both groups. Embryo number was lower for the experimental group compared to the control group. 130 gestational sacs were demonstrated after a transfer of 577 embryos in the control group while 76 gestational sacs were demonstrated out of 339 embryo transfers in the study group. The non-prematurely luteinised group and prematurely luteinised group had similar implantation rates. It was also found that 48.5% of the non-prematurely luteinised group achieved clinical pregnancies while 36.6% of the prematurely luteinised group achieved clinical pregnancies.

<pubmed>18603501</pubmed>

2) PMID 21793811

Impact of endometriosis on in vitro fertilization and embryo transfer cycles in young women; a stage-dependent interference

Due to the significantly higher prevalence of endometriosis in infertile women as compared to the general population, a causal relationship between endometriosis and infertility has been postulated. In vitro fertilisation and embryo transfer (IVF-ET) has been considered a suitable treatment for patients with a history of endometriosis. This study examines the effect of endometriosis on IVF-ET cycles on women younger than 35 years of age and who have had surgical treatment for endometriosis without clinical recurrence signs. The endometriosis group was compared to another group of patients also undergoing IVF-ET, but with tubal infertility without clinical signs of endometriosis. The results were analysed according to the different stages of endometriosis as classified by the American Society for Reproductive Medicine.

The experimental group consisted of 148 patients whereas the control group (tubal infertility patients) consisted of 72 patients. All groups consisted of patients that were less than 35 years of age and did not have clinical indication for any other cause of infertility. The experimental group underwent 164 IVF-ET cycles while the control group underwent 80 IVF-ET cycles. Patients received a long-acting down-regulation drug regime, a daily subcutaneous FSH dose, as well as gonadotropin doses which were decided individually according to age, basal FSH, ovarian volume and ovarian response. After two or more follicles reached maximal diameter of 17-18mm, hCG was administered and oocytes were obtained 36 hours later using vaginal ultrasonography, to then be fertilised on the same day. Embryo transfers were made two to three days after oocyte retrieval. Natural progesterone in oil was then administered. Plasma beta-hCG values were used to assess pregnancy. Clinical pregnancy was determined when at least one gestational sac was found with a fetal pole and heart activity through ultrasond.

It was found that the experimental group had significantly lower numbers of follicles on the hCG day, oocytes obtained and transferred when compared to the control group, despite receiving a higher FSH dose. However no significant differences were found regardingt cycle cancellation rate, peak E2 levels of the length of the stimulation phase. 11.6% of clinical pregnancies per started cucle were observed in the experimental group as compared to 22.5% in the control group. However, this value wa not significant when the clinical pregnancy rate was considered per oocyte retrieval or per embryo transfer. It was also found that patients at stage I-II of endomtriosis had a significantly lower rate of fertilisation when compared to the control group patients. Patients at stage III-IV of endometriosis had a large reduction in pregnancy rate than the control group, however the fertilisation rate was comparable. Patients at stage III-IV had lower peak E2 concentrations, less follicles on the hCG day, fewer oocytes at retrieval and lower implantation rates. Furthermore, poor ovarion responses in 15 out of 109 cycles resulted in discontinuation of the cycle in patients at stage III-IV of the endometriosis group, compared to 2 of 55 in the stage I-II group and 3 of 80 in the control group.

<pubmed>21793811</pubmed>

--[[User:Z8600021|Mark Hill]] ([[User talk:Z8600021|talk]]) 14:08, 16 September 2015 (AEST) These are good summaries of the se 2 articles. You should make an effort to clearly identify what you have written as opposed to quoting directly from the paper.(5/5)

==Week 2 Assessment==

[[File:Epigenetic factors Influencing Human Development.jpg|300px]]

PMID 26216216

--[[User:Z8600021|Mark Hill]] ([[User talk:Z8600021|talk]]) 14:12, 16 September 2015 (AEST) Image uploaded and named correctly. Image summary includes information, reference, copyright and student image template. (5/5)

==Week 3 Assessment==

PMID 26074966
<pubmed>26074966</pubmed>

PMID 20416867
<pubmed>20416867</pubmed>

PMID 23873146
<pubmed>23873146</pubmed>

The three key pathways by which the incidence of OHSS has been curtailed involve identifying risk factors to predict OHSS development, modifying treatment regimes on the basis of the identified risk factors and intervention to prevent progression to OHSS once the patient has undergone Controlled Ovarian Stimulation.

1) Risk factors

Primary: Preexisting factors likely to exacerbate the ovarian stimulation response. Include: young age, low body weight, history of elevated response to gonadotropins, Polycystic Ovary Syndrome (PCOS), isolated PCOS characteristic or a previous history of OHSS. Anti-Mullerian Hormone markers (AMH) are a newly developed predictive tool with a sensitivity of 90.5% and specificity of 81.3%. Ultrasonographic markers including antral follicle count
PMID 26074966

Secondary:

2) Prevention

Primary:
a) Gonadotropins: reduce duration, reduce dose, avoid GnRH Agonists PMID 23873146

b) Use Metformin Therapy

c) Target Unifollicular Ovulation

d) Avoid hCG

e) In Vitro Maturation

Secondary:
a) Reduce hCG dose

b) Coasting

c) Cryopreservation of Embryos

d) Cancel Cycle

e) Use alternative Agents

PMID 20416867

--[[User:Z8600021|Mark Hill]] ([[User talk:Z8600021|talk]]) 14:12, 16 September 2015 (AEST) These are relevant to your group project. Hopefully these will be useful in the final project page. (5/5)

==Week 4 Assessment==
===Fertilisation Quiz===

<quiz display=simple>

{Which of the following statements is incorrect in regards to the acrosome:
|type="()"}
-The acrosome reaction allows for the exposure of the inner-acrosomal membrane
-Only acrosome reacted spermatozoa fuse with the oocyte
-The acrosome within the spermatozoa is derived from the golgi apparatus
+Zona Pellucida Binding Protein 1 is synthesised by the oocyte
-The enzymatic contents of the acrosome degrade the zona pellucida
||This is correct, the [[Z#zona pellucida binding protein 1|zona pellucida binding protein 1]] is in fact a spermatozoa protein located on the acrosome surface, and binds to the zona pellucida of the oocyte during fertilisation.

{Which of the following statements about the zona pellucida is incorrect:
|type="()"}
-It is an insoluble extracellular matrix
-It expresses several glycoproteins
-It surrounds the blastocyst
-It surrounds the developing oocyte
+It prevents sperm binding
||Yes, the [[Z#zona pellucida|zona pellucida]] is a specialised extracellular matrix which surrounds the developing oocyte. It expresses several glycoproteins including ZP1, ZP2, ZP3 and ZP4, all of which play an important role in fertilisation. The zona pellucida facilitates sperm binding as the ZP2 binds the spermatozoa before fertilisation. Following fertilisation, the zona pellucida continues to surround the blastocyst during the first week of development, before being broken down through uterine and blastula secretions.

{Fertilisation does not:
|type="()"}
+result in the formation of the first polar body after the second meiotic division
-often occurs in the first 1/3 of the oviduct
-involve spermatozoa and oocyte fusion
-require the exocytosis of cortical granules in the cortical reaction
- require the exocytosis of acrosomal enzymes during the acrosome reaction
||Yes, [[F#fertilization|fertilization]] results in the formation of the second polar body after the second meiotic division. The first polar body forms during the first meiotic division.

</quiz>

--[[User:Z8600021|Mark Hill]] ([[User talk:Z8600021|talk]]) 14:20, 16 September 2015 (AEST) Three negative questions. Q1 An interesting range of options. I suggest that your question might be more instructive. The incorrect option (zona pellucida binding protein 1) is a bit of a give away as why would the oocyte make this protein? A student using simple logic (rather than knowledge) may get this right. Q2 A little simplistic, as we spent some time on ZP sperm binding. Q3 has too simple options and is not well structured. (7/10)

[[ANAT2341 Student 2015 Quiz Questions]]
==Week 5 Assessment==

What is the difference between gastroschisis and omphalocele?

Gastroschisis and Omphalocele are both congenital abdominal wall defects. Omphalocele is a condition involving the umbilical ring whereby the internal organs, typically consisting of the small intestine, colon, liver and spleen, are disemboweled in a sac made of peritoneum, Wharton's jelly and amnion. Gastroschisis is an anterior abdominal wall defect often located to the right of the umbilical cord, where like Omphalocele, there is a protrusion of the bowel. However, in Gastroschisis there is no sac covering the herniation. As such, both conditions defer with respect to location and presence of a sac. Omphalocele is caused by an abnormality in the embryo before week 9 of gestation whereby the bowel loops are malrotated or non rotated and do not return to the abdominal cavity. There are several competing theories as to the cause of Gastroschisis. A leading hypothesis suggests that Gastroschisis results from the inability of the vitelline structures and yolk sac to be incorporated into the body stalk.

Gastroschisis and Omphalocele represent the two most common abdominal wall defects. Gastroschisis is more common of the two and occurs at a rate of one per 600 live births. Omphalocele occurs in about one in 3000 to 10000 live births. Whilst the incidence of Omphalocele is stable, the incidence of Gastroschisis appears to be increasing. It is suspected that this may be due to better technology and screening methods. The male to female ratio of Omphalocele is 1:1.5 while the male to female ratio of Gastroschisis is equivalent. The maternal age of mothers who give birth to a child suffering from Omphalocele is typically 30 years of age. A mother who gives birth to a child from Gastroschisis is typically 22 years of age.

A key difference between Gastroschisis and Omphalocele is that congenital Omphaloceles are frequently associated with other abnormalities while Gastroschisis is not. In Omphalocele, chromosomal defects are found in 30-40% of cases while multiple associated anomalies including chromosomal changes are observed in 67-80% of cases. It is rare for associated anomalies to occur with Gastroschisis. These include: intestinal atresia which is found in 10% of cases, as well as cardiac, renal, musculoskeletal and central nervous system anomalies.

PMID 25459013

<pubmed>25459013</pubmed>

PMID 26229394

<pubmed>26229394</pubmed>

--[[User:Z8600021|Mark Hill]] ([[User talk:Z8600021|talk]]) 14:20, 16 September 2015 (AEST) These are good summaries. (5/5)

==Week 7 Assessment==

PMID 26395490

<pubmed>26395490</pubmed>

1. Although it is currently thought that thyroid C cells originate from cephalic neural crest cells, growing evidence suggests that the embryonic origin may in fact be from Sox17+ anterior endoderm. This study traced Wtn1 expressing cells to determine neural crest origin. Wtn1 expression occurs in the dorsal neural tube and is necessary for neural crest cell expansion. Foregut endoderm origin was established from tracing Sox17 expression, as it is known that transient expression of Sox17 occurs during formation of endoderm. Through fate mapping, the study in mice found that thyroid C cells derived from Sox17+ anterior endoderm, rather than Wtn1 expressing neural crest progeny. However, Wtn1 neural crest cells play a role in the development of thyroid connective tissue. Through lineage tracing, it was also found that in thyroid C cell precursors, the transcription factors Foxa1 and Foxa2 are differentially expressed. These transcription factors are commonly expressed in endoderm organs, and were also found in the thyroid bud and pharyngeal pouch, from which the ultimobranchial bodies that give rise to the thyroid emerge. Within embryonic thyroid C cells, the two transcription factors are coexpressed.

2.Tooth Development consists of ectoderm, mesoderm and neural crest ectomesenchyme involvement. The Ameloblasts produce enamel. Odontoblasts derive from neural crest mesenchyme and form predentin which calcifies to form dentin. The periodontal ligament secures the tooth in the bone socket, acts as a shock absorber, transmits chew forces from bone to tooth and relays sensory information.

==Peer Reviews==

'''Group 1'''

This Group Project has a lot of potential. Information is presented in an engaging way through an introductory video documenting a case, timeline providing retrospective insight as well as diagrams detailing the complex processes in a concise manner. I also found some subsections interesting and relevant, including the discussion on ethics, Current research areas, as well as the glossary which provides a quick reference.

Although I understand you intend to elaborate more on certain areas including current research, the project does seem a little thin in regards to text. There are many papers that are linked with no explanation. For example, with regards to the table under prohibitions, I am confused as to what exactly those countries prohibit (all genetic modification? mitochondrial techniques only?) and also whether there is any more nuance to the discussion (do they ban different things?). Of course, one could click through the links under each country, but i think some text before the table itself would only add to your project and bring more context to the table itself. Diagrams themselves can also be referred to in the text (as you would find in a textbook), to add context and create a more cohesive wikipedia page (e.g. for Pronuclear transfer). In terms of the information provided, a little deeper exploration or discussion about certain issues including the reasoning behind ethics arguments may be relevant. If the articles listed under the headings are anything to go by, it seems you intend to do this.

Finally, some proofreading will be very beneficial in polishing up the wikipedia page. There are some sentences like "And it effectiveness in doing so. And the processes that occur in the oocyte when this method is used" under Human Embryo Model, which may well do with some editing. I would like to add that the referencing has been fantastic and consistent. Good Luck!

'''Group 3'''

I found this Wikipedia page particularly interesting. A wide assortment of visual media including histological slides, ultrasound images, geographical maps, tables, flow diagrams and hand-drawn images, all add a richness and balance to the text. This page does well to direct the reader's attention with highlighted text as well, to make for an aesthetically pleasing article. In particular, i found the hand-drawn diagram particularly intelligent and impressive.

In terms of text, i think this article is of adequate complexity and provides educational value to its intended audience of fellow university students. However, more diagrams to accompany the pathophysiological mechanisms and simplify the process may be of benefit. The text under 'Causes' is informative, but there is an imbalance of information for the various subsections within that heading. I assume, you intend to elaborate on those subsections that seem a little thin. It may be more effective to break up the 'genetic factors' section to a simple list of genetic influences, with details of studies relevant to that factor alongside it. This way, you don't have to read through several paragraphs to get to a particular gene/information point. Also, some arrows pointing to the actual cysts explicitly in the histological slide may be useful, as already done in the Ultrasound slide.

Finally, although the Wikipedia page is organised logically and contains particularly relevant sections, it may do with some more. As an age old issue, I'm interested in the epidemiology of PCOS and a bit about its history (or where/when we know what we do about it). Other than that, the page looks pretty good and reads well too.

'''Group 4'''

This Group Project is impressively detailed and provides a comprehensive view of male infertility detailing the normal process as well as the various disorder types and causes. The wikipedia page flows logically, provides excellent summaries and may well be an excellent educational resource. The video chosen is fantastic and tables have been used well to present information quickly.

I find that the Introduction is clear and concise. However, i feel it may be improved further by an introductory visual. Other than that, the page has many relevant diagrams and images. In terms of the 'development of gonadotropin preparations', it does seem a little out of place as it isn't particularly referred to in the text. I understand timelines add a richness to the text and can give perspective, but i feel that it may be of more relevance if given regarding male infertility treatments as a whole, rather than gonadotropin preparations. Of course, you can always have both.

Other than that, I am quite impressed with this wikipedia page. It is referenced well and information is backed with reference to the findings of various studies. A final tip may be to add a simple glossary for ease of reference as opposed to having to scroll back up to the section (e.g. varicocele) to remind oneself of the meaning. However, it should be commended that jargon was defined well throughout the article.

'''Group 5'''

This Group Project covers a wide breadth of topics in a very easy to understand manner. The types of chemotherapy treatments or drugs for example, were very easy to read and understand. The various tables and histological slides employed also make for an interesting and easy to digest wikipedia article. The visual aids detailing the IVF process was also well appreciated and balanced well with the text.

However, I feel that in general there should be more visual media to accompany the text. An issue of a current image I have (patient undergoing chemotherapy) is that I don't think it adds much to the wikipedia page and is not informative. Furthermore, I was hoping there would be an introduction to the wikipedia page that would explicitly detail what it aims to cover. This would provide more structure and give a logical flow to the wikipedia page. Another way to improve the logical flow, is to subdivide sections into male and female (e.g. surgeries and drugs, the transition from surgeries for males to drugs for female infertility was abrupt and disorienting). The top half of the page may be made less verbose through the use of more jargon e.g. in the Radiation section "cells can't grow and divide" etc. Naturally, a glossary is also a convenient reference point that may be included.

Also, there is an imbalance in detail with more input within cancer cells section than other sections more directly relevant in ART including IVF. However, I do understand this Group Project is still a work in progress. Overall, there is a lot of potential in the wikipedia page.

'''Group 6'''

This wikipedia article is impressively organised and easy to follow. It is sufficiently detailed, and despite being content heavy it has a good layout as it is well spaced out. This article is well referenced as well, a testament to the work that has been put in.

I understand that the advantages and disadvantages are listed as bullet points. Have you thought of organising it in a table? It may be a way to include a 'visual aid' in order to reach a balance in terms of visual/text content. Generally, more diagrams will only improve this article. Cohesion between the visual and written text may be increased by referrals to the diagrams/images throughout e.g. human blastocyst biopsy as opposed to a caption only. Also, having a section directly comparing the genetic techniques/purpose/effectivity/results in a table may be interesting.

Overall, wonderful work. In my opinion this is definitely a frontrunner and particularly difficult to critique.

==Week 10 Assessment==

[https://embryology.med.unsw.edu.au/embryology/Slides/Embryo_Stages/Stage22/08-eye/Stage22-08-eye.html?zoom=6&lat=-3223.5&lon=3922&layers=B Stage 22 Eye]

Hyaloid artery supplies the developing lens and is surrounded by the vitreous. Developing lens consists of lens fibers which derive from surface ectoderm.

[[Vision - Lens Development]] --Development Overview

==References==

PMID 26244658
look at this <ref><pubmed>26244658</pubmed>

here's the list
<references/>

User:Z3372824

2015-10-23T02:07:01Z

Z3372824:

==Lab Attendance==

--[[User:Z3372824|Z3372824]] ([[User talk:Z3372824|talk]]) 13:46, 7 August 2015 (AEST)

--[[User:Z3372824|Z3372824]] ([[User talk:Z3372824|talk]]) 13:38, 14 August 2015 (AEST)

--[[User:Z3372824|Z3372824]] ([[User talk:Z3372824|talk]]) 15:14, 21 August 2015 (AEST)

--[[User:Z3372824|Z3372824]] ([[User talk:Z3372824|talk]]) 12:12, 28 August 2015 (AEST)

--[[User:Z3372824|Z3372824]] ([[User talk:Z3372824|talk]]) 12:14, 4 September 2015 (AEST)

--[[User:Z3372824|Z3372824]] ([[User talk:Z3372824|talk]]) 12:57, 25 September 2015 (AEST)

--[[User:Z3372824|Z3372824]] ([[User talk:Z3372824|talk]]) 12:48, 9 October 2015 (AEDT)

--[[User:Z3372824|Z3372824]] ([[User talk:Z3372824|talk]]) 13:37, 16 October 2015 (AEDT)

----

{{StudentPage2015}}

[[Test student 2015]]

==Week 1 Assessment==

1) PMID 18603501

Increased Progesterone/Estradiol Ration on the Day of hCG Administration Adversely Affects Success of In Vitro Fertilisation-Embryo Transfer in Patients Stimulated with Gonadotropin-releasing Hormone Agonist and Recombinant Follicle-stimulating Hormone

This study examines the influence of premature luteinisation, with respect to ovarian response, during IVF. This was done using gonadotropin-releasing hormone agonist (GnRHa) and recombinant follicle-stimulating hormone (rFSH).The study defined premature luteinisation as a ratio between progesterone and estradiol of greater than one, the day hCG was administered. The experimental group of prematurely luteinised was then compared to the non-prematurely luteinised groups.

The study was performed on 311 infertile couples, in which a total of 339 cycles of ovarian hyperstimulation with GnRHa and rFSH. The females studied were aged from 20 to 40 years, and did not undergo cycles incorporating hMG, nor did they receive oocyte donations. The patients underwent ovarian stimulation, a long stimulation protocol of GnRHa therapy, rFSH administration as well as transvaginal oocyte retrieval, respectively. hCG was administered after adequate follicular maturation and oocytes were obtained 35-37 hours after hCG administration using transvaginal aspiration with ultrasound assistance. The follicular fluids and follicular washes were examined using a dissecting stereomicroscope that was incubated at 37 degrees with 5%CO2. Sperm insemination procedures were also performed, after which the oocytes were inseminated with spermatozoa. The oocytes were removed after 2 hour exposures to the spermatozoa and cultured in fresh IVF medium. The control group underwent ICSI procedures, while the experimental group underwent IVF procedures. The oocytes were then cultured and assessed for pronuclei presence 16-18 hours incubation in order to determine fertilisation (presence of 2 pronuclei). Embryos were then cultured and classified, as were the blastocysts.

The study found 137 out of the 339 cycles to have premature luteinisation. Poor ovarian response was more common in the experimental group. It was also found the the experimental group had a higher progesterone level and lower E2 level on the hCG administration day. However the mean luteinising hormone on day 6 of stimulation was similar in both control and study groups but higher in the control group on hCG administeration day. The experimental group demonstrated a lower number of oocytes obtained, and lower number of mature oocytes recovered. It should be noted that fertilisation rates were similar in both groups. Embryo number was lower for the experimental group compared to the control group. 130 gestational sacs were demonstrated after a transfer of 577 embryos in the control group while 76 gestational sacs were demonstrated out of 339 embryo transfers in the study group. The non-prematurely luteinised group and prematurely luteinised group had similar implantation rates. It was also found that 48.5% of the non-prematurely luteinised group achieved clinical pregnancies while 36.6% of the prematurely luteinised group achieved clinical pregnancies.

<pubmed>18603501</pubmed>

2) PMID 21793811

Impact of endometriosis on in vitro fertilization and embryo transfer cycles in young women; a stage-dependent interference

Due to the significantly higher prevalence of endometriosis in infertile women as compared to the general population, a causal relationship between endometriosis and infertility has been postulated. In vitro fertilisation and embryo transfer (IVF-ET) has been considered a suitable treatment for patients with a history of endometriosis. This study examines the effect of endometriosis on IVF-ET cycles on women younger than 35 years of age and who have had surgical treatment for endometriosis without clinical recurrence signs. The endometriosis group was compared to another group of patients also undergoing IVF-ET, but with tubal infertility without clinical signs of endometriosis. The results were analysed according to the different stages of endometriosis as classified by the American Society for Reproductive Medicine.

The experimental group consisted of 148 patients whereas the control group (tubal infertility patients) consisted of 72 patients. All groups consisted of patients that were less than 35 years of age and did not have clinical indication for any other cause of infertility. The experimental group underwent 164 IVF-ET cycles while the control group underwent 80 IVF-ET cycles. Patients received a long-acting down-regulation drug regime, a daily subcutaneous FSH dose, as well as gonadotropin doses which were decided individually according to age, basal FSH, ovarian volume and ovarian response. After two or more follicles reached maximal diameter of 17-18mm, hCG was administered and oocytes were obtained 36 hours later using vaginal ultrasonography, to then be fertilised on the same day. Embryo transfers were made two to three days after oocyte retrieval. Natural progesterone in oil was then administered. Plasma beta-hCG values were used to assess pregnancy. Clinical pregnancy was determined when at least one gestational sac was found with a fetal pole and heart activity through ultrasond.

It was found that the experimental group had significantly lower numbers of follicles on the hCG day, oocytes obtained and transferred when compared to the control group, despite receiving a higher FSH dose. However no significant differences were found regardingt cycle cancellation rate, peak E2 levels of the length of the stimulation phase. 11.6% of clinical pregnancies per started cucle were observed in the experimental group as compared to 22.5% in the control group. However, this value wa not significant when the clinical pregnancy rate was considered per oocyte retrieval or per embryo transfer. It was also found that patients at stage I-II of endomtriosis had a significantly lower rate of fertilisation when compared to the control group patients. Patients at stage III-IV of endometriosis had a large reduction in pregnancy rate than the control group, however the fertilisation rate was comparable. Patients at stage III-IV had lower peak E2 concentrations, less follicles on the hCG day, fewer oocytes at retrieval and lower implantation rates. Furthermore, poor ovarion responses in 15 out of 109 cycles resulted in discontinuation of the cycle in patients at stage III-IV of the endometriosis group, compared to 2 of 55 in the stage I-II group and 3 of 80 in the control group.

<pubmed>21793811</pubmed>

--[[User:Z8600021|Mark Hill]] ([[User talk:Z8600021|talk]]) 14:08, 16 September 2015 (AEST) These are good summaries of the se 2 articles. You should make an effort to clearly identify what you have written as opposed to quoting directly from the paper.(5/5)

==Week 2 Assessment==

[[File:Epigenetic factors Influencing Human Development.jpg|300px]]

PMID 26216216

--[[User:Z8600021|Mark Hill]] ([[User talk:Z8600021|talk]]) 14:12, 16 September 2015 (AEST) Image uploaded and named correctly. Image summary includes information, reference, copyright and student image template. (5/5)

==Week 3 Assessment==

PMID 26074966
<pubmed>26074966</pubmed>

PMID 20416867
<pubmed>20416867</pubmed>

PMID 23873146
<pubmed>23873146</pubmed>

The three key pathways by which the incidence of OHSS has been curtailed involve identifying risk factors to predict OHSS development, modifying treatment regimes on the basis of the identified risk factors and intervention to prevent progression to OHSS once the patient has undergone Controlled Ovarian Stimulation.

1) Risk factors

Primary: Preexisting factors likely to exacerbate the ovarian stimulation response. Include: young age, low body weight, history of elevated response to gonadotropins, Polycystic Ovary Syndrome (PCOS), isolated PCOS characteristic or a previous history of OHSS. Anti-Mullerian Hormone markers (AMH) are a newly developed predictive tool with a sensitivity of 90.5% and specificity of 81.3%. Ultrasonographic markers including antral follicle count
PMID 26074966

Secondary:

2) Prevention

Primary:
a) Gonadotropins: reduce duration, reduce dose, avoid GnRH Agonists PMID 23873146

b) Use Metformin Therapy

c) Target Unifollicular Ovulation

d) Avoid hCG

e) In Vitro Maturation

Secondary:
a) Reduce hCG dose

b) Coasting

c) Cryopreservation of Embryos

d) Cancel Cycle

e) Use alternative Agents

PMID 20416867

--[[User:Z8600021|Mark Hill]] ([[User talk:Z8600021|talk]]) 14:12, 16 September 2015 (AEST) These are relevant to your group project. Hopefully these will be useful in the final project page. (5/5)

==Week 4 Assessment==
===Fertilisation Quiz===

<quiz display=simple>

{Which of the following statements is incorrect in regards to the acrosome:
|type="()"}
-The acrosome reaction allows for the exposure of the inner-acrosomal membrane
-Only acrosome reacted spermatozoa fuse with the oocyte
-The acrosome within the spermatozoa is derived from the golgi apparatus
+Zona Pellucida Binding Protein 1 is synthesised by the oocyte
-The enzymatic contents of the acrosome degrade the zona pellucida
||This is correct, the [[Z#zona pellucida binding protein 1|zona pellucida binding protein 1]] is in fact a spermatozoa protein located on the acrosome surface, and binds to the zona pellucida of the oocyte during fertilisation.

{Which of the following statements about the zona pellucida is incorrect:
|type="()"}
-It is an insoluble extracellular matrix
-It expresses several glycoproteins
-It surrounds the blastocyst
-It surrounds the developing oocyte
+It prevents sperm binding
||Yes, the [[Z#zona pellucida|zona pellucida]] is a specialised extracellular matrix which surrounds the developing oocyte. It expresses several glycoproteins including ZP1, ZP2, ZP3 and ZP4, all of which play an important role in fertilisation. The zona pellucida facilitates sperm binding as the ZP2 binds the spermatozoa before fertilisation. Following fertilisation, the zona pellucida continues to surround the blastocyst during the first week of development, before being broken down through uterine and blastula secretions.

{Fertilisation does not:
|type="()"}
+result in the formation of the first polar body after the second meiotic division
-often occurs in the first 1/3 of the oviduct
-involve spermatozoa and oocyte fusion
-require the exocytosis of cortical granules in the cortical reaction
- require the exocytosis of acrosomal enzymes during the acrosome reaction
||Yes, [[F#fertilization|fertilization]] results in the formation of the second polar body after the second meiotic division. The first polar body forms during the first meiotic division.

</quiz>

--[[User:Z8600021|Mark Hill]] ([[User talk:Z8600021|talk]]) 14:20, 16 September 2015 (AEST) Three negative questions. Q1 An interesting range of options. I suggest that your question might be more instructive. The incorrect option (zona pellucida binding protein 1) is a bit of a give away as why would the oocyte make this protein? A student using simple logic (rather than knowledge) may get this right. Q2 A little simplistic, as we spent some time on ZP sperm binding. Q3 has too simple options and is not well structured. (7/10)

[[ANAT2341 Student 2015 Quiz Questions]]
==Week 5 Assessment==

What is the difference between gastroschisis and omphalocele?

Gastroschisis and Omphalocele are both congenital abdominal wall defects. Omphalocele is a condition involving the umbilical ring whereby the internal organs, typically consisting of the small intestine, colon, liver and spleen, are disemboweled in a sac made of peritoneum, Wharton's jelly and amnion. Gastroschisis is an anterior abdominal wall defect often located to the right of the umbilical cord, where like Omphalocele, there is a protrusion of the bowel. However, in Gastroschisis there is no sac covering the herniation. As such, both conditions defer with respect to location and presence of a sac. Omphalocele is caused by an abnormality in the embryo before week 9 of gestation whereby the bowel loops are malrotated or non rotated and do not return to the abdominal cavity. There are several competing theories as to the cause of Gastroschisis. A leading hypothesis suggests that Gastroschisis results from the inability of the vitelline structures and yolk sac to be incorporated into the body stalk.

Gastroschisis and Omphalocele represent the two most common abdominal wall defects. Gastroschisis is more common of the two and occurs at a rate of one per 600 live births. Omphalocele occurs in about one in 3000 to 10000 live births. Whilst the incidence of Omphalocele is stable, the incidence of Gastroschisis appears to be increasing. It is suspected that this may be due to better technology and screening methods. The male to female ratio of Omphalocele is 1:1.5 while the male to female ratio of Gastroschisis is equivalent. The maternal age of mothers who give birth to a child suffering from Omphalocele is typically 30 years of age. A mother who gives birth to a child from Gastroschisis is typically 22 years of age.

A key difference between Gastroschisis and Omphalocele is that congenital Omphaloceles are frequently associated with other abnormalities while Gastroschisis is not. In Omphalocele, chromosomal defects are found in 30-40% of cases while multiple associated anomalies including chromosomal changes are observed in 67-80% of cases. It is rare for associated anomalies to occur with Gastroschisis. These include: intestinal atresia which is found in 10% of cases, as well as cardiac, renal, musculoskeletal and central nervous system anomalies.

PMID 25459013

<pubmed>25459013</pubmed>

PMID 26229394

<pubmed>26229394</pubmed>

--[[User:Z8600021|Mark Hill]] ([[User talk:Z8600021|talk]]) 14:20, 16 September 2015 (AEST) These are good summaries. (5/5)

==Week 7 Assessment==

PMID 26395490

<pubmed>26395490</pubmed>

1. Although it is currently thought that thyroid C cells originate from cephalic neural crest cells, growing evidence suggests that the embryonic origin may in fact be from Sox17+ anterior endoderm. This study traced Wtn1 expressing cells to determine neural crest origin. Wtn1 expression occurs in the dorsal neural tube and is necessary for neural crest cell expansion. Foregut endoderm origin was established from tracing Sox17 expression, as it is known that transient expression of Sox17 occurs during formation of endoderm. Through fate mapping, the study in mice found that thyroid C cells derived from Sox17+ anterior endoderm, rather than Wtn1 expressing neural crest progeny. However, Wtn1 neural crest cells play a role in the development of thyroid connective tissue. Through lineage tracing, it was also found that in thyroid C cell precursors, the transcription factors Foxa1 and Foxa2 are differentially expressed. These transcription factors are commonly expressed in endoderm organs, and were also found in the thyroid bud and pharyngeal pouch, from which the ultimobranchial bodies that give rise to the thyroid emerge. Within embryonic thyroid C cells, the two transcription factors are coexpressed.

2.Tooth Development consists of ectoderm, mesoderm and neural crest ectomesenchyme involvement. The Ameloblasts produce enamel. Odontoblasts derive from neural crest mesenchyme and form predentin which calcifies to form dentin. The periodontal ligament secures the tooth in the bone socket, acts as a shock absorber, transmits chew forces from bone to tooth and relays sensory information.

==Peer Reviews==

'''Group 1'''

This Group Project has a lot of potential. Information is presented in an engaging way through an introductory video documenting a case, timeline providing retrospective insight as well as diagrams detailing the complex processes in a concise manner. I also found some subsections interesting and relevant, including the discussion on ethics, Current research areas, as well as the glossary which provides a quick reference.

Although I understand you intend to elaborate more on certain areas including current research, the project does seem a little thin in regards to text. There are many papers that are linked with no explanation. For example, with regards to the table under prohibitions, I am confused as to what exactly those countries prohibit (all genetic modification? mitochondrial techniques only?) and also whether there is any more nuance to the discussion (do they ban different things?). Of course, one could click through the links under each country, but i think some text before the table itself would only add to your project and bring more context to the table itself. Diagrams themselves can also be referred to in the text (as you would find in a textbook), to add context and create a more cohesive wikipedia page (e.g. for Pronuclear transfer). In terms of the information provided, a little deeper exploration or discussion about certain issues including the reasoning behind ethics arguments may be relevant. If the articles listed under the headings are anything to go by, it seems you intend to do this.

Finally, some proofreading will be very beneficial in polishing up the wikipedia page. There are some sentences like "And it effectiveness in doing so. And the processes that occur in the oocyte when this method is used" under Human Embryo Model, which may well do with some editing. I would like to add that the referencing has been fantastic and consistent. Good Luck!

'''Group 3'''

I found this Wikipedia page particularly interesting. A wide assortment of visual media including histological slides, ultrasound images, geographical maps, tables, flow diagrams and hand-drawn images, all add a richness and balance to the text. This page does well to direct the reader's attention with highlighted text as well, to make for an aesthetically pleasing article. In particular, i found the hand-drawn diagram particularly intelligent and impressive.

In terms of text, i think this article is of adequate complexity and provides educational value to its intended audience of fellow university students. However, more diagrams to accompany the pathophysiological mechanisms and simplify the process may be of benefit. The text under 'Causes' is informative, but there is an imbalance of information for the various subsections within that heading. I assume, you intend to elaborate on those subsections that seem a little thin. It may be more effective to break up the 'genetic factors' section to a simple list of genetic influences, with details of studies relevant to that factor alongside it. This way, you don't have to read through several paragraphs to get to a particular gene/information point. Also, some arrows pointing to the actual cysts explicitly in the histological slide may be useful, as already done in the Ultrasound slide.

Finally, although the Wikipedia page is organised logically and contains particularly relevant sections, it may do with some more. As an age old issue, I'm interested in the epidemiology of PCOS and a bit about its history (or where/when we know what we do about it). Other than that, the page looks pretty good and reads well too.

'''Group 4'''

This Group Project is impressively detailed and provides a comprehensive view of male infertility detailing the normal process as well as the various disorder types and causes. The wikipedia page flows logically, provides excellent summaries and may well be an excellent educational resource. The video chosen is fantastic and tables have been used well to present information quickly.

I find that the Introduction is clear and concise. However, i feel it may be improved further by an introductory visual. Other than that, the page has many relevant diagrams and images. In terms of the 'development of gonadotropin preparations', it does seem a little out of place as it isn't particularly referred to in the text. I understand timelines add a richness to the text and can give perspective, but i feel that it may be of more relevance if given regarding male infertility treatments as a whole, rather than gonadotropin preparations. Of course, you can always have both.

Other than that, I am quite impressed with this wikipedia page. It is referenced well and information is backed with reference to the findings of various studies. A final tip may be to add a simple glossary for ease of reference as opposed to having to scroll back up to the section (e.g. varicocele) to remind oneself of the meaning. However, it should be commended that jargon was defined well throughout the article.

'''Group 5'''

This Group Project covers a wide breadth of topics in a very easy to understand manner. The types of chemotherapy treatments or drugs for example, were very easy to read and understand. The various tables and histological slides employed also make for an interesting and easy to digest wikipedia article. The visual aids detailing the IVF process was also well appreciated and balanced well with the text.

However, I feel that in general there should be more visual media to accompany the text. An issue of a current image I have (patient undergoing chemotherapy) is that I don't think it adds much to the wikipedia page and is not informative. Furthermore, I was hoping there would be an introduction to the wikipedia page that would explicitly detail what it aims to cover. This would provide more structure and give a logical flow to the wikipedia page. Another way to improve the logical flow, is to subdivide sections into male and female (e.g. surgeries and drugs, the transition from surgeries for males to drugs for female infertility was abrupt and disorienting). The top half of the page may be made less verbose through the use of more jargon e.g. in the Radiation section "cells can't grow and divide" etc. Naturally, a glossary is also a convenient reference point that may be included.

Also, there is an imbalance in detail with more input within cancer cells section than other sections more directly relevant in ART including IVF. However, I do understand this Group Project is still a work in progress. Overall, there is a lot of potential in the wikipedia page.

'''Group 6'''

This wikipedia article is impressively organised and easy to follow. It is sufficiently detailed, and despite being content heavy it has a good layout as it is well spaced out. This article is well referenced as well, a testament to the work that has been put in.

I understand that the advantages and disadvantages are listed as bullet points. Have you thought of organising it in a table? It may be a way to include a 'visual aid' in order to reach a balance in terms of visual/text content. Generally, more diagrams will only improve this article. Cohesion between the visual and written text may be increased by referrals to the diagrams/images throughout e.g. human blastocyst biopsy as opposed to a caption only. Also, having a section directly comparing the genetic techniques/purpose/effectivity/results in a table may be interesting.

Overall, wonderful work. In my opinion this is definitely a frontrunner and particularly difficult to critique.

====Week 10 Assessment====

[https://embryology.med.unsw.edu.au/embryology/Slides/Embryo_Stages/Stage22/08-eye/Stage22-08-eye.html?zoom=6&lat=-3223.5&lon=3922&layers=B Stage 22 Eye]

Hyaloid artery supplies the developing lens and is surrounded by the vitreous. Developing lens consists of lens fibers which derive from surface ectoderm.

[[Vision - Lens Development]] --Development Overview

==References==

PMID 26244658
look at this <ref><pubmed>26244658</pubmed>

here's the list
<references/>

User:Z3372824

2015-10-23T02:05:47Z

Z3372824:

==Lab Attendance==

--[[User:Z3372824|Z3372824]] ([[User talk:Z3372824|talk]]) 13:46, 7 August 2015 (AEST)

--[[User:Z3372824|Z3372824]] ([[User talk:Z3372824|talk]]) 13:38, 14 August 2015 (AEST)

--[[User:Z3372824|Z3372824]] ([[User talk:Z3372824|talk]]) 15:14, 21 August 2015 (AEST)

--[[User:Z3372824|Z3372824]] ([[User talk:Z3372824|talk]]) 12:12, 28 August 2015 (AEST)

--[[User:Z3372824|Z3372824]] ([[User talk:Z3372824|talk]]) 12:14, 4 September 2015 (AEST)

--[[User:Z3372824|Z3372824]] ([[User talk:Z3372824|talk]]) 12:57, 25 September 2015 (AEST)

--[[User:Z3372824|Z3372824]] ([[User talk:Z3372824|talk]]) 12:48, 9 October 2015 (AEDT)

--[[User:Z3372824|Z3372824]] ([[User talk:Z3372824|talk]]) 13:37, 16 October 2015 (AEDT)

----

{{StudentPage2015}}

[[Test student 2015]]

==Week 1 Assessment==

1) PMID 18603501

Increased Progesterone/Estradiol Ration on the Day of hCG Administration Adversely Affects Success of In Vitro Fertilisation-Embryo Transfer in Patients Stimulated with Gonadotropin-releasing Hormone Agonist and Recombinant Follicle-stimulating Hormone

This study examines the influence of premature luteinisation, with respect to ovarian response, during IVF. This was done using gonadotropin-releasing hormone agonist (GnRHa) and recombinant follicle-stimulating hormone (rFSH).The study defined premature luteinisation as a ratio between progesterone and estradiol of greater than one, the day hCG was administered. The experimental group of prematurely luteinised was then compared to the non-prematurely luteinised groups.

The study was performed on 311 infertile couples, in which a total of 339 cycles of ovarian hyperstimulation with GnRHa and rFSH. The females studied were aged from 20 to 40 years, and did not undergo cycles incorporating hMG, nor did they receive oocyte donations. The patients underwent ovarian stimulation, a long stimulation protocol of GnRHa therapy, rFSH administration as well as transvaginal oocyte retrieval, respectively. hCG was administered after adequate follicular maturation and oocytes were obtained 35-37 hours after hCG administration using transvaginal aspiration with ultrasound assistance. The follicular fluids and follicular washes were examined using a dissecting stereomicroscope that was incubated at 37 degrees with 5%CO2. Sperm insemination procedures were also performed, after which the oocytes were inseminated with spermatozoa. The oocytes were removed after 2 hour exposures to the spermatozoa and cultured in fresh IVF medium. The control group underwent ICSI procedures, while the experimental group underwent IVF procedures. The oocytes were then cultured and assessed for pronuclei presence 16-18 hours incubation in order to determine fertilisation (presence of 2 pronuclei). Embryos were then cultured and classified, as were the blastocysts.

The study found 137 out of the 339 cycles to have premature luteinisation. Poor ovarian response was more common in the experimental group. It was also found the the experimental group had a higher progesterone level and lower E2 level on the hCG administration day. However the mean luteinising hormone on day 6 of stimulation was similar in both control and study groups but higher in the control group on hCG administeration day. The experimental group demonstrated a lower number of oocytes obtained, and lower number of mature oocytes recovered. It should be noted that fertilisation rates were similar in both groups. Embryo number was lower for the experimental group compared to the control group. 130 gestational sacs were demonstrated after a transfer of 577 embryos in the control group while 76 gestational sacs were demonstrated out of 339 embryo transfers in the study group. The non-prematurely luteinised group and prematurely luteinised group had similar implantation rates. It was also found that 48.5% of the non-prematurely luteinised group achieved clinical pregnancies while 36.6% of the prematurely luteinised group achieved clinical pregnancies.

<pubmed>18603501</pubmed>

2) PMID 21793811

Impact of endometriosis on in vitro fertilization and embryo transfer cycles in young women; a stage-dependent interference

Due to the significantly higher prevalence of endometriosis in infertile women as compared to the general population, a causal relationship between endometriosis and infertility has been postulated. In vitro fertilisation and embryo transfer (IVF-ET) has been considered a suitable treatment for patients with a history of endometriosis. This study examines the effect of endometriosis on IVF-ET cycles on women younger than 35 years of age and who have had surgical treatment for endometriosis without clinical recurrence signs. The endometriosis group was compared to another group of patients also undergoing IVF-ET, but with tubal infertility without clinical signs of endometriosis. The results were analysed according to the different stages of endometriosis as classified by the American Society for Reproductive Medicine.

The experimental group consisted of 148 patients whereas the control group (tubal infertility patients) consisted of 72 patients. All groups consisted of patients that were less than 35 years of age and did not have clinical indication for any other cause of infertility. The experimental group underwent 164 IVF-ET cycles while the control group underwent 80 IVF-ET cycles. Patients received a long-acting down-regulation drug regime, a daily subcutaneous FSH dose, as well as gonadotropin doses which were decided individually according to age, basal FSH, ovarian volume and ovarian response. After two or more follicles reached maximal diameter of 17-18mm, hCG was administered and oocytes were obtained 36 hours later using vaginal ultrasonography, to then be fertilised on the same day. Embryo transfers were made two to three days after oocyte retrieval. Natural progesterone in oil was then administered. Plasma beta-hCG values were used to assess pregnancy. Clinical pregnancy was determined when at least one gestational sac was found with a fetal pole and heart activity through ultrasond.

It was found that the experimental group had significantly lower numbers of follicles on the hCG day, oocytes obtained and transferred when compared to the control group, despite receiving a higher FSH dose. However no significant differences were found regardingt cycle cancellation rate, peak E2 levels of the length of the stimulation phase. 11.6% of clinical pregnancies per started cucle were observed in the experimental group as compared to 22.5% in the control group. However, this value wa not significant when the clinical pregnancy rate was considered per oocyte retrieval or per embryo transfer. It was also found that patients at stage I-II of endomtriosis had a significantly lower rate of fertilisation when compared to the control group patients. Patients at stage III-IV of endometriosis had a large reduction in pregnancy rate than the control group, however the fertilisation rate was comparable. Patients at stage III-IV had lower peak E2 concentrations, less follicles on the hCG day, fewer oocytes at retrieval and lower implantation rates. Furthermore, poor ovarion responses in 15 out of 109 cycles resulted in discontinuation of the cycle in patients at stage III-IV of the endometriosis group, compared to 2 of 55 in the stage I-II group and 3 of 80 in the control group.

<pubmed>21793811</pubmed>

--[[User:Z8600021|Mark Hill]] ([[User talk:Z8600021|talk]]) 14:08, 16 September 2015 (AEST) These are good summaries of the se 2 articles. You should make an effort to clearly identify what you have written as opposed to quoting directly from the paper.(5/5)

==Week 2 Assessment==

[[File:Epigenetic factors Influencing Human Development.jpg|300px]]

PMID 26216216

--[[User:Z8600021|Mark Hill]] ([[User talk:Z8600021|talk]]) 14:12, 16 September 2015 (AEST) Image uploaded and named correctly. Image summary includes information, reference, copyright and student image template. (5/5)

==Week 3 Assessment==

PMID 26074966
<pubmed>26074966</pubmed>

PMID 20416867
<pubmed>20416867</pubmed>

PMID 23873146
<pubmed>23873146</pubmed>

The three key pathways by which the incidence of OHSS has been curtailed involve identifying risk factors to predict OHSS development, modifying treatment regimes on the basis of the identified risk factors and intervention to prevent progression to OHSS once the patient has undergone Controlled Ovarian Stimulation.

1) Risk factors

Primary: Preexisting factors likely to exacerbate the ovarian stimulation response. Include: young age, low body weight, history of elevated response to gonadotropins, Polycystic Ovary Syndrome (PCOS), isolated PCOS characteristic or a previous history of OHSS. Anti-Mullerian Hormone markers (AMH) are a newly developed predictive tool with a sensitivity of 90.5% and specificity of 81.3%. Ultrasonographic markers including antral follicle count
PMID 26074966

Secondary:

2) Prevention

Primary:
a) Gonadotropins: reduce duration, reduce dose, avoid GnRH Agonists PMID 23873146

b) Use Metformin Therapy

c) Target Unifollicular Ovulation

d) Avoid hCG

e) In Vitro Maturation

Secondary:
a) Reduce hCG dose

b) Coasting

c) Cryopreservation of Embryos

d) Cancel Cycle

e) Use alternative Agents

PMID 20416867

--[[User:Z8600021|Mark Hill]] ([[User talk:Z8600021|talk]]) 14:12, 16 September 2015 (AEST) These are relevant to your group project. Hopefully these will be useful in the final project page. (5/5)

==Week 4 Assessment==
===Fertilisation Quiz===

<quiz display=simple>

{Which of the following statements is incorrect in regards to the acrosome:
|type="()"}
-The acrosome reaction allows for the exposure of the inner-acrosomal membrane
-Only acrosome reacted spermatozoa fuse with the oocyte
-The acrosome within the spermatozoa is derived from the golgi apparatus
+Zona Pellucida Binding Protein 1 is synthesised by the oocyte
-The enzymatic contents of the acrosome degrade the zona pellucida
||This is correct, the [[Z#zona pellucida binding protein 1|zona pellucida binding protein 1]] is in fact a spermatozoa protein located on the acrosome surface, and binds to the zona pellucida of the oocyte during fertilisation.

{Which of the following statements about the zona pellucida is incorrect:
|type="()"}
-It is an insoluble extracellular matrix
-It expresses several glycoproteins
-It surrounds the blastocyst
-It surrounds the developing oocyte
+It prevents sperm binding
||Yes, the [[Z#zona pellucida|zona pellucida]] is a specialised extracellular matrix which surrounds the developing oocyte. It expresses several glycoproteins including ZP1, ZP2, ZP3 and ZP4, all of which play an important role in fertilisation. The zona pellucida facilitates sperm binding as the ZP2 binds the spermatozoa before fertilisation. Following fertilisation, the zona pellucida continues to surround the blastocyst during the first week of development, before being broken down through uterine and blastula secretions.

{Fertilisation does not:
|type="()"}
+result in the formation of the first polar body after the second meiotic division
-often occurs in the first 1/3 of the oviduct
-involve spermatozoa and oocyte fusion
-require the exocytosis of cortical granules in the cortical reaction
- require the exocytosis of acrosomal enzymes during the acrosome reaction
||Yes, [[F#fertilization|fertilization]] results in the formation of the second polar body after the second meiotic division. The first polar body forms during the first meiotic division.

</quiz>

--[[User:Z8600021|Mark Hill]] ([[User talk:Z8600021|talk]]) 14:20, 16 September 2015 (AEST) Three negative questions. Q1 An interesting range of options. I suggest that your question might be more instructive. The incorrect option (zona pellucida binding protein 1) is a bit of a give away as why would the oocyte make this protein? A student using simple logic (rather than knowledge) may get this right. Q2 A little simplistic, as we spent some time on ZP sperm binding. Q3 has too simple options and is not well structured. (7/10)

[[ANAT2341 Student 2015 Quiz Questions]]
==Week 5 Assessment==

What is the difference between gastroschisis and omphalocele?

Gastroschisis and Omphalocele are both congenital abdominal wall defects. Omphalocele is a condition involving the umbilical ring whereby the internal organs, typically consisting of the small intestine, colon, liver and spleen, are disemboweled in a sac made of peritoneum, Wharton's jelly and amnion. Gastroschisis is an anterior abdominal wall defect often located to the right of the umbilical cord, where like Omphalocele, there is a protrusion of the bowel. However, in Gastroschisis there is no sac covering the herniation. As such, both conditions defer with respect to location and presence of a sac. Omphalocele is caused by an abnormality in the embryo before week 9 of gestation whereby the bowel loops are malrotated or non rotated and do not return to the abdominal cavity. There are several competing theories as to the cause of Gastroschisis. A leading hypothesis suggests that Gastroschisis results from the inability of the vitelline structures and yolk sac to be incorporated into the body stalk.

Gastroschisis and Omphalocele represent the two most common abdominal wall defects. Gastroschisis is more common of the two and occurs at a rate of one per 600 live births. Omphalocele occurs in about one in 3000 to 10000 live births. Whilst the incidence of Omphalocele is stable, the incidence of Gastroschisis appears to be increasing. It is suspected that this may be due to better technology and screening methods. The male to female ratio of Omphalocele is 1:1.5 while the male to female ratio of Gastroschisis is equivalent. The maternal age of mothers who give birth to a child suffering from Omphalocele is typically 30 years of age. A mother who gives birth to a child from Gastroschisis is typically 22 years of age.

A key difference between Gastroschisis and Omphalocele is that congenital Omphaloceles are frequently associated with other abnormalities while Gastroschisis is not. In Omphalocele, chromosomal defects are found in 30-40% of cases while multiple associated anomalies including chromosomal changes are observed in 67-80% of cases. It is rare for associated anomalies to occur with Gastroschisis. These include: intestinal atresia which is found in 10% of cases, as well as cardiac, renal, musculoskeletal and central nervous system anomalies.

PMID 25459013

<pubmed>25459013</pubmed>

PMID 26229394

<pubmed>26229394</pubmed>

--[[User:Z8600021|Mark Hill]] ([[User talk:Z8600021|talk]]) 14:20, 16 September 2015 (AEST) These are good summaries. (5/5)

==Week 7 Assessment==

PMID 26395490

<pubmed>26395490</pubmed>

1. Although it is currently thought that thyroid C cells originate from cephalic neural crest cells, growing evidence suggests that the embryonic origin may in fact be from Sox17+ anterior endoderm. This study traced Wtn1 expressing cells to determine neural crest origin. Wtn1 expression occurs in the dorsal neural tube and is necessary for neural crest cell expansion. Foregut endoderm origin was established from tracing Sox17 expression, as it is known that transient expression of Sox17 occurs during formation of endoderm. Through fate mapping, the study in mice found that thyroid C cells derived from Sox17+ anterior endoderm, rather than Wtn1 expressing neural crest progeny. However, Wtn1 neural crest cells play a role in the development of thyroid connective tissue. Through lineage tracing, it was also found that in thyroid C cell precursors, the transcription factors Foxa1 and Foxa2 are differentially expressed. These transcription factors are commonly expressed in endoderm organs, and were also found in the thyroid bud and pharyngeal pouch, from which the ultimobranchial bodies that give rise to the thyroid emerge. Within embryonic thyroid C cells, the two transcription factors are coexpressed.

2.Tooth Development consists of ectoderm, mesoderm and neural crest ectomesenchyme involvement. The Ameloblasts produce enamel. Odontoblasts derive from neural crest mesenchyme and form predentin which calcifies to form dentin. The periodontal ligament secures the tooth in the bone socket, acts as a shock absorber, transmits chew forces from bone to tooth and relays sensory information.

==Peer Reviews==

'''Group 1'''

This Group Project has a lot of potential. Information is presented in an engaging way through an introductory video documenting a case, timeline providing retrospective insight as well as diagrams detailing the complex processes in a concise manner. I also found some subsections interesting and relevant, including the discussion on ethics, Current research areas, as well as the glossary which provides a quick reference.

Although I understand you intend to elaborate more on certain areas including current research, the project does seem a little thin in regards to text. There are many papers that are linked with no explanation. For example, with regards to the table under prohibitions, I am confused as to what exactly those countries prohibit (all genetic modification? mitochondrial techniques only?) and also whether there is any more nuance to the discussion (do they ban different things?). Of course, one could click through the links under each country, but i think some text before the table itself would only add to your project and bring more context to the table itself. Diagrams themselves can also be referred to in the text (as you would find in a textbook), to add context and create a more cohesive wikipedia page (e.g. for Pronuclear transfer). In terms of the information provided, a little deeper exploration or discussion about certain issues including the reasoning behind ethics arguments may be relevant. If the articles listed under the headings are anything to go by, it seems you intend to do this.

Finally, some proofreading will be very beneficial in polishing up the wikipedia page. There are some sentences like "And it effectiveness in doing so. And the processes that occur in the oocyte when this method is used" under Human Embryo Model, which may well do with some editing. I would like to add that the referencing has been fantastic and consistent. Good Luck!

'''Group 3'''

I found this Wikipedia page particularly interesting. A wide assortment of visual media including histological slides, ultrasound images, geographical maps, tables, flow diagrams and hand-drawn images, all add a richness and balance to the text. This page does well to direct the reader's attention with highlighted text as well, to make for an aesthetically pleasing article. In particular, i found the hand-drawn diagram particularly intelligent and impressive.

In terms of text, i think this article is of adequate complexity and provides educational value to its intended audience of fellow university students. However, more diagrams to accompany the pathophysiological mechanisms and simplify the process may be of benefit. The text under 'Causes' is informative, but there is an imbalance of information for the various subsections within that heading. I assume, you intend to elaborate on those subsections that seem a little thin. It may be more effective to break up the 'genetic factors' section to a simple list of genetic influences, with details of studies relevant to that factor alongside it. This way, you don't have to read through several paragraphs to get to a particular gene/information point. Also, some arrows pointing to the actual cysts explicitly in the histological slide may be useful, as already done in the Ultrasound slide.

Finally, although the Wikipedia page is organised logically and contains particularly relevant sections, it may do with some more. As an age old issue, I'm interested in the epidemiology of PCOS and a bit about its history (or where/when we know what we do about it). Other than that, the page looks pretty good and reads well too.

'''Group 4'''

This Group Project is impressively detailed and provides a comprehensive view of male infertility detailing the normal process as well as the various disorder types and causes. The wikipedia page flows logically, provides excellent summaries and may well be an excellent educational resource. The video chosen is fantastic and tables have been used well to present information quickly.

I find that the Introduction is clear and concise. However, i feel it may be improved further by an introductory visual. Other than that, the page has many relevant diagrams and images. In terms of the 'development of gonadotropin preparations', it does seem a little out of place as it isn't particularly referred to in the text. I understand timelines add a richness to the text and can give perspective, but i feel that it may be of more relevance if given regarding male infertility treatments as a whole, rather than gonadotropin preparations. Of course, you can always have both.

Other than that, I am quite impressed with this wikipedia page. It is referenced well and information is backed with reference to the findings of various studies. A final tip may be to add a simple glossary for ease of reference as opposed to having to scroll back up to the section (e.g. varicocele) to remind oneself of the meaning. However, it should be commended that jargon was defined well throughout the article.

'''Group 5'''

This Group Project covers a wide breadth of topics in a very easy to understand manner. The types of chemotherapy treatments or drugs for example, were very easy to read and understand. The various tables and histological slides employed also make for an interesting and easy to digest wikipedia article. The visual aids detailing the IVF process was also well appreciated and balanced well with the text.

However, I feel that in general there should be more visual media to accompany the text. An issue of a current image I have (patient undergoing chemotherapy) is that I don't think it adds much to the wikipedia page and is not informative. Furthermore, I was hoping there would be an introduction to the wikipedia page that would explicitly detail what it aims to cover. This would provide more structure and give a logical flow to the wikipedia page. Another way to improve the logical flow, is to subdivide sections into male and female (e.g. surgeries and drugs, the transition from surgeries for males to drugs for female infertility was abrupt and disorienting). The top half of the page may be made less verbose through the use of more jargon e.g. in the Radiation section "cells can't grow and divide" etc. Naturally, a glossary is also a convenient reference point that may be included.

Also, there is an imbalance in detail with more input within cancer cells section than other sections more directly relevant in ART including IVF. However, I do understand this Group Project is still a work in progress. Overall, there is a lot of potential in the wikipedia page.

'''Group 6'''

This wikipedia article is impressively organised and easy to follow. It is sufficiently detailed, and despite being content heavy it has a good layout as it is well spaced out. This article is well referenced as well, a testament to the work that has been put in.

I understand that the advantages and disadvantages are listed as bullet points. Have you thought of organising it in a table? It may be a way to include a 'visual aid' in order to reach a balance in terms of visual/text content. Generally, more diagrams will only improve this article. Cohesion between the visual and written text may be increased by referrals to the diagrams/images throughout e.g. human blastocyst biopsy as opposed to a caption only. Also, having a section directly comparing the genetic techniques/purpose/effectivity/results in a table may be interesting.

Overall, wonderful work. In my opinion this is definitely a frontrunner and particularly difficult to critique.

===Permalink===

[https://embryology.med.unsw.edu.au/embryology/Slides/Embryo_Stages/Stage22/08-eye/Stage22-08-eye.html?zoom=6&lat=-3223.5&lon=3922&layers=B Stage 22 Eye]

Hyaloid artery supplies the developing lens surrounded by vitreous. Developing lens consists of lens fibers which derive from surface ectoderm.

[[Vision - Lens Development]] --Development Overview

==References==

PMID 26244658
look at this <ref><pubmed>26244658</pubmed>

here's the list
<references/>

User:Z3372824

2015-10-23T01:13:35Z

Z3372824:

==Lab Attendance==

--[[User:Z3372824|Z3372824]] ([[User talk:Z3372824|talk]]) 13:46, 7 August 2015 (AEST)

--[[User:Z3372824|Z3372824]] ([[User talk:Z3372824|talk]]) 13:38, 14 August 2015 (AEST)

--[[User:Z3372824|Z3372824]] ([[User talk:Z3372824|talk]]) 15:14, 21 August 2015 (AEST)

--[[User:Z3372824|Z3372824]] ([[User talk:Z3372824|talk]]) 12:12, 28 August 2015 (AEST)

--[[User:Z3372824|Z3372824]] ([[User talk:Z3372824|talk]]) 12:14, 4 September 2015 (AEST)

--[[User:Z3372824|Z3372824]] ([[User talk:Z3372824|talk]]) 12:57, 25 September 2015 (AEST)

--[[User:Z3372824|Z3372824]] ([[User talk:Z3372824|talk]]) 12:48, 9 October 2015 (AEDT)

--[[User:Z3372824|Z3372824]] ([[User talk:Z3372824|talk]]) 13:37, 16 October 2015 (AEDT)

----

{{StudentPage2015}}

[[Test student 2015]]

==Week 1 Assessment==

1) PMID 18603501

Increased Progesterone/Estradiol Ration on the Day of hCG Administration Adversely Affects Success of In Vitro Fertilisation-Embryo Transfer in Patients Stimulated with Gonadotropin-releasing Hormone Agonist and Recombinant Follicle-stimulating Hormone

This study examines the influence of premature luteinisation, with respect to ovarian response, during IVF. This was done using gonadotropin-releasing hormone agonist (GnRHa) and recombinant follicle-stimulating hormone (rFSH).The study defined premature luteinisation as a ratio between progesterone and estradiol of greater than one, the day hCG was administered. The experimental group of prematurely luteinised was then compared to the non-prematurely luteinised groups.

The study was performed on 311 infertile couples, in which a total of 339 cycles of ovarian hyperstimulation with GnRHa and rFSH. The females studied were aged from 20 to 40 years, and did not undergo cycles incorporating hMG, nor did they receive oocyte donations. The patients underwent ovarian stimulation, a long stimulation protocol of GnRHa therapy, rFSH administration as well as transvaginal oocyte retrieval, respectively. hCG was administered after adequate follicular maturation and oocytes were obtained 35-37 hours after hCG administration using transvaginal aspiration with ultrasound assistance. The follicular fluids and follicular washes were examined using a dissecting stereomicroscope that was incubated at 37 degrees with 5%CO2. Sperm insemination procedures were also performed, after which the oocytes were inseminated with spermatozoa. The oocytes were removed after 2 hour exposures to the spermatozoa and cultured in fresh IVF medium. The control group underwent ICSI procedures, while the experimental group underwent IVF procedures. The oocytes were then cultured and assessed for pronuclei presence 16-18 hours incubation in order to determine fertilisation (presence of 2 pronuclei). Embryos were then cultured and classified, as were the blastocysts.

The study found 137 out of the 339 cycles to have premature luteinisation. Poor ovarian response was more common in the experimental group. It was also found the the experimental group had a higher progesterone level and lower E2 level on the hCG administration day. However the mean luteinising hormone on day 6 of stimulation was similar in both control and study groups but higher in the control group on hCG administeration day. The experimental group demonstrated a lower number of oocytes obtained, and lower number of mature oocytes recovered. It should be noted that fertilisation rates were similar in both groups. Embryo number was lower for the experimental group compared to the control group. 130 gestational sacs were demonstrated after a transfer of 577 embryos in the control group while 76 gestational sacs were demonstrated out of 339 embryo transfers in the study group. The non-prematurely luteinised group and prematurely luteinised group had similar implantation rates. It was also found that 48.5% of the non-prematurely luteinised group achieved clinical pregnancies while 36.6% of the prematurely luteinised group achieved clinical pregnancies.

<pubmed>18603501</pubmed>

2) PMID 21793811

Impact of endometriosis on in vitro fertilization and embryo transfer cycles in young women; a stage-dependent interference

Due to the significantly higher prevalence of endometriosis in infertile women as compared to the general population, a causal relationship between endometriosis and infertility has been postulated. In vitro fertilisation and embryo transfer (IVF-ET) has been considered a suitable treatment for patients with a history of endometriosis. This study examines the effect of endometriosis on IVF-ET cycles on women younger than 35 years of age and who have had surgical treatment for endometriosis without clinical recurrence signs. The endometriosis group was compared to another group of patients also undergoing IVF-ET, but with tubal infertility without clinical signs of endometriosis. The results were analysed according to the different stages of endometriosis as classified by the American Society for Reproductive Medicine.

The experimental group consisted of 148 patients whereas the control group (tubal infertility patients) consisted of 72 patients. All groups consisted of patients that were less than 35 years of age and did not have clinical indication for any other cause of infertility. The experimental group underwent 164 IVF-ET cycles while the control group underwent 80 IVF-ET cycles. Patients received a long-acting down-regulation drug regime, a daily subcutaneous FSH dose, as well as gonadotropin doses which were decided individually according to age, basal FSH, ovarian volume and ovarian response. After two or more follicles reached maximal diameter of 17-18mm, hCG was administered and oocytes were obtained 36 hours later using vaginal ultrasonography, to then be fertilised on the same day. Embryo transfers were made two to three days after oocyte retrieval. Natural progesterone in oil was then administered. Plasma beta-hCG values were used to assess pregnancy. Clinical pregnancy was determined when at least one gestational sac was found with a fetal pole and heart activity through ultrasond.

It was found that the experimental group had significantly lower numbers of follicles on the hCG day, oocytes obtained and transferred when compared to the control group, despite receiving a higher FSH dose. However no significant differences were found regardingt cycle cancellation rate, peak E2 levels of the length of the stimulation phase. 11.6% of clinical pregnancies per started cucle were observed in the experimental group as compared to 22.5% in the control group. However, this value wa not significant when the clinical pregnancy rate was considered per oocyte retrieval or per embryo transfer. It was also found that patients at stage I-II of endomtriosis had a significantly lower rate of fertilisation when compared to the control group patients. Patients at stage III-IV of endometriosis had a large reduction in pregnancy rate than the control group, however the fertilisation rate was comparable. Patients at stage III-IV had lower peak E2 concentrations, less follicles on the hCG day, fewer oocytes at retrieval and lower implantation rates. Furthermore, poor ovarion responses in 15 out of 109 cycles resulted in discontinuation of the cycle in patients at stage III-IV of the endometriosis group, compared to 2 of 55 in the stage I-II group and 3 of 80 in the control group.

<pubmed>21793811</pubmed>

--[[User:Z8600021|Mark Hill]] ([[User talk:Z8600021|talk]]) 14:08, 16 September 2015 (AEST) These are good summaries of the se 2 articles. You should make an effort to clearly identify what you have written as opposed to quoting directly from the paper.(5/5)

==Week 2 Assessment==

[[File:Epigenetic factors Influencing Human Development.jpg|300px]]

PMID 26216216

--[[User:Z8600021|Mark Hill]] ([[User talk:Z8600021|talk]]) 14:12, 16 September 2015 (AEST) Image uploaded and named correctly. Image summary includes information, reference, copyright and student image template. (5/5)

==Week 3 Assessment==

PMID 26074966
<pubmed>26074966</pubmed>

PMID 20416867
<pubmed>20416867</pubmed>

PMID 23873146
<pubmed>23873146</pubmed>

The three key pathways by which the incidence of OHSS has been curtailed involve identifying risk factors to predict OHSS development, modifying treatment regimes on the basis of the identified risk factors and intervention to prevent progression to OHSS once the patient has undergone Controlled Ovarian Stimulation.

1) Risk factors

Primary: Preexisting factors likely to exacerbate the ovarian stimulation response. Include: young age, low body weight, history of elevated response to gonadotropins, Polycystic Ovary Syndrome (PCOS), isolated PCOS characteristic or a previous history of OHSS. Anti-Mullerian Hormone markers (AMH) are a newly developed predictive tool with a sensitivity of 90.5% and specificity of 81.3%. Ultrasonographic markers including antral follicle count
PMID 26074966

Secondary:

2) Prevention

Primary:
a) Gonadotropins: reduce duration, reduce dose, avoid GnRH Agonists PMID 23873146

b) Use Metformin Therapy

c) Target Unifollicular Ovulation

d) Avoid hCG

e) In Vitro Maturation

Secondary:
a) Reduce hCG dose

b) Coasting

c) Cryopreservation of Embryos

d) Cancel Cycle

e) Use alternative Agents

PMID 20416867

--[[User:Z8600021|Mark Hill]] ([[User talk:Z8600021|talk]]) 14:12, 16 September 2015 (AEST) These are relevant to your group project. Hopefully these will be useful in the final project page. (5/5)

==Week 4 Assessment==
===Fertilisation Quiz===

<quiz display=simple>

{Which of the following statements is incorrect in regards to the acrosome:
|type="()"}
-The acrosome reaction allows for the exposure of the inner-acrosomal membrane
-Only acrosome reacted spermatozoa fuse with the oocyte
-The acrosome within the spermatozoa is derived from the golgi apparatus
+Zona Pellucida Binding Protein 1 is synthesised by the oocyte
-The enzymatic contents of the acrosome degrade the zona pellucida
||This is correct, the [[Z#zona pellucida binding protein 1|zona pellucida binding protein 1]] is in fact a spermatozoa protein located on the acrosome surface, and binds to the zona pellucida of the oocyte during fertilisation.

{Which of the following statements about the zona pellucida is incorrect:
|type="()"}
-It is an insoluble extracellular matrix
-It expresses several glycoproteins
-It surrounds the blastocyst
-It surrounds the developing oocyte
+It prevents sperm binding
||Yes, the [[Z#zona pellucida|zona pellucida]] is a specialised extracellular matrix which surrounds the developing oocyte. It expresses several glycoproteins including ZP1, ZP2, ZP3 and ZP4, all of which play an important role in fertilisation. The zona pellucida facilitates sperm binding as the ZP2 binds the spermatozoa before fertilisation. Following fertilisation, the zona pellucida continues to surround the blastocyst during the first week of development, before being broken down through uterine and blastula secretions.

{Fertilisation does not:
|type="()"}
+result in the formation of the first polar body after the second meiotic division
-often occurs in the first 1/3 of the oviduct
-involve spermatozoa and oocyte fusion
-require the exocytosis of cortical granules in the cortical reaction
- require the exocytosis of acrosomal enzymes during the acrosome reaction
||Yes, [[F#fertilization|fertilization]] results in the formation of the second polar body after the second meiotic division. The first polar body forms during the first meiotic division.

</quiz>

--[[User:Z8600021|Mark Hill]] ([[User talk:Z8600021|talk]]) 14:20, 16 September 2015 (AEST) Three negative questions. Q1 An interesting range of options. I suggest that your question might be more instructive. The incorrect option (zona pellucida binding protein 1) is a bit of a give away as why would the oocyte make this protein? A student using simple logic (rather than knowledge) may get this right. Q2 A little simplistic, as we spent some time on ZP sperm binding. Q3 has too simple options and is not well structured. (7/10)

[[ANAT2341 Student 2015 Quiz Questions]]
==Week 5 Assessment==

What is the difference between gastroschisis and omphalocele?

Gastroschisis and Omphalocele are both congenital abdominal wall defects. Omphalocele is a condition involving the umbilical ring whereby the internal organs, typically consisting of the small intestine, colon, liver and spleen, are disemboweled in a sac made of peritoneum, Wharton's jelly and amnion. Gastroschisis is an anterior abdominal wall defect often located to the right of the umbilical cord, where like Omphalocele, there is a protrusion of the bowel. However, in Gastroschisis there is no sac covering the herniation. As such, both conditions defer with respect to location and presence of a sac. Omphalocele is caused by an abnormality in the embryo before week 9 of gestation whereby the bowel loops are malrotated or non rotated and do not return to the abdominal cavity. There are several competing theories as to the cause of Gastroschisis. A leading hypothesis suggests that Gastroschisis results from the inability of the vitelline structures and yolk sac to be incorporated into the body stalk.

Gastroschisis and Omphalocele represent the two most common abdominal wall defects. Gastroschisis is more common of the two and occurs at a rate of one per 600 live births. Omphalocele occurs in about one in 3000 to 10000 live births. Whilst the incidence of Omphalocele is stable, the incidence of Gastroschisis appears to be increasing. It is suspected that this may be due to better technology and screening methods. The male to female ratio of Omphalocele is 1:1.5 while the male to female ratio of Gastroschisis is equivalent. The maternal age of mothers who give birth to a child suffering from Omphalocele is typically 30 years of age. A mother who gives birth to a child from Gastroschisis is typically 22 years of age.

A key difference between Gastroschisis and Omphalocele is that congenital Omphaloceles are frequently associated with other abnormalities while Gastroschisis is not. In Omphalocele, chromosomal defects are found in 30-40% of cases while multiple associated anomalies including chromosomal changes are observed in 67-80% of cases. It is rare for associated anomalies to occur with Gastroschisis. These include: intestinal atresia which is found in 10% of cases, as well as cardiac, renal, musculoskeletal and central nervous system anomalies.

PMID 25459013

<pubmed>25459013</pubmed>

PMID 26229394

<pubmed>26229394</pubmed>

--[[User:Z8600021|Mark Hill]] ([[User talk:Z8600021|talk]]) 14:20, 16 September 2015 (AEST) These are good summaries. (5/5)

==Week 7 Assessment==

PMID 26395490

<pubmed>26395490</pubmed>

1. Although it is currently thought that thyroid C cells originate from cephalic neural crest cells, growing evidence suggests that the embryonic origin may in fact be from Sox17+ anterior endoderm. This study traced Wtn1 expressing cells to determine neural crest origin. Wtn1 expression occurs in the dorsal neural tube and is necessary for neural crest cell expansion. Foregut endoderm origin was established from tracing Sox17 expression, as it is known that transient expression of Sox17 occurs during formation of endoderm. Through fate mapping, the study in mice found that thyroid C cells derived from Sox17+ anterior endoderm, rather than Wtn1 expressing neural crest progeny. However, Wtn1 neural crest cells play a role in the development of thyroid connective tissue. Through lineage tracing, it was also found that in thyroid C cell precursors, the transcription factors Foxa1 and Foxa2 are differentially expressed. These transcription factors are commonly expressed in endoderm organs, and were also found in the thyroid bud and pharyngeal pouch, from which the ultimobranchial bodies that give rise to the thyroid emerge. Within embryonic thyroid C cells, the two transcription factors are coexpressed.

2.Tooth Development consists of ectoderm, mesoderm and neural crest ectomesenchyme involvement. The Ameloblasts produce enamel. Odontoblasts derive from neural crest mesenchyme and form predentin which calcifies to form dentin. The periodontal ligament secures the tooth in the bone socket, acts as a shock absorber, transmits chew forces from bone to tooth and relays sensory information.

==Peer Reviews==

'''Group 1'''

This Group Project has a lot of potential. Information is presented in an engaging way through an introductory video documenting a case, timeline providing retrospective insight as well as diagrams detailing the complex processes in a concise manner. I also found some subsections interesting and relevant, including the discussion on ethics, Current research areas, as well as the glossary which provides a quick reference.

Although I understand you intend to elaborate more on certain areas including current research, the project does seem a little thin in regards to text. There are many papers that are linked with no explanation. For example, with regards to the table under prohibitions, I am confused as to what exactly those countries prohibit (all genetic modification? mitochondrial techniques only?) and also whether there is any more nuance to the discussion (do they ban different things?). Of course, one could click through the links under each country, but i think some text before the table itself would only add to your project and bring more context to the table itself. Diagrams themselves can also be referred to in the text (as you would find in a textbook), to add context and create a more cohesive wikipedia page (e.g. for Pronuclear transfer). In terms of the information provided, a little deeper exploration or discussion about certain issues including the reasoning behind ethics arguments may be relevant. If the articles listed under the headings are anything to go by, it seems you intend to do this.

Finally, some proofreading will be very beneficial in polishing up the wikipedia page. There are some sentences like "And it effectiveness in doing so. And the processes that occur in the oocyte when this method is used" under Human Embryo Model, which may well do with some editing. I would like to add that the referencing has been fantastic and consistent. Good Luck!

'''Group 3'''

I found this Wikipedia page particularly interesting. A wide assortment of visual media including histological slides, ultrasound images, geographical maps, tables, flow diagrams and hand-drawn images, all add a richness and balance to the text. This page does well to direct the reader's attention with highlighted text as well, to make for an aesthetically pleasing article. In particular, i found the hand-drawn diagram particularly intelligent and impressive.

In terms of text, i think this article is of adequate complexity and provides educational value to its intended audience of fellow university students. However, more diagrams to accompany the pathophysiological mechanisms and simplify the process may be of benefit. The text under 'Causes' is informative, but there is an imbalance of information for the various subsections within that heading. I assume, you intend to elaborate on those subsections that seem a little thin. It may be more effective to break up the 'genetic factors' section to a simple list of genetic influences, with details of studies relevant to that factor alongside it. This way, you don't have to read through several paragraphs to get to a particular gene/information point. Also, some arrows pointing to the actual cysts explicitly in the histological slide may be useful, as already done in the Ultrasound slide.

Finally, although the Wikipedia page is organised logically and contains particularly relevant sections, it may do with some more. As an age old issue, I'm interested in the epidemiology of PCOS and a bit about its history (or where/when we know what we do about it). Other than that, the page looks pretty good and reads well too.

'''Group 4'''

This Group Project is impressively detailed and provides a comprehensive view of male infertility detailing the normal process as well as the various disorder types and causes. The wikipedia page flows logically, provides excellent summaries and may well be an excellent educational resource. The video chosen is fantastic and tables have been used well to present information quickly.

I find that the Introduction is clear and concise. However, i feel it may be improved further by an introductory visual. Other than that, the page has many relevant diagrams and images. In terms of the 'development of gonadotropin preparations', it does seem a little out of place as it isn't particularly referred to in the text. I understand timelines add a richness to the text and can give perspective, but i feel that it may be of more relevance if given regarding male infertility treatments as a whole, rather than gonadotropin preparations. Of course, you can always have both.

Other than that, I am quite impressed with this wikipedia page. It is referenced well and information is backed with reference to the findings of various studies. A final tip may be to add a simple glossary for ease of reference as opposed to having to scroll back up to the section (e.g. varicocele) to remind oneself of the meaning. However, it should be commended that jargon was defined well throughout the article.

'''Group 5'''

This Group Project covers a wide breadth of topics in a very easy to understand manner. The types of chemotherapy treatments or drugs for example, were very easy to read and understand. The various tables and histological slides employed also make for an interesting and easy to digest wikipedia article. The visual aids detailing the IVF process was also well appreciated and balanced well with the text.

However, I feel that in general there should be more visual media to accompany the text. An issue of a current image I have (patient undergoing chemotherapy) is that I don't think it adds much to the wikipedia page and is not informative. Furthermore, I was hoping there would be an introduction to the wikipedia page that would explicitly detail what it aims to cover. This would provide more structure and give a logical flow to the wikipedia page. Another way to improve the logical flow, is to subdivide sections into male and female (e.g. surgeries and drugs, the transition from surgeries for males to drugs for female infertility was abrupt and disorienting). The top half of the page may be made less verbose through the use of more jargon e.g. in the Radiation section "cells can't grow and divide" etc. Naturally, a glossary is also a convenient reference point that may be included.

Also, there is an imbalance in detail with more input within cancer cells section than other sections more directly relevant in ART including IVF. However, I do understand this Group Project is still a work in progress. Overall, there is a lot of potential in the wikipedia page.

'''Group 6'''

This wikipedia article is impressively organised and easy to follow. It is sufficiently detailed, and despite being content heavy it has a good layout as it is well spaced out. This article is well referenced as well, a testament to the work that has been put in.

I understand that the advantages and disadvantages are listed as bullet points. Have you thought of organising it in a table? It may be a way to include a 'visual aid' in order to reach a balance in terms of visual/text content. Generally, more diagrams will only improve this article. Cohesion between the visual and written text may be increased by referrals to the diagrams/images throughout e.g. human blastocyst biopsy as opposed to a caption only. Also, having a section directly comparing the genetic techniques/purpose/effectivity/results in a table may be interesting.

Overall, wonderful work. In my opinion this is definitely a frontrunner and particularly difficult to critique.

===Permalink===

[https://embryology.med.unsw.edu.au/embryology/Slides/Embryo_Stages/Stage22/08-eye/Stage22-08-eye.html?zoom=6&lat=-3223.5&lon=3922&layers=B Stage 22 Eye]
==References==

PMID 26244658
look at this <ref><pubmed>26244658</pubmed>

here's the list
<references/>

User:Z3372824

2015-10-23T01:13:07Z

Z3372824:

==Lab Attendance==

--[[User:Z3372824|Z3372824]] ([[User talk:Z3372824|talk]]) 13:46, 7 August 2015 (AEST)

--[[User:Z3372824|Z3372824]] ([[User talk:Z3372824|talk]]) 13:38, 14 August 2015 (AEST)

--[[User:Z3372824|Z3372824]] ([[User talk:Z3372824|talk]]) 15:14, 21 August 2015 (AEST)

--[[User:Z3372824|Z3372824]] ([[User talk:Z3372824|talk]]) 12:12, 28 August 2015 (AEST)

--[[User:Z3372824|Z3372824]] ([[User talk:Z3372824|talk]]) 12:14, 4 September 2015 (AEST)

--[[User:Z3372824|Z3372824]] ([[User talk:Z3372824|talk]]) 12:57, 25 September 2015 (AEST)

--[[User:Z3372824|Z3372824]] ([[User talk:Z3372824|talk]]) 12:48, 9 October 2015 (AEDT)

--[[User:Z3372824|Z3372824]] ([[User talk:Z3372824|talk]]) 13:37, 16 October 2015 (AEDT)

----

{{StudentPage2015}}

[[Test student 2015]]

==Week 1 Assessment==

1) PMID 18603501

Increased Progesterone/Estradiol Ration on the Day of hCG Administration Adversely Affects Success of In Vitro Fertilisation-Embryo Transfer in Patients Stimulated with Gonadotropin-releasing Hormone Agonist and Recombinant Follicle-stimulating Hormone

This study examines the influence of premature luteinisation, with respect to ovarian response, during IVF. This was done using gonadotropin-releasing hormone agonist (GnRHa) and recombinant follicle-stimulating hormone (rFSH).The study defined premature luteinisation as a ratio between progesterone and estradiol of greater than one, the day hCG was administered. The experimental group of prematurely luteinised was then compared to the non-prematurely luteinised groups.

The study was performed on 311 infertile couples, in which a total of 339 cycles of ovarian hyperstimulation with GnRHa and rFSH. The females studied were aged from 20 to 40 years, and did not undergo cycles incorporating hMG, nor did they receive oocyte donations. The patients underwent ovarian stimulation, a long stimulation protocol of GnRHa therapy, rFSH administration as well as transvaginal oocyte retrieval, respectively. hCG was administered after adequate follicular maturation and oocytes were obtained 35-37 hours after hCG administration using transvaginal aspiration with ultrasound assistance. The follicular fluids and follicular washes were examined using a dissecting stereomicroscope that was incubated at 37 degrees with 5%CO2. Sperm insemination procedures were also performed, after which the oocytes were inseminated with spermatozoa. The oocytes were removed after 2 hour exposures to the spermatozoa and cultured in fresh IVF medium. The control group underwent ICSI procedures, while the experimental group underwent IVF procedures. The oocytes were then cultured and assessed for pronuclei presence 16-18 hours incubation in order to determine fertilisation (presence of 2 pronuclei). Embryos were then cultured and classified, as were the blastocysts.

The study found 137 out of the 339 cycles to have premature luteinisation. Poor ovarian response was more common in the experimental group. It was also found the the experimental group had a higher progesterone level and lower E2 level on the hCG administration day. However the mean luteinising hormone on day 6 of stimulation was similar in both control and study groups but higher in the control group on hCG administeration day. The experimental group demonstrated a lower number of oocytes obtained, and lower number of mature oocytes recovered. It should be noted that fertilisation rates were similar in both groups. Embryo number was lower for the experimental group compared to the control group. 130 gestational sacs were demonstrated after a transfer of 577 embryos in the control group while 76 gestational sacs were demonstrated out of 339 embryo transfers in the study group. The non-prematurely luteinised group and prematurely luteinised group had similar implantation rates. It was also found that 48.5% of the non-prematurely luteinised group achieved clinical pregnancies while 36.6% of the prematurely luteinised group achieved clinical pregnancies.

<pubmed>18603501</pubmed>

2) PMID 21793811

Impact of endometriosis on in vitro fertilization and embryo transfer cycles in young women; a stage-dependent interference

Due to the significantly higher prevalence of endometriosis in infertile women as compared to the general population, a causal relationship between endometriosis and infertility has been postulated. In vitro fertilisation and embryo transfer (IVF-ET) has been considered a suitable treatment for patients with a history of endometriosis. This study examines the effect of endometriosis on IVF-ET cycles on women younger than 35 years of age and who have had surgical treatment for endometriosis without clinical recurrence signs. The endometriosis group was compared to another group of patients also undergoing IVF-ET, but with tubal infertility without clinical signs of endometriosis. The results were analysed according to the different stages of endometriosis as classified by the American Society for Reproductive Medicine.

The experimental group consisted of 148 patients whereas the control group (tubal infertility patients) consisted of 72 patients. All groups consisted of patients that were less than 35 years of age and did not have clinical indication for any other cause of infertility. The experimental group underwent 164 IVF-ET cycles while the control group underwent 80 IVF-ET cycles. Patients received a long-acting down-regulation drug regime, a daily subcutaneous FSH dose, as well as gonadotropin doses which were decided individually according to age, basal FSH, ovarian volume and ovarian response. After two or more follicles reached maximal diameter of 17-18mm, hCG was administered and oocytes were obtained 36 hours later using vaginal ultrasonography, to then be fertilised on the same day. Embryo transfers were made two to three days after oocyte retrieval. Natural progesterone in oil was then administered. Plasma beta-hCG values were used to assess pregnancy. Clinical pregnancy was determined when at least one gestational sac was found with a fetal pole and heart activity through ultrasond.

It was found that the experimental group had significantly lower numbers of follicles on the hCG day, oocytes obtained and transferred when compared to the control group, despite receiving a higher FSH dose. However no significant differences were found regardingt cycle cancellation rate, peak E2 levels of the length of the stimulation phase. 11.6% of clinical pregnancies per started cucle were observed in the experimental group as compared to 22.5% in the control group. However, this value wa not significant when the clinical pregnancy rate was considered per oocyte retrieval or per embryo transfer. It was also found that patients at stage I-II of endomtriosis had a significantly lower rate of fertilisation when compared to the control group patients. Patients at stage III-IV of endometriosis had a large reduction in pregnancy rate than the control group, however the fertilisation rate was comparable. Patients at stage III-IV had lower peak E2 concentrations, less follicles on the hCG day, fewer oocytes at retrieval and lower implantation rates. Furthermore, poor ovarion responses in 15 out of 109 cycles resulted in discontinuation of the cycle in patients at stage III-IV of the endometriosis group, compared to 2 of 55 in the stage I-II group and 3 of 80 in the control group.

<pubmed>21793811</pubmed>

--[[User:Z8600021|Mark Hill]] ([[User talk:Z8600021|talk]]) 14:08, 16 September 2015 (AEST) These are good summaries of the se 2 articles. You should make an effort to clearly identify what you have written as opposed to quoting directly from the paper.(5/5)

==Week 2 Assessment==

[[File:Epigenetic factors Influencing Human Development.jpg|300px]]

PMID 26216216

--[[User:Z8600021|Mark Hill]] ([[User talk:Z8600021|talk]]) 14:12, 16 September 2015 (AEST) Image uploaded and named correctly. Image summary includes information, reference, copyright and student image template. (5/5)

==Week 3 Assessment==

PMID 26074966
<pubmed>26074966</pubmed>

PMID 20416867
<pubmed>20416867</pubmed>

PMID 23873146
<pubmed>23873146</pubmed>

The three key pathways by which the incidence of OHSS has been curtailed involve identifying risk factors to predict OHSS development, modifying treatment regimes on the basis of the identified risk factors and intervention to prevent progression to OHSS once the patient has undergone Controlled Ovarian Stimulation.

1) Risk factors

Primary: Preexisting factors likely to exacerbate the ovarian stimulation response. Include: young age, low body weight, history of elevated response to gonadotropins, Polycystic Ovary Syndrome (PCOS), isolated PCOS characteristic or a previous history of OHSS. Anti-Mullerian Hormone markers (AMH) are a newly developed predictive tool with a sensitivity of 90.5% and specificity of 81.3%. Ultrasonographic markers including antral follicle count
PMID 26074966

Secondary:

2) Prevention

Primary:
a) Gonadotropins: reduce duration, reduce dose, avoid GnRH Agonists PMID 23873146

b) Use Metformin Therapy

c) Target Unifollicular Ovulation

d) Avoid hCG

e) In Vitro Maturation

Secondary:
a) Reduce hCG dose

b) Coasting

c) Cryopreservation of Embryos

d) Cancel Cycle

e) Use alternative Agents

PMID 20416867

--[[User:Z8600021|Mark Hill]] ([[User talk:Z8600021|talk]]) 14:12, 16 September 2015 (AEST) These are relevant to your group project. Hopefully these will be useful in the final project page. (5/5)

==Week 4 Assessment==
===Fertilisation Quiz===

<quiz display=simple>

{Which of the following statements is incorrect in regards to the acrosome:
|type="()"}
-The acrosome reaction allows for the exposure of the inner-acrosomal membrane
-Only acrosome reacted spermatozoa fuse with the oocyte
-The acrosome within the spermatozoa is derived from the golgi apparatus
+Zona Pellucida Binding Protein 1 is synthesised by the oocyte
-The enzymatic contents of the acrosome degrade the zona pellucida
||This is correct, the [[Z#zona pellucida binding protein 1|zona pellucida binding protein 1]] is in fact a spermatozoa protein located on the acrosome surface, and binds to the zona pellucida of the oocyte during fertilisation.

{Which of the following statements about the zona pellucida is incorrect:
|type="()"}
-It is an insoluble extracellular matrix
-It expresses several glycoproteins
-It surrounds the blastocyst
-It surrounds the developing oocyte
+It prevents sperm binding
||Yes, the [[Z#zona pellucida|zona pellucida]] is a specialised extracellular matrix which surrounds the developing oocyte. It expresses several glycoproteins including ZP1, ZP2, ZP3 and ZP4, all of which play an important role in fertilisation. The zona pellucida facilitates sperm binding as the ZP2 binds the spermatozoa before fertilisation. Following fertilisation, the zona pellucida continues to surround the blastocyst during the first week of development, before being broken down through uterine and blastula secretions.

{Fertilisation does not:
|type="()"}
+result in the formation of the first polar body after the second meiotic division
-often occurs in the first 1/3 of the oviduct
-involve spermatozoa and oocyte fusion
-require the exocytosis of cortical granules in the cortical reaction
- require the exocytosis of acrosomal enzymes during the acrosome reaction
||Yes, [[F#fertilization|fertilization]] results in the formation of the second polar body after the second meiotic division. The first polar body forms during the first meiotic division.

</quiz>

--[[User:Z8600021|Mark Hill]] ([[User talk:Z8600021|talk]]) 14:20, 16 September 2015 (AEST) Three negative questions. Q1 An interesting range of options. I suggest that your question might be more instructive. The incorrect option (zona pellucida binding protein 1) is a bit of a give away as why would the oocyte make this protein? A student using simple logic (rather than knowledge) may get this right. Q2 A little simplistic, as we spent some time on ZP sperm binding. Q3 has too simple options and is not well structured. (7/10)

[[ANAT2341 Student 2015 Quiz Questions]]
==Week 5 Assessment==

What is the difference between gastroschisis and omphalocele?

Gastroschisis and Omphalocele are both congenital abdominal wall defects. Omphalocele is a condition involving the umbilical ring whereby the internal organs, typically consisting of the small intestine, colon, liver and spleen, are disemboweled in a sac made of peritoneum, Wharton's jelly and amnion. Gastroschisis is an anterior abdominal wall defect often located to the right of the umbilical cord, where like Omphalocele, there is a protrusion of the bowel. However, in Gastroschisis there is no sac covering the herniation. As such, both conditions defer with respect to location and presence of a sac. Omphalocele is caused by an abnormality in the embryo before week 9 of gestation whereby the bowel loops are malrotated or non rotated and do not return to the abdominal cavity. There are several competing theories as to the cause of Gastroschisis. A leading hypothesis suggests that Gastroschisis results from the inability of the vitelline structures and yolk sac to be incorporated into the body stalk.

Gastroschisis and Omphalocele represent the two most common abdominal wall defects. Gastroschisis is more common of the two and occurs at a rate of one per 600 live births. Omphalocele occurs in about one in 3000 to 10000 live births. Whilst the incidence of Omphalocele is stable, the incidence of Gastroschisis appears to be increasing. It is suspected that this may be due to better technology and screening methods. The male to female ratio of Omphalocele is 1:1.5 while the male to female ratio of Gastroschisis is equivalent. The maternal age of mothers who give birth to a child suffering from Omphalocele is typically 30 years of age. A mother who gives birth to a child from Gastroschisis is typically 22 years of age.

A key difference between Gastroschisis and Omphalocele is that congenital Omphaloceles are frequently associated with other abnormalities while Gastroschisis is not. In Omphalocele, chromosomal defects are found in 30-40% of cases while multiple associated anomalies including chromosomal changes are observed in 67-80% of cases. It is rare for associated anomalies to occur with Gastroschisis. These include: intestinal atresia which is found in 10% of cases, as well as cardiac, renal, musculoskeletal and central nervous system anomalies.

PMID 25459013

<pubmed>25459013</pubmed>

PMID 26229394

<pubmed>26229394</pubmed>

--[[User:Z8600021|Mark Hill]] ([[User talk:Z8600021|talk]]) 14:20, 16 September 2015 (AEST) These are good summaries. (5/5)

==Week 7 Assessment==

PMID 26395490

<pubmed>26395490</pubmed>

1. Although it is currently thought that thyroid C cells originate from cephalic neural crest cells, growing evidence suggests that the embryonic origin may in fact be from Sox17+ anterior endoderm. This study traced Wtn1 expressing cells to determine neural crest origin. Wtn1 expression occurs in the dorsal neural tube and is necessary for neural crest cell expansion. Foregut endoderm origin was established from tracing Sox17 expression, as it is known that transient expression of Sox17 occurs during formation of endoderm. Through fate mapping, the study in mice found that thyroid C cells derived from Sox17+ anterior endoderm, rather than Wtn1 expressing neural crest progeny. However, Wtn1 neural crest cells play a role in the development of thyroid connective tissue. Through lineage tracing, it was also found that in thyroid C cell precursors, the transcription factors Foxa1 and Foxa2 are differentially expressed. These transcription factors are commonly expressed in endoderm organs, and were also found in the thyroid bud and pharyngeal pouch, from which the ultimobranchial bodies that give rise to the thyroid emerge. Within embryonic thyroid C cells, the two transcription factors are coexpressed.

2.Tooth Development consists of ectoderm, mesoderm and neural crest ectomesenchyme involvement. The Ameloblasts produce enamel. Odontoblasts derive from neural crest mesenchyme and form predentin which calcifies to form dentin. The periodontal ligament secures the tooth in the bone socket, acts as a shock absorber, transmits chew forces from bone to tooth and relays sensory information.

==Peer Reviews==

'''Group 1'''

This Group Project has a lot of potential. Information is presented in an engaging way through an introductory video documenting a case, timeline providing retrospective insight as well as diagrams detailing the complex processes in a concise manner. I also found some subsections interesting and relevant, including the discussion on ethics, Current research areas, as well as the glossary which provides a quick reference.

Although I understand you intend to elaborate more on certain areas including current research, the project does seem a little thin in regards to text. There are many papers that are linked with no explanation. For example, with regards to the table under prohibitions, I am confused as to what exactly those countries prohibit (all genetic modification? mitochondrial techniques only?) and also whether there is any more nuance to the discussion (do they ban different things?). Of course, one could click through the links under each country, but i think some text before the table itself would only add to your project and bring more context to the table itself. Diagrams themselves can also be referred to in the text (as you would find in a textbook), to add context and create a more cohesive wikipedia page (e.g. for Pronuclear transfer). In terms of the information provided, a little deeper exploration or discussion about certain issues including the reasoning behind ethics arguments may be relevant. If the articles listed under the headings are anything to go by, it seems you intend to do this.

Finally, some proofreading will be very beneficial in polishing up the wikipedia page. There are some sentences like "And it effectiveness in doing so. And the processes that occur in the oocyte when this method is used" under Human Embryo Model, which may well do with some editing. I would like to add that the referencing has been fantastic and consistent. Good Luck!

'''Group 3'''

I found this Wikipedia page particularly interesting. A wide assortment of visual media including histological slides, ultrasound images, geographical maps, tables, flow diagrams and hand-drawn images, all add a richness and balance to the text. This page does well to direct the reader's attention with highlighted text as well, to make for an aesthetically pleasing article. In particular, i found the hand-drawn diagram particularly intelligent and impressive.

In terms of text, i think this article is of adequate complexity and provides educational value to its intended audience of fellow university students. However, more diagrams to accompany the pathophysiological mechanisms and simplify the process may be of benefit. The text under 'Causes' is informative, but there is an imbalance of information for the various subsections within that heading. I assume, you intend to elaborate on those subsections that seem a little thin. It may be more effective to break up the 'genetic factors' section to a simple list of genetic influences, with details of studies relevant to that factor alongside it. This way, you don't have to read through several paragraphs to get to a particular gene/information point. Also, some arrows pointing to the actual cysts explicitly in the histological slide may be useful, as already done in the Ultrasound slide.

Finally, although the Wikipedia page is organised logically and contains particularly relevant sections, it may do with some more. As an age old issue, I'm interested in the epidemiology of PCOS and a bit about its history (or where/when we know what we do about it). Other than that, the page looks pretty good and reads well too.

'''Group 4'''

This Group Project is impressively detailed and provides a comprehensive view of male infertility detailing the normal process as well as the various disorder types and causes. The wikipedia page flows logically, provides excellent summaries and may well be an excellent educational resource. The video chosen is fantastic and tables have been used well to present information quickly.

I find that the Introduction is clear and concise. However, i feel it may be improved further by an introductory visual. Other than that, the page has many relevant diagrams and images. In terms of the 'development of gonadotropin preparations', it does seem a little out of place as it isn't particularly referred to in the text. I understand timelines add a richness to the text and can give perspective, but i feel that it may be of more relevance if given regarding male infertility treatments as a whole, rather than gonadotropin preparations. Of course, you can always have both.

Other than that, I am quite impressed with this wikipedia page. It is referenced well and information is backed with reference to the findings of various studies. A final tip may be to add a simple glossary for ease of reference as opposed to having to scroll back up to the section (e.g. varicocele) to remind oneself of the meaning. However, it should be commended that jargon was defined well throughout the article.

'''Group 5'''

This Group Project covers a wide breadth of topics in a very easy to understand manner. The types of chemotherapy treatments or drugs for example, were very easy to read and understand. The various tables and histological slides employed also make for an interesting and easy to digest wikipedia article. The visual aids detailing the IVF process was also well appreciated and balanced well with the text.

However, I feel that in general there should be more visual media to accompany the text. An issue of a current image I have (patient undergoing chemotherapy) is that I don't think it adds much to the wikipedia page and is not informative. Furthermore, I was hoping there would be an introduction to the wikipedia page that would explicitly detail what it aims to cover. This would provide more structure and give a logical flow to the wikipedia page. Another way to improve the logical flow, is to subdivide sections into male and female (e.g. surgeries and drugs, the transition from surgeries for males to drugs for female infertility was abrupt and disorienting). The top half of the page may be made less verbose through the use of more jargon e.g. in the Radiation section "cells can't grow and divide" etc. Naturally, a glossary is also a convenient reference point that may be included.

Also, there is an imbalance in detail with more input within cancer cells section than other sections more directly relevant in ART including IVF. However, I do understand this Group Project is still a work in progress. Overall, there is a lot of potential in the wikipedia page.

'''Group 6'''

This wikipedia article is impressively organised and easy to follow. It is sufficiently detailed, and despite being content heavy it has a good layout as it is well spaced out. This article is well referenced as well, a testament to the work that has been put in.

I understand that the advantages and disadvantages are listed as bullet points. Have you thought of organising it in a table? It may be a way to include a 'visual aid' in order to reach a balance in terms of visual/text content. Generally, more diagrams will only improve this article. Cohesion between the visual and written text may be increased by referrals to the diagrams/images throughout e.g. human blastocyst biopsy as opposed to a caption only. Also, having a section directly comparing the genetic techniques/purpose/effectivity/results in a table may be interesting.

Overall, wonderful work. In my opinion this is definitely a frontrunner and particularly difficult to critique.

===Permalink===

[https://embryology.med.unsw.edu.au/embryology/Slides/Embryo_Stages/Stage22/08-eye/Stage22-08-eye.html?zoom=6&lat=-3223.5&lon=3922&layers=B Stage 22 Ear]
==References==

PMID 26244658
look at this <ref><pubmed>26244658</pubmed>

here's the list
<references/>

User:Z3372824

2015-10-23T01:12:14Z

Z3372824:

==Lab Attendance==

--[[User:Z3372824|Z3372824]] ([[User talk:Z3372824|talk]]) 13:46, 7 August 2015 (AEST)

--[[User:Z3372824|Z3372824]] ([[User talk:Z3372824|talk]]) 13:38, 14 August 2015 (AEST)

--[[User:Z3372824|Z3372824]] ([[User talk:Z3372824|talk]]) 15:14, 21 August 2015 (AEST)

--[[User:Z3372824|Z3372824]] ([[User talk:Z3372824|talk]]) 12:12, 28 August 2015 (AEST)

--[[User:Z3372824|Z3372824]] ([[User talk:Z3372824|talk]]) 12:14, 4 September 2015 (AEST)

--[[User:Z3372824|Z3372824]] ([[User talk:Z3372824|talk]]) 12:57, 25 September 2015 (AEST)

--[[User:Z3372824|Z3372824]] ([[User talk:Z3372824|talk]]) 12:48, 9 October 2015 (AEDT)

--[[User:Z3372824|Z3372824]] ([[User talk:Z3372824|talk]]) 13:37, 16 October 2015 (AEDT)

----

{{StudentPage2015}}

[[Test student 2015]]

==Week 1 Assessment==

1) PMID 18603501

Increased Progesterone/Estradiol Ration on the Day of hCG Administration Adversely Affects Success of In Vitro Fertilisation-Embryo Transfer in Patients Stimulated with Gonadotropin-releasing Hormone Agonist and Recombinant Follicle-stimulating Hormone

This study examines the influence of premature luteinisation, with respect to ovarian response, during IVF. This was done using gonadotropin-releasing hormone agonist (GnRHa) and recombinant follicle-stimulating hormone (rFSH).The study defined premature luteinisation as a ratio between progesterone and estradiol of greater than one, the day hCG was administered. The experimental group of prematurely luteinised was then compared to the non-prematurely luteinised groups.

The study was performed on 311 infertile couples, in which a total of 339 cycles of ovarian hyperstimulation with GnRHa and rFSH. The females studied were aged from 20 to 40 years, and did not undergo cycles incorporating hMG, nor did they receive oocyte donations. The patients underwent ovarian stimulation, a long stimulation protocol of GnRHa therapy, rFSH administration as well as transvaginal oocyte retrieval, respectively. hCG was administered after adequate follicular maturation and oocytes were obtained 35-37 hours after hCG administration using transvaginal aspiration with ultrasound assistance. The follicular fluids and follicular washes were examined using a dissecting stereomicroscope that was incubated at 37 degrees with 5%CO2. Sperm insemination procedures were also performed, after which the oocytes were inseminated with spermatozoa. The oocytes were removed after 2 hour exposures to the spermatozoa and cultured in fresh IVF medium. The control group underwent ICSI procedures, while the experimental group underwent IVF procedures. The oocytes were then cultured and assessed for pronuclei presence 16-18 hours incubation in order to determine fertilisation (presence of 2 pronuclei). Embryos were then cultured and classified, as were the blastocysts.

The study found 137 out of the 339 cycles to have premature luteinisation. Poor ovarian response was more common in the experimental group. It was also found the the experimental group had a higher progesterone level and lower E2 level on the hCG administration day. However the mean luteinising hormone on day 6 of stimulation was similar in both control and study groups but higher in the control group on hCG administeration day. The experimental group demonstrated a lower number of oocytes obtained, and lower number of mature oocytes recovered. It should be noted that fertilisation rates were similar in both groups. Embryo number was lower for the experimental group compared to the control group. 130 gestational sacs were demonstrated after a transfer of 577 embryos in the control group while 76 gestational sacs were demonstrated out of 339 embryo transfers in the study group. The non-prematurely luteinised group and prematurely luteinised group had similar implantation rates. It was also found that 48.5% of the non-prematurely luteinised group achieved clinical pregnancies while 36.6% of the prematurely luteinised group achieved clinical pregnancies.

<pubmed>18603501</pubmed>

2) PMID 21793811

Impact of endometriosis on in vitro fertilization and embryo transfer cycles in young women; a stage-dependent interference

Due to the significantly higher prevalence of endometriosis in infertile women as compared to the general population, a causal relationship between endometriosis and infertility has been postulated. In vitro fertilisation and embryo transfer (IVF-ET) has been considered a suitable treatment for patients with a history of endometriosis. This study examines the effect of endometriosis on IVF-ET cycles on women younger than 35 years of age and who have had surgical treatment for endometriosis without clinical recurrence signs. The endometriosis group was compared to another group of patients also undergoing IVF-ET, but with tubal infertility without clinical signs of endometriosis. The results were analysed according to the different stages of endometriosis as classified by the American Society for Reproductive Medicine.

The experimental group consisted of 148 patients whereas the control group (tubal infertility patients) consisted of 72 patients. All groups consisted of patients that were less than 35 years of age and did not have clinical indication for any other cause of infertility. The experimental group underwent 164 IVF-ET cycles while the control group underwent 80 IVF-ET cycles. Patients received a long-acting down-regulation drug regime, a daily subcutaneous FSH dose, as well as gonadotropin doses which were decided individually according to age, basal FSH, ovarian volume and ovarian response. After two or more follicles reached maximal diameter of 17-18mm, hCG was administered and oocytes were obtained 36 hours later using vaginal ultrasonography, to then be fertilised on the same day. Embryo transfers were made two to three days after oocyte retrieval. Natural progesterone in oil was then administered. Plasma beta-hCG values were used to assess pregnancy. Clinical pregnancy was determined when at least one gestational sac was found with a fetal pole and heart activity through ultrasond.

It was found that the experimental group had significantly lower numbers of follicles on the hCG day, oocytes obtained and transferred when compared to the control group, despite receiving a higher FSH dose. However no significant differences were found regardingt cycle cancellation rate, peak E2 levels of the length of the stimulation phase. 11.6% of clinical pregnancies per started cucle were observed in the experimental group as compared to 22.5% in the control group. However, this value wa not significant when the clinical pregnancy rate was considered per oocyte retrieval or per embryo transfer. It was also found that patients at stage I-II of endomtriosis had a significantly lower rate of fertilisation when compared to the control group patients. Patients at stage III-IV of endometriosis had a large reduction in pregnancy rate than the control group, however the fertilisation rate was comparable. Patients at stage III-IV had lower peak E2 concentrations, less follicles on the hCG day, fewer oocytes at retrieval and lower implantation rates. Furthermore, poor ovarion responses in 15 out of 109 cycles resulted in discontinuation of the cycle in patients at stage III-IV of the endometriosis group, compared to 2 of 55 in the stage I-II group and 3 of 80 in the control group.

<pubmed>21793811</pubmed>

--[[User:Z8600021|Mark Hill]] ([[User talk:Z8600021|talk]]) 14:08, 16 September 2015 (AEST) These are good summaries of the se 2 articles. You should make an effort to clearly identify what you have written as opposed to quoting directly from the paper.(5/5)

==Week 2 Assessment==

[[File:Epigenetic factors Influencing Human Development.jpg|300px]]

PMID 26216216

--[[User:Z8600021|Mark Hill]] ([[User talk:Z8600021|talk]]) 14:12, 16 September 2015 (AEST) Image uploaded and named correctly. Image summary includes information, reference, copyright and student image template. (5/5)

==Week 3 Assessment==

PMID 26074966
<pubmed>26074966</pubmed>

PMID 20416867
<pubmed>20416867</pubmed>

PMID 23873146
<pubmed>23873146</pubmed>

The three key pathways by which the incidence of OHSS has been curtailed involve identifying risk factors to predict OHSS development, modifying treatment regimes on the basis of the identified risk factors and intervention to prevent progression to OHSS once the patient has undergone Controlled Ovarian Stimulation.

1) Risk factors

Primary: Preexisting factors likely to exacerbate the ovarian stimulation response. Include: young age, low body weight, history of elevated response to gonadotropins, Polycystic Ovary Syndrome (PCOS), isolated PCOS characteristic or a previous history of OHSS. Anti-Mullerian Hormone markers (AMH) are a newly developed predictive tool with a sensitivity of 90.5% and specificity of 81.3%. Ultrasonographic markers including antral follicle count
PMID 26074966

Secondary:

2) Prevention

Primary:
a) Gonadotropins: reduce duration, reduce dose, avoid GnRH Agonists PMID 23873146

b) Use Metformin Therapy

c) Target Unifollicular Ovulation

d) Avoid hCG

e) In Vitro Maturation

Secondary:
a) Reduce hCG dose

b) Coasting

c) Cryopreservation of Embryos

d) Cancel Cycle

e) Use alternative Agents

PMID 20416867

--[[User:Z8600021|Mark Hill]] ([[User talk:Z8600021|talk]]) 14:12, 16 September 2015 (AEST) These are relevant to your group project. Hopefully these will be useful in the final project page. (5/5)

==Week 4 Assessment==
===Fertilisation Quiz===

<quiz display=simple>

{Which of the following statements is incorrect in regards to the acrosome:
|type="()"}
-The acrosome reaction allows for the exposure of the inner-acrosomal membrane
-Only acrosome reacted spermatozoa fuse with the oocyte
-The acrosome within the spermatozoa is derived from the golgi apparatus
+Zona Pellucida Binding Protein 1 is synthesised by the oocyte
-The enzymatic contents of the acrosome degrade the zona pellucida
||This is correct, the [[Z#zona pellucida binding protein 1|zona pellucida binding protein 1]] is in fact a spermatozoa protein located on the acrosome surface, and binds to the zona pellucida of the oocyte during fertilisation.

{Which of the following statements about the zona pellucida is incorrect:
|type="()"}
-It is an insoluble extracellular matrix
-It expresses several glycoproteins
-It surrounds the blastocyst
-It surrounds the developing oocyte
+It prevents sperm binding
||Yes, the [[Z#zona pellucida|zona pellucida]] is a specialised extracellular matrix which surrounds the developing oocyte. It expresses several glycoproteins including ZP1, ZP2, ZP3 and ZP4, all of which play an important role in fertilisation. The zona pellucida facilitates sperm binding as the ZP2 binds the spermatozoa before fertilisation. Following fertilisation, the zona pellucida continues to surround the blastocyst during the first week of development, before being broken down through uterine and blastula secretions.

{Fertilisation does not:
|type="()"}
+result in the formation of the first polar body after the second meiotic division
-often occurs in the first 1/3 of the oviduct
-involve spermatozoa and oocyte fusion
-require the exocytosis of cortical granules in the cortical reaction
- require the exocytosis of acrosomal enzymes during the acrosome reaction
||Yes, [[F#fertilization|fertilization]] results in the formation of the second polar body after the second meiotic division. The first polar body forms during the first meiotic division.

</quiz>

--[[User:Z8600021|Mark Hill]] ([[User talk:Z8600021|talk]]) 14:20, 16 September 2015 (AEST) Three negative questions. Q1 An interesting range of options. I suggest that your question might be more instructive. The incorrect option (zona pellucida binding protein 1) is a bit of a give away as why would the oocyte make this protein? A student using simple logic (rather than knowledge) may get this right. Q2 A little simplistic, as we spent some time on ZP sperm binding. Q3 has too simple options and is not well structured. (7/10)

[[ANAT2341 Student 2015 Quiz Questions]]
==Week 5 Assessment==

What is the difference between gastroschisis and omphalocele?

Gastroschisis and Omphalocele are both congenital abdominal wall defects. Omphalocele is a condition involving the umbilical ring whereby the internal organs, typically consisting of the small intestine, colon, liver and spleen, are disemboweled in a sac made of peritoneum, Wharton's jelly and amnion. Gastroschisis is an anterior abdominal wall defect often located to the right of the umbilical cord, where like Omphalocele, there is a protrusion of the bowel. However, in Gastroschisis there is no sac covering the herniation. As such, both conditions defer with respect to location and presence of a sac. Omphalocele is caused by an abnormality in the embryo before week 9 of gestation whereby the bowel loops are malrotated or non rotated and do not return to the abdominal cavity. There are several competing theories as to the cause of Gastroschisis. A leading hypothesis suggests that Gastroschisis results from the inability of the vitelline structures and yolk sac to be incorporated into the body stalk.

Gastroschisis and Omphalocele represent the two most common abdominal wall defects. Gastroschisis is more common of the two and occurs at a rate of one per 600 live births. Omphalocele occurs in about one in 3000 to 10000 live births. Whilst the incidence of Omphalocele is stable, the incidence of Gastroschisis appears to be increasing. It is suspected that this may be due to better technology and screening methods. The male to female ratio of Omphalocele is 1:1.5 while the male to female ratio of Gastroschisis is equivalent. The maternal age of mothers who give birth to a child suffering from Omphalocele is typically 30 years of age. A mother who gives birth to a child from Gastroschisis is typically 22 years of age.

A key difference between Gastroschisis and Omphalocele is that congenital Omphaloceles are frequently associated with other abnormalities while Gastroschisis is not. In Omphalocele, chromosomal defects are found in 30-40% of cases while multiple associated anomalies including chromosomal changes are observed in 67-80% of cases. It is rare for associated anomalies to occur with Gastroschisis. These include: intestinal atresia which is found in 10% of cases, as well as cardiac, renal, musculoskeletal and central nervous system anomalies.

PMID 25459013

<pubmed>25459013</pubmed>

PMID 26229394

<pubmed>26229394</pubmed>

--[[User:Z8600021|Mark Hill]] ([[User talk:Z8600021|talk]]) 14:20, 16 September 2015 (AEST) These are good summaries. (5/5)

==Week 7 Assessment==

PMID 26395490

<pubmed>26395490</pubmed>

1. Although it is currently thought that thyroid C cells originate from cephalic neural crest cells, growing evidence suggests that the embryonic origin may in fact be from Sox17+ anterior endoderm. This study traced Wtn1 expressing cells to determine neural crest origin. Wtn1 expression occurs in the dorsal neural tube and is necessary for neural crest cell expansion. Foregut endoderm origin was established from tracing Sox17 expression, as it is known that transient expression of Sox17 occurs during formation of endoderm. Through fate mapping, the study in mice found that thyroid C cells derived from Sox17+ anterior endoderm, rather than Wtn1 expressing neural crest progeny. However, Wtn1 neural crest cells play a role in the development of thyroid connective tissue. Through lineage tracing, it was also found that in thyroid C cell precursors, the transcription factors Foxa1 and Foxa2 are differentially expressed. These transcription factors are commonly expressed in endoderm organs, and were also found in the thyroid bud and pharyngeal pouch, from which the ultimobranchial bodies that give rise to the thyroid emerge. Within embryonic thyroid C cells, the two transcription factors are coexpressed.

2.Tooth Development consists of ectoderm, mesoderm and neural crest ectomesenchyme involvement. The Ameloblasts produce enamel. Odontoblasts derive from neural crest mesenchyme and form predentin which calcifies to form dentin. The periodontal ligament secures the tooth in the bone socket, acts as a shock absorber, transmits chew forces from bone to tooth and relays sensory information.

==Peer Reviews==

'''Group 1'''

This Group Project has a lot of potential. Information is presented in an engaging way through an introductory video documenting a case, timeline providing retrospective insight as well as diagrams detailing the complex processes in a concise manner. I also found some subsections interesting and relevant, including the discussion on ethics, Current research areas, as well as the glossary which provides a quick reference.

Although I understand you intend to elaborate more on certain areas including current research, the project does seem a little thin in regards to text. There are many papers that are linked with no explanation. For example, with regards to the table under prohibitions, I am confused as to what exactly those countries prohibit (all genetic modification? mitochondrial techniques only?) and also whether there is any more nuance to the discussion (do they ban different things?). Of course, one could click through the links under each country, but i think some text before the table itself would only add to your project and bring more context to the table itself. Diagrams themselves can also be referred to in the text (as you would find in a textbook), to add context and create a more cohesive wikipedia page (e.g. for Pronuclear transfer). In terms of the information provided, a little deeper exploration or discussion about certain issues including the reasoning behind ethics arguments may be relevant. If the articles listed under the headings are anything to go by, it seems you intend to do this.

Finally, some proofreading will be very beneficial in polishing up the wikipedia page. There are some sentences like "And it effectiveness in doing so. And the processes that occur in the oocyte when this method is used" under Human Embryo Model, which may well do with some editing. I would like to add that the referencing has been fantastic and consistent. Good Luck!

'''Group 3'''

I found this Wikipedia page particularly interesting. A wide assortment of visual media including histological slides, ultrasound images, geographical maps, tables, flow diagrams and hand-drawn images, all add a richness and balance to the text. This page does well to direct the reader's attention with highlighted text as well, to make for an aesthetically pleasing article. In particular, i found the hand-drawn diagram particularly intelligent and impressive.

In terms of text, i think this article is of adequate complexity and provides educational value to its intended audience of fellow university students. However, more diagrams to accompany the pathophysiological mechanisms and simplify the process may be of benefit. The text under 'Causes' is informative, but there is an imbalance of information for the various subsections within that heading. I assume, you intend to elaborate on those subsections that seem a little thin. It may be more effective to break up the 'genetic factors' section to a simple list of genetic influences, with details of studies relevant to that factor alongside it. This way, you don't have to read through several paragraphs to get to a particular gene/information point. Also, some arrows pointing to the actual cysts explicitly in the histological slide may be useful, as already done in the Ultrasound slide.

Finally, although the Wikipedia page is organised logically and contains particularly relevant sections, it may do with some more. As an age old issue, I'm interested in the epidemiology of PCOS and a bit about its history (or where/when we know what we do about it). Other than that, the page looks pretty good and reads well too.

'''Group 4'''

This Group Project is impressively detailed and provides a comprehensive view of male infertility detailing the normal process as well as the various disorder types and causes. The wikipedia page flows logically, provides excellent summaries and may well be an excellent educational resource. The video chosen is fantastic and tables have been used well to present information quickly.

I find that the Introduction is clear and concise. However, i feel it may be improved further by an introductory visual. Other than that, the page has many relevant diagrams and images. In terms of the 'development of gonadotropin preparations', it does seem a little out of place as it isn't particularly referred to in the text. I understand timelines add a richness to the text and can give perspective, but i feel that it may be of more relevance if given regarding male infertility treatments as a whole, rather than gonadotropin preparations. Of course, you can always have both.

Other than that, I am quite impressed with this wikipedia page. It is referenced well and information is backed with reference to the findings of various studies. A final tip may be to add a simple glossary for ease of reference as opposed to having to scroll back up to the section (e.g. varicocele) to remind oneself of the meaning. However, it should be commended that jargon was defined well throughout the article.

'''Group 5'''

This Group Project covers a wide breadth of topics in a very easy to understand manner. The types of chemotherapy treatments or drugs for example, were very easy to read and understand. The various tables and histological slides employed also make for an interesting and easy to digest wikipedia article. The visual aids detailing the IVF process was also well appreciated and balanced well with the text.

However, I feel that in general there should be more visual media to accompany the text. An issue of a current image I have (patient undergoing chemotherapy) is that I don't think it adds much to the wikipedia page and is not informative. Furthermore, I was hoping there would be an introduction to the wikipedia page that would explicitly detail what it aims to cover. This would provide more structure and give a logical flow to the wikipedia page. Another way to improve the logical flow, is to subdivide sections into male and female (e.g. surgeries and drugs, the transition from surgeries for males to drugs for female infertility was abrupt and disorienting). The top half of the page may be made less verbose through the use of more jargon e.g. in the Radiation section "cells can't grow and divide" etc. Naturally, a glossary is also a convenient reference point that may be included.

Also, there is an imbalance in detail with more input within cancer cells section than other sections more directly relevant in ART including IVF. However, I do understand this Group Project is still a work in progress. Overall, there is a lot of potential in the wikipedia page.

'''Group 6'''

This wikipedia article is impressively organised and easy to follow. It is sufficiently detailed, and despite being content heavy it has a good layout as it is well spaced out. This article is well referenced as well, a testament to the work that has been put in.

I understand that the advantages and disadvantages are listed as bullet points. Have you thought of organising it in a table? It may be a way to include a 'visual aid' in order to reach a balance in terms of visual/text content. Generally, more diagrams will only improve this article. Cohesion between the visual and written text may be increased by referrals to the diagrams/images throughout e.g. human blastocyst biopsy as opposed to a caption only. Also, having a section directly comparing the genetic techniques/purpose/effectivity/results in a table may be interesting.

Overall, wonderful work. In my opinion this is definitely a frontrunner and particularly difficult to critique.

===Permalink===

[https://embryology.med.unsw.edu.au/embryology/Slides/Embryo_Stages/Stage22/08-eye/Stage22-08-eye.html?zoom=6&lat=-3223.5&lon=3922&layers=B]
==References==

PMID 26244658
look at this <ref><pubmed>26244658</pubmed>

here's the list
<references/>

2015 Group Project 2

2015-10-22T23:32:08Z

Z3372824: /* Risk factors */

{{ANAT2341Project2015header}}

==<span style="font-size:120%">'''Ovarian Hyper-stimulation Syndrome (OHSS)'''</span>==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

Ovarian Hyper stimulation Syndrome (OHSS) is an iatrogenic complication of '''Assisted Reproduction Technology''' (ART), in which women take medications to stimulate oocyte growth. It is generally identified by cystic enlargements of the ovaries and fluid accumulation in the peritoneal cavity due to the increased capillary permeability and ovarian neoangiogenesis <ref name="PMID22065820"><pubmed>22065820</pubmed></ref>. It is an occurrence which is dependent on the controlled stimulation of the ovaries in preparation for IVF i.e. administration of human Chorionic Gonadotropin (hCG).

OHSS was first described in 1943 as ''“syndrome d’hyperluteinisation massive
des ovaries”''. It was during this time that gonadotropins were prepared from animals such as sheep to bring on ovulation in women. The first recorded death as a result of OHSS occurred in 1951 and was due to renal failure as a result of oligouria, a complication of the syndrome <ref name="OHSS"> Marie M. Budev, DO, MPH; Alejandro C. Arroliga, MD; Tommaso Falcone, MD, [ http://utilis.net/Morning%20Topics/REI/Ovarian%20Hyperstimulation.pdf ], 'Ovarian Hyperstimulation Syndrome'</ref> <ref name="PMID12638783"><pubmed>12638783</pubmed></ref>.

<span style="color:#FA58D0">This wikipage aims to provide clear information on various areas surrounding OHSS such as diagnosis, prevention and complications and will look into the genetics behind the disorder and the various animals models used to research it.</span>

<html5media height="350" width="450">https://www.youtube.com/watch?v=aXmjJw234a4</html5media>

'''Overview of the Ovarian Hyperstimulation Syndrome''' <ref> Howcast (2013, August 27) Ovarian Hyperstimulation Syndrome | Infertility. Retrieved from https://www.youtube.com/watch?v=aXmjJw234a4</ref>

</div>

==Epidemiology==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

Ovarian Hyper-Stimulation Syndrome (OHSS) rarely occurs sporadically, and if it does, it is usually the result of an underlying genetic problem. The majority of OHSS is due to the ovaries being stimulated to mature and release an abundance of oocytes, in response to hormones Human Chorionic Gonadotropin (hCG) and Follicle Stimulating hormone (FSH), during IVF. Rarely, Clomifene Citrate therapy can cause OHSS.<ref name="WikiOHSS"> Wikipedia, [ https://en.wikipedia.org/wiki/Ovarian_hyperstimulation_syndrome ], 'Ovarian Hyperstimulation Syndrome'</ref>

OHSS only affects '''0.5-5%''' of women undergoing Ovarian Hyper-stimulation, but despite its small prevalence, it is a potentially fatal outcome of a non-vital procedure and remains a prevalent problem for fertility specialists <ref name="PMID12498425"><pubmed>12498425</pubmed></ref> <ref name="PMID12638783"><pubmed>12638783</pubmed></ref>. Age has been cited as a factor affecting those with OHSS, with younger women more at risk. Additionally, women with allergies were seen to have a higher incidence of OHSS. It is important to note that at this point in time, there is no positive correlation between gonadotropin dose and OHSS.

Of the 0.5-5% of women affected with OHSS mentioned above, 2% of those women will require hospitalisation. As of 2011, it has been reported that the incidence of OHSS was '''increasing''', resulting in approximately 3 deaths per 100,000 women undergoing ovarian stimulation per year <ref name="PMID21828116"><pubmed>21828116</pubmed></ref>. This is particularly worrying as in 2008, in the United States alone, there were around 150,000 IVF cycles undertaken.

{|
|-bgcolor="F8E0F1"
|
'''With the field of Assisted Reproductive Technologies expanding and more women partaking in IVF treatments, the threat of women developing OHSS is an ongoing and increasing one''' <ref name="PMID21828116" />.
|}
{| class="wikitable mw-collapsible mw-collapsed"
! Characteristics of women by complication group <ref name="PMID19591989"><pubmed>19591989</pubmed></ref>
|-
! scope="col" width="100px" height="60px" style="text-align:center| '''Characteristic'''
! scope="col" width="100px" height="60px" style="text-align:center| '''No Complications
(N = 212,041)'''
! scope="col" width="100px" height="60px" style="text-align:center| '''Moderate OHSS
(N = 1,523)'''
! scope="col" width="100px" height="60px" style="text-align:center| '''Severe OHSS
(N = 655)'''
|-
|style="text-align:center; background: #FF99FF;"| '''Maternal Age (Mean ± SD)'''
|style="text-align:center; background: #F6CEEC;"| 35.6 ± 4.6
|style="text-align:center; background: #F6CEEC;"| 33.0 ± 4.3
|style="text-align:center; background: #F6CEEC;"| 33.1 ± 4.4
|-
|style="text-align:center; background: #FF99FF;"| '''Maternal Age (%)'''
|-
|style="text-align:left; background: #F6CEEC;"| <30 years
|style="text-align:center; background: #F6CEEC;"| 10 %
|style="text-align:center; background: #F6CEEC;"| 21.1 %
|style="text-align:center; background: #F6CEEC;"| 20.6 %
|-
|style="text-align:left; background: #F6CEEC;"| 30-34 years
|style="text-align:center; background: #F6CEEC;"| 30.4 %
|style="text-align:center; background: #F6CEEC;"| 43.2 %
|style="text-align:center; background: #F6CEEC;"| 40.5 %
|-
|style="text-align:left; background: #F6CEEC;"| 35-39 years
|style="text-align:center; background: #F6CEEC;"| 37.8 %
|style="text-align:center; background: #F6CEEC;"| 27.2 %
|style="text-align:center; background: #F6CEEC;"| 32.5 %
|-
|style="text-align:left; background: #F6CEEC;"| >40 years
|style="text-align:center; background: #F6CEEC;"| 21.8 %
|style="text-align:center; background: #F6CEEC;"| 8.4 %
|style="text-align:center; background: #F6CEEC;"| 6.4 %
|-
|style="text-align:center; background: #FF99FF;"| '''Nulligravida (%)'''
|style="text-align:center; background: #F6CEEC;"| 45.8 %
|style="text-align:center; background: #F6CEEC;"| 51.5 %
|style="text-align:center; background: #F6CEEC;"| 51.8 %
|-
|style="text-align:center; background: #FF99FF;"| '''Infertility Diagnosis (%)'''
|-
|style="text-align:left; background: #F6CEEC;"| Male factor
|style="text-align:center; background: #F6CEEC;"| 37.7 %
|style="text-align:center; background: #F6CEEC;"| 41.0 %
|style="text-align:center; background: #F6CEEC;"| 33.4 %
|-
|style="text-align:left; background: #F6CEEC;"| Endometriosis
|style="text-align:center; background: #F6CEEC;"| 13.5 %
|style="text-align:center; background: #F6CEEC;"| 13.5 %
|style="text-align:center; background: #F6CEEC;"| 10.7 %
|-
|style="text-align:left; background: #F6CEEC;"| Ovulation Disorders
|style="text-align:center; background: #F6CEEC;"| 14.0 %
|style="text-align:center; background: #F6CEEC;"| 29.5 %
|style="text-align:center; background: #F6CEEC;"| 22.4 %
|-
|style="text-align:left; background: #F6CEEC;"| Diminished ovarian reserve
|style="text-align:center; background: #F6CEEC;"| 16.9 %
|style="text-align:center; background: #F6CEEC;"| 3.2 %
|style="text-align:center; background: #F6CEEC;"| 2.4 %
|-
|style="text-align:left; background: #F6CEEC;"| Tubal factors
|style="text-align:center; background: #F6CEEC;"| 20.4 %
|style="text-align:center; background: #F6CEEC;"| 22.6 %
|style="text-align:center; background: #F6CEEC;"| 22.3 %
|-
|style="text-align:left; background: #F6CEEC;"| Uterine factors
|style="text-align:center; background: #F6CEEC;"| 5.1 %
|style="text-align:center; background: #F6CEEC;"| 4.3 %
|style="text-align:center; background: #F6CEEC;"| 3.1 %
|-
|style="text-align:left; background: #F6CEEC;"| Other factors
|style="text-align:center; background: #F6CEEC;"| 13.9 %
|style="text-align:center; background: #F6CEEC;"| 13.1 %
|style="text-align:center; background: #F6CEEC;"| 10.4 %
|-
|style="text-align:left; background: #F6CEEC;"| Unexplained factor
|style="text-align:center; background: #F6CEEC;"| 12.7 %
|style="text-align:center; background: #F6CEEC;"| 11.8 %
|style="text-align:center; background: #F6CEEC;"| 18.6 %
|-
|}
</div>

==Causative Agents==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

[[File:Follicular Development.jpeg|right|thumbnail|500px|Infertility treatments aim to facilitate follicular development and induce ovulation to improve chances of fertilisation <ref name="PMID24717179"><pubmed>24717179</pubmed></ref>]]

Normally a woman produces one egg per month from the ovaries, which travel down the Fallopian tube to be fertilized or be released from the body. In cases where women have difficulty falling pregnant, they are given medication which help them to produce and release eggs (as shown in the diagram to the right), further increasing their chances of fertilization and pregnancy <ref><pubmed>19573285</pubmed></ref>. Ovarian Hyper stimulation Syndrome generally occurs during infertility treatments when the ovaries are overstimulated by the fertility medication which causes the ovaries to swell and leak fluids into the belly and abdomen. The prevalence of OHSS onset is linked with excessive number of follicle development in response to the administration of injectable Follicle Stimulating Hormones (FSH) followed by the '''Human Chorionic Gonadotrophins''' (hCG) which triggers the release of the oocytes <ref><pubmed>26190539</pubmed></ref>.

'''Follicle Stimulating Hormones''' (FSH) <ref name="PMID9020850"><pubmed>9020850</pubmed></ref> are glycoprotein hormones that are produced and secreted from the Anterior Pituitary gland into the bloodstream, which regulate the developmental, growth, maturation and the reproductive processes within the body. In females, the Follicle Stimulating Hormones initiates the stages of growth and development of immature ovarian follicles within the ovaries before the release of an egg from a follicle at ovulation. When FSH is administered to a patient who is suffering from infertility, the increase FSH levels affect the rate of development and production, in turn increasing the amount of follicles which are ready to be released during ovulation.

</div>

==Symptoms==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

OHSS is classified based on a criteria from mild, moderate and severe <ref name="WikiOHSS" />:

'''Mild Symptoms'''- abdominal bloating, minimal weight gain, nausea, diarrhoea and a feeling of fullness.

'''Moderate Symptoms'''- Substantial weight gain (on average 2 or more pounds a day), increased abdominal girth, darkend urine and excessive thirst in addition to the mild symptoms.

'''Severe Symptoms'''- In addition to the symptoms associated with Mild and Moderate OHSS, in severe OHSS, you see shortness of breath, calf and chest pains and pleural effusion.

<span style="font-size:100%">'''Classifications of Ovarian Hyper-stimulation Syndrome:'''</span> <ref name="PMID22065820"><pubmed>22065820</pubmed></ref>
{| class="wikitable" style="text-align:center
|-
! scope="col" width="70px"| '''Classification'''
! scope="col" width="650px"| '''Symptoms'''
|-
|style="text-align:center; background: #F6CEEC;"| '''Mild'''
|style="height: 60px; background: #F6CEEC;"| '''Grade 1''' - Abdominal distention and discomfort
'''Grade 2''' - Abdominal distention, discomfort with nausea, vomiting and/or diarrhea and ovarian enlargement from 5~12cm
|-
|style="text-align:center; background: #F8E0F1;"| '''Moderate'''
|style="height: 60px; background: #F8E0F1;"| '''Grade 3''' - All features of Mild OHSS with ultrasonographic evidence of ascites
|-
|style="text-align:center; background: #F6CEEC;"| '''Severe'''
|style="height: 60px; background: #F6CEEC;"| '''Grade 4''' - All features of Moderate OHSS with the addition of clinical evidence of ascites and breathing difficulties present
'''Grade 5''' - All of the above symptoms along with a change in the blood volume, increased blood viscosity due to coagulation and diminished renal function
|}

</div>

==Diagnosis==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

Whilst symptoms of OHSS can occur as soon as 24 hours post hCG administration, they are usually seen in women 7-10 days post administration. Initially women with OHSS will present with abdominal bloating, as a result of fluid in the peritoneal cavity and an increase in ovary size. When women present with severe OHSS they are often dehydrated, due to increased vascular permeability, and have hemoconcentration. The above results in a decrease in intravascular volume, leading to '''oligouria''' <ref name="PMID22416285" />.

===History===

Initially a thorough history of the patient is taken during which the clinician looks for evidence of ovarian stimulation, followed by ovulation. During this history taking, the clinician will inquire into any weight gain noticed, urine output, and the woman's ability to maintain oral hydration. A key diagnostic tool for clinicians regarding women who are taking gonadotropins is to identify if they are at an increased risk of developing OHSS. Some risk factors include woman aged less than 30, women who have polycystic ovaries, woman with a previous history of OHSS and women who have had greater than 20 oocytes retrieved <ref name="PMID22416285" />.

===Physical Exam===
[[File:Vaginal_Ultrasonography_in_Sagittal_Plane.jpg|right|thumbnail|600px|Vaginal Ultrasonography in Sagittal plane <ref name="Wikiversity Journal of Medicine"> Häggström, Mikael. "Medical gallery of Mikael Häggström 2014". Wikiversity Journal of Medicine 1 (2). DOI:10.15347/wjm/2014.008. ISSN 20018762</ref>]]
After a history of the patient is taken, the next step is to perform a physical exam on the patient. Women who present with abdominal bloating will produce a shifting dullness upon abdominal percussion. Additionally the clinician will test the woman's vital signs, measure her abdominal girth, weight and will look for evidence of ascites or increase in calf size (usually unilateral)<ref name="PMID22416285" />.

===Investigations===

If the clinician further suspects a women of having OHSS, various investigations can be done such as an ultrasound.The intraperitoneal fluid is best imaged via vaginal ultrasound due to the enlarged ovaries making it difficult to image the pelvis using transabdominal ultrasound. The clinician can also order laboratory testing to look for urine specific gravity and and complete blood count to look for hemoconcentration with a hematocrit. Additionally, liver function tests can be ordered to look for elevated function. The clinician will also look for evidence of elevated D-dimers and fibrinogen and decreased levels of anti-thrombin 3 <ref name="SAHealth"> Government of South Australia Health [ http://www.sahealth.sa.gov.au/wps/wcm/connect/9b61ed004ee5348da663afd150ce4f37/Ovarian-hyperstimulation-syndrome-WCHN-PPG-17072012.pdf?MOD=AJPERES&CACHEID=9b61ed004ee5348da663afd150ce4f37 ], 'South Australian Paediatric Clinical Guidelines OHSS'</ref>.

====Ultrasound====

Typical appearances of the ultrasound include <ref name="Ultrasound"> Radiopaedia [ http://radiopaedia.org/articles/ovarian-hyperstimulation-syndrome-1 ], 'Ovarian Hyperstimulation Syndrome'</ref>:

*Bilaterally and symmetrically enlarged ovaries (>12cm)
* "Spoke-Wheel appearance" - presence of multiple cysts of varying size
*May also see ascites (fluid)

===Severity===

Once a clinician has deduced a women is suffering from OHSS, the severity of their condition needs to be established as either mild, moderate or severe. This is done by referring to the criteria under the sub-heading [[Symptoms]].The subsequent course of treatment for the woman will be based upon this evaluation.

{|
|-bgcolor="F6CEEC"
|
'''Further investigations''' can be done including a Chest X-ray to check for pleural effusions and oedema and USS with Doppler's to check for ascites or possible ovary torsion. <ref name="PMID22416285"><pubmed>22416285</pubmed></ref>
|}

===Differential Diagnosis===

Conditions presenting with similar symptoms or ultrasound images include <ref name="Ultrasound" />:

*Polycystic Ovaries (PO)
:: The difference is that with PO is that the cycts are typically smaller than OHSS cysts and there is no evidence of ascited or pleural effusion
*Mucinous Ovarian Malignancy
:: A type of Ovarian Epithelial tumour
*Ectopic Pregnancy <ref name="Casereport"> Australian Medical Student Journal [ http://www.amsj.org/wpcontent/uploads/files/articles/amsj_v2_i1/AMSJ_v2_i1_pg58-60.pdf ], 'Ovarian hyperstimulation syndrome'</ref>
::A pregnancy in which the foetus develops outside of the uterus e.g. in the fallopian tube

</div>

==Pathophysiology==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

[[File:Pathogenesis_of_OHSS.png|600px|thumb|Pathogenesis of OHSS <ref name="PMID20416867"><pubmed>20416867</pubmed></ref>]]

The definition of Ovarian Stimulation is enlarged ovaries with many luteinized cysts, that can present with secondary complications. What distinguishes Ovarian Stimulation from OHSS is the presence of vascular hyper-permeability that results in fluids being redirected elsewhere in the body.

The key process to OHSS appears to be caused by '''Vascular Endothelial Growth Factor''' (VEGF), that is released along with other cytokines, estrogen and progesterone, due to the ovary undergoing luteinization as a result of stimulation by hCG. VEGF increases vascular permeability and as a result the capillaries become more "leaky" to the fluids in them. These fluids can then escape the capillaries and accumulate in the pleural and abdominal cavities as ascites. The woman then becomes hypovolemic and is at an increased risk of circulatory, renal and respiratory issues such as arterial thromboembolism due to the thickening of the blood. Note, the blood is thickened as fluid is leaving the capillaries, leaving behind red blood cells and other cellular components of the blood <ref name="WikiOHSS" />.

The increase in expression of VEGF and VEGF Receptor 2 (VEGFR2) is attributed to the greatly increased amount of their mRNA present in the body after stimulation with hCG <ref name="PMID21082502"><pubmed>21082502</pubmed></ref>. VEGF interacts with VEGF2 and VEGF Receptor 1 (VEGFR1) to create a strong angiogenic effect. Both VEGFR2 and VEGFR1 belong to a family of receptors called tyrosine kinases. VEGF2 is involved in the regulation of angiogenesis and vascular permeability whilst VEGF1 has a slightly contradictory role in that is is involved in the maintenance of the tight junctions between endothelial cells in blood vessels. A study by Gómez ''et. al.'' <ref name="PMID21082502" /> showed that women experiencing OHSS had substantially higher plasma levels of VEGF and lower levels of VEGFR1.

</div>

==Complications==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

Ovarian torsion or rupture, renal insufficiency and thrombophlebitis can all complicate OHSS. If a pregnancy occurs, symptoms may persist longer than the usual 1 to 2 weeks and become more severe, however, even with severe OHSS, they do not extend past the first trimester <ref name="WikiOHSS" />.

<span style="color:#FA58D0"> '''1-2% of women who undergo ovarian stimulation develop a severe form of OHSS''' </span>. Complications from severe OHSS include:

*Fluid collection in the abdomen
*Electrolyte disturbances (sodium and potassium)
*Kidney failure
*Ovary twisting
*Rupture of a cyst in an ovary
*Breathing problems
*Blood clots in large vessels (most commonly the legs)
*Pregnancy loss from miscarriage or termination
*Rarely, death

A study by Nouri ''et. al.'' <ref name="PMID24996451"><pubmed>24996451</pubmed></ref> found that women with '''Polycystic Ovarian Syndrome''' (PCOS) and those that were induced with hCG experienced longer recovery times from severe OHSS than women who were not pregnant. They looked at a cohort of women hospitalised for the first time with severe OHSS and subject them to the same treatments. Based on a defined criteria, they established the recovery time of these women and compared the times between those that were pregnant to those that were not pregnant. They also found that whether a woman had PCOS or ovulation induction did not affect her risk of developing OHSS if she was not pregnant. It is only a risk factor for pregnant women.

===Thromboembolic events===

A frequent and deadly complication of OHSS are thromboembolic events due to increased blood clotting. This increase in blood clotting has been attributed to a variety of complications such as hemoconcentration (which thickens the blood), hypovolemia and an increase in the permeability of blood vessels as a result of increased vasoactive substances in the body of ovarian origin. Thromboembolic events include venous thromboses often in the upper extremities and arterial thromboses such as those in the cerebrovascular region. These events can lead to amputations of extremities, brain damage, miscarriage and death. To avoid this, anti-coagulants are given to pateitns with OHSS and they are fitted with compression stockings (see [[Treatment]]) <ref name="PMID23378404"><pubmed>23378404</pubmed></ref>.

{|
|-bgcolor="F8E0F1"
|
The risk of a woman developing OHSS is higher if she is having a '''twin pregnancy''', as she is exposed to higher concentration of hCG. <ref name="PMID9756273"><pubmed>9756273</pubmed></ref>
|}

</div>

==Treatment==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

'''General treatment
'''
*''Acetaminophen'' with or without a narcotic agent- used to treat abdominal discomfort
*Women are encouraged to drink 2-3 litres of water a day to prevent hemoconcentration
*Women are advised to avoid sexual intercourse and vigorous exercise at the risk of torsion or rupture of the ovaries
*NSAID's with anti-platelet properties should NOT be used as they may effect renal function in a women with OHSS
*Patients with significantly painful ascites or breathing problems may undergo ''Paracentesis'' (drainage of the ascites)
*''Culdocentesis'' (extraction of fluid from recto-uterine pouch) can be done to decrease the likelihood of a woman with moderate OHSS progressing to severe OHSS.<ref name="PMID22416285" />

===Mild to Moderate OHSS===

Mild OHSS can often resolve on its own, however, moderate OHSS may include treatments such as<ref name="WikiOHSS" />:

*Anti-nausea medication and prescription painkillers
*Regular physical examinations and ultrasounds
*Daily weigh-ins and waist measurements
*Measuring the amount of urine produced each day
*Frequent blood tests for monitoring dehydration and electrolyte imbalance
*Maintaining a high balance of fluids
*Drainage of excess abdominal fluid by inserting a needle in the abdominal cavity
*Wearing support stockings which help prevent blood clots/thrombosis

===Severe OHSS===

Severe OHSS requires hospital care in order for constant monitoring and treatment such as <ref name="WikiOHSS" />:

*Intravenous fluids with a crystalloid solution (100-150mL/hr)
*Intravenous Albumin is administered is IV fluids are insufficient (15-20mL/hr of 25% albumin for 4 hrs)
*In addition to Acetaminophen, ''Opioid analgesics'' can be administered for pain relief
*''Antiemetics'' can be used to subside nauseas and/or vomiting
*Woman administered to hospital of OHSS are considered at high risk of thromboembolic complications and are given low molecular weight ''heparin'', an anti-coagulant
*''Cabergoline''- lessens OHSS symptoms
*''GnRH agonist''- suppresses ovarian activity
**If at risk of OHSS, alternates include using a GnRH agonist instead of hCG however its effects on pregnancy rates are questionable. Using a GnRH agonist to replace the use of hCG for final oocyte stimulation will see a 6% decrease in delivery rate.

*Daily monitoring of creatine, urea, creatine clearance C-reactive protein (to rule out infection) are all required in combination with weekly tests such as liver and renal function tests and chest x-rays (to check for pleural effusion) <ref name="PMID12638783" />.

If there are serious complications then additional treatments are required:

*Surgery for a ruptured ovarian cyst
*Intensive care for the liver or lung complications

====Paracentesis====

For women with severe/grade 3 OHSS, paracentesis, the removal of fluid from the body using an aspiration needle, can be undertaken. It is a diagnostic and a therapeutic method that can be done trans-abdominally and trans-vaginally. It is used to relieve symptoms, improve haemodynamics e.g. Urinary output, and shorten the women's hospital stay. Complications of paracentesis include bleeding, infection and organ injury, however are note common <ref name="Paracentesis"> S. Monica Soni, HMS 3, Gillian Lieberman, MD [ http://eradiology.bidmc.harvard.edu/LearningLab/genito/Soni.pdf ], 'Ovarian Hyperstimulation Syndrome'</ref>.

{|
|-bgcolor="F8E0F1"
|
The most important aspect of treatment for any women with OHSS is close and constant '''monitoring''' with her healthcare professional. Counselling may also be provided to women and their partners or families in order to provide them with the best possible knowledge base to manage and treat their OHSS. It is important to note that there is '''no one cure or treatment''' for OHSS. Treatment involves managing and eliminating the symptoms until such time as the syndrome resolves itself <ref name="WikiOHSS" />.
|}

</div>

==Prevention==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

There are three key avenues through which the incidence of OHSS may be prevented. These include identifying risk factors to predict OHSS development, modifying treatment regimes on the basis of the identified risk factors and intervention to prevent progression to OHSS once the patient has undergone '''Controlled Ovarian Stimulation''' (COS).

=== Risk factors===

'''Primary risk factors'''

Pre-existing factors likely to exacerbate the ovarian stimulation response. Primary risk factors include <ref name="PMID26074966"><pubmed>26074966</pubmed></ref>:

*Young age
*Low body weight
*History of elevated response to gonadotropins
*Polycystic Ovary Syndrome (PCOS)
*Isolated PCOS characteristic
*Previous history of OHSS.
*High pretreatment basal Anti-Mullerian Hormone (AMH) concentration
*Large Antral Follicle Count (AFC)

'''Secondary risk factors'''

Secondary risk factors involve the monitoring of ovarian response parameters once COS has been initiated. These parameters are monitored for <ref name="PMID19007627"><pubmed>19007627</pubmed></ref>:

*rapidly rising E2 levels
*E2 concentration larger than 2500 pg/mL
*large number of developing follicles (10-14mm) on the day hCG is administered
*large number of oocytes retrieved

These factors in combination, act as a predictive tool to assess the likelihood of severe OHSS development, with a 83% sensitivity and 84% specificity. <ref name="PMID19007627"/>

=== Primary Prevention===

Primary Prevention involves the modification of treatment regimens on the basis of OHSS risk classifications, in order to prevent OHSS occurrence.

'''Ovulation Induction'''

Unifollicular Ovulation Induction through Ovulation Induction (OI) is a primary means of avoiding OHSS in women with Polycystic Ovarian Syndrome, who are at an increased risk. In order to promote unifollicular development, the ovaries are stimulated with a low starting dose of FSH (75 IU).<ref name="PMID20416867"><pubmed>20416867</pubmed></ref> Studies suggests that a minimum gonadotropin dose lowers OHSS risk and thus a step-up regimen is utilised to achieve an ovarian response, whereby the FSH dosage is increased every 7 days until follicular development of greater than 10mm is noted.<ref name="PMID26074966" /> Alternatively, a step-down regimen may be followed, whereby a high initial FSH dosage is lowered according to the ovarian response. Another method to increase FSH levels during OI, is through '''Aromatase Inhibitors''' which promote folliculogenesis by increasing pituitary secretion of FSH, and downregulate oestrogen production through a negative feedback loop. However, Aromatase Inhibitors have not been shown to reduce OHSS incidence in comparison to other methods of OI.<ref name="PMID26074966" /> During OI, a key objective is to prevent early cycle cancellation due to premature luteinisation from pituitary secretion of LH. In order to downregulate LH secretion, Gonadotropin-releasing hormone agonists '''GnRHa''' are administered in addition to gonadotropins. Alternatively, '''GnRH antagonists''' may be administered to downregulate endogenous LH secretion. Comparative studies have shown that the GnRH antagonist protocol has a greater effect in lowering the incidence of mild to severe OHSS. However due to the rare nature of OHSS, and insufficient sample sizes, the difference was not found to be significant. <ref name="PMID21082508"><pubmed>21082508</pubmed></ref>. Generally, the duration of exposure to gonadotropins and subsequent risk of OHSS may be minimised through mild stimulation protocols which administer FSH only in the mid to late follicular phase.<ref name="PMID20416867" />

'''Adjuvant Metformin Therapy'''

Adjuvant Metformin Therapy has been found to lower the risk of OHSS by 63%.<ref name="PMID25406011"><pubmed>25406011</pubmed></ref> It involves the administration of metformin at a daily dosage of 1000 to 2000mg, 2 months prior to Controlled Ovarian Stimulation <ref name="PMID26074966"/>. Metformin lowers the elevated insulin levels in PCOS which consequently reduce intraovarian androgen levels. This leads to a reduced sensitivity and expression of granulosa cell-follicle stimulating hormone receptors which result in a less exaggerated response to gonadotropins. Furthermore, it is suggested that Metformin prevents OHSS by controlling vascular permeability through the inhibition of various vasoactive molecules, including VEGF.

'''Avoiding hCG during Luteal Phase Support

Following Controlled Ovarian Stimulation, the steroid levels of E2 and P4 are reduced during the luteal phase due to the negative feedback on the pituitary. This leads to low endogenous LH levels, which consequently reduce endometrial receptivity as well as the luteal phase duration itself. As a result, implantation and pregnancy rates are reduced and early pregnancy loss rates are increased.<ref name="PMID20416867" /> Luteal Phase Support (LPS) serves to combat these adverse events with the use of hCG. However, hCG has been found to increase the risk of OHSS. Alternatively, the use of progesterone has been found to not only halve the risk of OHSS, but also induce similar improvements in pregnancy and miscarriage rates as hCG.<ref name="PMID26148507"><pubmed>26148507</pubmed></ref>

===Secondary Prevention===

Secondary Prevention aims to prevent progression to OHSS once COS has been initiated and the patient has been found to mount an exaggerated response. <ref name="PMID20416867" />

'''Coasting'''

Coasting is a first-line secondary preventative strategy. It consists of the withdrawal of gonadotrophins when a critical number of follicles and/or E2 concentration is reached. hCG is administered once the E2 concentration reduces to a safe level, before the process of oocyte retrieval commences. This preventative strategy is conducted for a period of less than 3 days in order to avoid compromising IVF outcomes.

'''Cryopreservation'''

Cryopreservation of embryos after oocyte retrieval is another avenue which may avert OHSS progression. The cryopreserved embryos are only reimplanted once the patient's hormone serum levels have normalised. Using oocyte vitrification, crystal formation within embryo tissue is avoided and so cryopreserved embryos have been found to produce better pregnancy rates with a 32% increase, than fresh embryo transfer. Recent studies suggest cryopreservation itself does not reduce OHSS rates, but must be followed by a GnRHa trigger to avert OHSS.

'''Cycle cancellation'''

Cycle cancellation is a guaranteed method to prevent early OHSS whereby hCG is withheld. This is a last resort strategy as it carries the risk of significant psychological distress and financial loss for the patient.

</div>

==Effect on the Newborn==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

</div>
Women who develop OHSS while undergoing Assisted Reproductive Technologies (ART) treatment are not only more likely to achieve a pregnancy, but have a live birth as the pregnancy outcome. This live birth is also more likely to be a multiple birth of two, three or more children. <ref name="PMID19591989"><pubmed>19591989</pubmed></ref> It has been postulated that a multifetal pregnancy leads to a more rapid increase in hCG levels, resulting in an increased risk of OHSS. However, the causal nature between multifetal pregnancy and OHSS development is disputed and further research is required to distinguish correlation from causation. <ref name="PMID19573292"><pubmed>19573292</pubmed></ref>

OHSS development is also associated with an increased risk of adverse outcomes including stillbirth, premature birth and low birthweight.<ref name="PMID19591989" /> Although the cause for the increased risk in adverse pregnancy outcomes is unknown, it is suggested that as the incidence of OHSS is reduced through various prevention strategies, the risk of such outcomes may be also be reduced.

==Genetics==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

Despite OHSS typically being of iatrogenic origin as a result of ovarian stimulation with gonadotropins, research has been conducted into the potential genetics behind OHSS as many sporadic and familial cases have been observed. '''Mutations''' in the receptor for hormones such as Follicle Simulating Hormone (FSH), Lutenizing Hormone (LH) and hCG have all been targets of OHSS genetics research. Interestingly, they too also arise from a common ancestral gene.

===Follicle Stimulating Hormome===

Dr. Botros Rizk, of the University of South Alabama College of Medicine <ref name="PMID19573286"><pubmed>19573286</pubmed></ref>, has written extensively regarding the genetics behind OHSS. In particular, he talks about '''FSH receptors''' (FSHR) and their role in the syndrome. He hypothesises that mutations in these receptors could be activating or inactivating, leading to an increased risk of developing OHSS or sterility respectively. Currently, 744 single nucleotide polymorphisms (a type of mutation) have been found in the gene encoding the FSHR, 8 of which are located in its exons (coding regions of the gene). How the ovary responds is resultant on the FSHR genotype. For example, Ser680Asn, a polymorphism in the FSHR gene has been shown to aid in predicting the severity of a woman's OHSS. Ordinarily FSH stimulates the growth of ovarian follicles, however, when mutated, it is stimulated by the hCG resulting in excessive follicle development.

Spontaneous OHSS, OHSS that arises and cannot be attributed to any form of ovarian stimulation or Assisted Reproductive Technology, has been linked to activating mutations in the FSHR <ref name="PMID23499866"><pubmed>23499866</pubmed></ref>. This familial disorder is an autosomal dominant one. In most cases the FSHR can be stimulated by the presence of Thyroid Stimulating Hormone (TSH) or hCG, in the absence of FSH (the ligand for FSHR).

===Lutenizing Hormome===

The '''Lutenizing Hormone Receptor''' (LHR) gene in humans is comprised of 11 exons. Animal studies have shown that many primates exhibit a similar gene which is comprised of only 10 exons, however a gene lacking the 10th exon has been identified and termed the type 2 LHR. Expression of the type 2 LHR has been seen in humans. The type 2 LHR, compared to the wild-type LHR appears to be repaired with regard to its function. Defects in the type 2 LHR include a decrease in efficiency of transport to the plasma membrane and irregularities in signal transduction. Inactivating mutations in the LHR have been seen to cause infertility in women as well as amenorrhoea. Activating LHR gene mutations are asymptomatic and are not associated with OHSS in women.

===Bone Morphogenic Protein===

An imporant growth factor, derived from oocytes called '''BMP-15''' (Bone Morphogenic Protein 15) is vital for female fertility. It belongs to the family of growth factors, Transforming Growth Factor β (TGF-β) and is heavily involved in folliculogenesis. It has been found that mutations in the BMP-15 gene caused infertility in female sheep. Conversely, it has also been indicated in enhanced fertility when BMP-15 is present is high amounts in follicular fluid <ref name="PMID19573286" />.

A case study done by Hanevik ''et. al.'' in 2013 <ref name="PMID21565556"><pubmed>21565556</pubmed></ref> found that a Single Nuclear Polymorphism (SNP) in the BMP-15 gene is responsible for a high response to ovarian hyper-stimulation. The aim of the study was to test the effect the SNP had on BMP-15 with regard to high and low responders buy taking blood from 53 high responders, 38 low responders and 100 non-responders (controls) and analysing 5 noted SNP's. Results from their study showed a correlation between a high response to ovarian hyper-stimulation and the BMP-15 9G allele. The article does state however, that further research is required into the molecular effects of SNP's on the function of BMP-15.

===Vascular Endothelial Growth Factor===

'''Vascular endothelial growth factor''' (VEGF) has been indicated as one of the key agents causing vascular permeability and subsequent ascites in OHSS. The gene, which is located on chromosome 12, is made up of 8 exons (coding regions), of which exons 6 and 7 do not always appear due to the exons being spliced out.The splicing of this gene allows for various isoforms of the gene to exist of which VEGF 121 and 165 appear to play a role in angiogenesis. There are two VEGF Receptors, VEGFR-1 and VEGFR-2 that belong to the tyrosine kinase family of receptors (for more information on VEGF see [[Pathophysiology]]). Because of its distinct role in OHSS, it has been targeted as an area for research for potential treatments. The idea is that if the genetic expression of VEGF and its receptors can be controlled, OHSS can be avoided or treated.<ref name="PMID19573286" />

A different study by Hanevik ''et. al.'' , <ref name="PMID22587628"><pubmed>22587628</pubmed></ref> done in 2012 involved analysing blood samples from 53 women with OHSS and 100 women without it (controls) and analysing 6 SNP's in the VEGFR2 gene to find any genetic variations. They found a correlation between women with the VEGF +405cc genotype and the development of OHSS indicating women that undergo controlled ovarian hyper-stimulation and posses his genotype, are at an increased risk of developing OHSS.

</div>

== Current Research on Animal Models==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">
{|
|-bgcolor="F8E0F1"
|
<span style="font-size:120%">'''Inhibition of Cyclooxygenase-2 (COX-2) by Meloxican decreasing the incidence of OHSS in Rat Model'''</span> <ref name="PMID18166186"><pubmed>18166186</pubmed></ref>

Reasearch was carried out to investigate the effects of selective inhibition of the enzyme COX-2 on the Ovarian Hyperstimulation Syndrome (OHSS) using Female Wistar rates as the subjects. The research aimed to find results by measuring the number of antral and luteinized follicles, ovarian weight, vascualr endothelial growth factors and COX-2 immunohistochemistry. The rats being tested were all 22 days old and were divided into four equal groups;

'''Group 1 (Control group)''' was subject to a 0.1 ml of Intraperitoneal Saline from days 22 ~ 26

'''Group 2 (Mildly-stimulated group)''' subject to 10IU of pregnant mare serum gonadotrophin (PMSG) on day 24 and then 10IU of Human Chorionic Gonadotrophin (hCG) on day 26

'''Group 3 (OHSS positive group)''' was subject to 10IU of PMSG from days 22 ~ 26 and then administered 30IU of hCG on day 26 to induce OHSS

'''Group 4 (OHSS positive variant group)''' received 15mg/ml of Meloxicam 2 hours prior to administration of 10IU PMSG from days 22 ~ 26

Results showed there was no difference in ovarian weight in samples from Group 1 and Group 2, however Group 3 showed signs of significant ovarian weight increase which in group 4 was suppressed by the introduction of Meloxicam. No differences were observed in the number of antral follicles amongst the four test groups. Results from Group 2 and Group 3 showed that the granulosa cells of preovulatory follicles and the stromal cells were highly VEGF immunoreactive, however the Meloxicam treated Group 4 showed less immunoreactivity than Group 2 and Group 3 which indicated the correlation between Meloxicam and the diminished VEGF expression. Group 3 presented an increased COS-2 immunoreactivity which was highly diminished than in Group 4.

The research concluded that in a rat model, the enzyme Meloxicam has a beneficial effect on OHSS by reducing the increase of ovarian weight and the expression of VEGF associated with OHSS, the effects of which may be mediated by the inhibitory capacity of COX-2 on Meloxicam
|}

{|
|-bgcolor="FF99FF"
|
<span style="font-size:120%">'''Inhibition of Ovarian VEGF secretion by activation of Dopamine Receptor 2'''</span> <ref name="PMID25217874"><pubmed>25217874</pubmed></ref>

This research was carried out to investigate a possibility in whether a Dopamine Receptor 2 agonist '''(D2-ag)''' can assist in the prevention of Ovarian Hyperstimulation Syndrome, using rat models, by decreasing the ovarian vascular endothelial growth factor '''(VEGF)''' production. Using Immature Wistar rats (22 days old) as their animal model, the rats were initially stimulated with Gonadotrophins to mimic the onset and effects of OHSS and then subjected to treatment with a D2-agonist and/or a D2-antagonist (D2-ant). The vascular permeability was measured at the endpoint after day 26 by measuring the peritoneal extravasion of a previously injected dye and ovaries from all subjects were collected to assess the effects of D2-ag and D2-ant on the production of Ovarian VEGF. The expression of VEGF mRNA was measured by quantitative real time PCR and the levels of VEGF proteins were measured by Western Blots.

Results showed that the D2-ag caused a large reduction in the vascular permeability which was in turn associated with the great decreased in VEGF protein production in the OHSS rat ovaries, whereas the introduction of D2-ant showed opposite results with a increase in the vascular permeability leading to the increase of VEGF protein production in the ovaries. Ovarian VEGF mRNA levels were found to be unaffected by the introduction of these drugs in OHSS rat subjects. Conclusions were drawn on the fact that Dopamine Receptor 2 agonists prevent the increase of vascular permeability in subjects with OHSS by decreasing the ovarian production of VEGF and also that due to the dose-dependent inhibitory effect of the D2-ag on ovarian VEGF, current OHSS therapies used in humans can benefit by increasing the intraovarian concentration of D2-ag.
|}
</div>

==Glossary==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

'''Aromatase Inhibitor''' - A drug that inhibits enzyme aromatase, which in turn suppresses estrogen synthesis.

'''Ascites''' - An accumulation of fluid in the peritoneal cavity with resultant abdominal swelling.

'''Cabergoline''' - A dopamine receptor agonist used to treat hormone imbalance.

'''Controlled Ovarian Stimulation''' - female infertility treatment using medications to stimulate the ovaries to develop follicles.

'''Cryopreservation''' - Cooling and storing biological material at extremely low temperatures.

'''E2''' - Estradiol - Potent estrogen sex hormone.

'''FSH''' - Follicle Stimulating Hormone

'''Gonadotropin''' - Any hormone that has a stimulating effect on the gonads.

'''GnRH agonist''' - Gonadotropin Releasing Hormone - A class of compounds that mimic the effect of the natural Gonadotropin Releasing Hormone.

'''GnRH antagonist''' - Gonadotropin Releasing Hormone - A class of compounds that are similar in terms of the structure of natural Gonadotropin Releasing Hormone but has a antagonistic effect.

'''hCG'''- Human Chorionic Gonadotropin

'''Hemoconcentration''' - An increase in the concentration of circulating red blood cells in response to a decrease in blood plasma volume.

'''Hypovolemic''' - A decrease in circulating blood volume.

'''Iatrogenic''' - Illness caused as a result of a medical examination or treatment.

'''Intravenous fluids''' - Is the infusion of liquid substances directly into a vein.

'''IVF''' - In-vitro Fertilization

'''LH''' - Luteinizing Hormone

'''Metformin''' - A biguanide, antidiabetic drug used as an adjuvant to modify the effect of other agents.

'''NSAID''' - Non-steroidal Anti-Inflammatory Drug e.g. Ibuprofen

'''oocyte vitrification''' - technique for cryopreservation of oocytes.

'''OHSS''' - Ovarian Hyper-stimulation Syndrome

'''Oliguria'''- Decreased urine output/small amounts of urine produced.

'''P4''' - Progesterone - endogenous progestogen sex hormone.

'''PCOS''' - Polycystic Ovarian Syndrome. An endrocrine system disorder whereby the ovaries are enlarged with small collections of fluid.

</div>

==References==

2015 Group Project 2

2015-10-22T23:30:58Z

Z3372824: /* Risk factors */

{{ANAT2341Project2015header}}

==<span style="font-size:120%">'''Ovarian Hyper-stimulation Syndrome (OHSS)'''</span>==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

Ovarian Hyper stimulation Syndrome (OHSS) is an iatrogenic complication of '''Assisted Reproduction Technology''' (ART), in which women take medications to stimulate oocyte growth. It is generally identified by cystic enlargements of the ovaries and fluid accumulation in the peritoneal cavity due to the increased capillary permeability and ovarian neoangiogenesis <ref name="PMID22065820"><pubmed>22065820</pubmed></ref>. It is an occurrence which is dependent on the controlled stimulation of the ovaries in preparation for IVF i.e. administration of human Chorionic Gonadotropin (hCG).

OHSS was first described in 1943 as ''“syndrome d’hyperluteinisation massive
des ovaries”''. It was during this time that gonadotropins were prepared from animals such as sheep to bring on ovulation in women. The first recorded death as a result of OHSS occurred in 1951 and was due to renal failure as a result of oligouria, a complication of the syndrome <ref name="OHSS"> Marie M. Budev, DO, MPH; Alejandro C. Arroliga, MD; Tommaso Falcone, MD, [ http://utilis.net/Morning%20Topics/REI/Ovarian%20Hyperstimulation.pdf ], 'Ovarian Hyperstimulation Syndrome'</ref> <ref name="PMID12638783"><pubmed>12638783</pubmed></ref>.

<span style="color:#FA58D0">This wikipage aims to provide clear information on various areas surrounding OHSS such as diagnosis, prevention and complications and will look into the genetics behind the disorder and the various animals models used to research it.</span>

<html5media height="350" width="450">https://www.youtube.com/watch?v=aXmjJw234a4</html5media>

'''Overview of the Ovarian Hyperstimulation Syndrome''' <ref> Howcast (2013, August 27) Ovarian Hyperstimulation Syndrome | Infertility. Retrieved from https://www.youtube.com/watch?v=aXmjJw234a4</ref>

</div>

==Epidemiology==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

Ovarian Hyper-Stimulation Syndrome (OHSS) rarely occurs sporadically, and if it does, it is usually the result of an underlying genetic problem. The majority of OHSS is due to the ovaries being stimulated to mature and release an abundance of oocytes, in response to hormones Human Chorionic Gonadotropin (hCG) and Follicle Stimulating hormone (FSH), during IVF. Rarely, Clomifene Citrate therapy can cause OHSS.<ref name="WikiOHSS"> Wikipedia, [ https://en.wikipedia.org/wiki/Ovarian_hyperstimulation_syndrome ], 'Ovarian Hyperstimulation Syndrome'</ref>

OHSS only affects '''0.5-5%''' of women undergoing Ovarian Hyper-stimulation, but despite its small prevalence, it is a potentially fatal outcome of a non-vital procedure and remains a prevalent problem for fertility specialists <ref name="PMID12498425"><pubmed>12498425</pubmed></ref> <ref name="PMID12638783"><pubmed>12638783</pubmed></ref>. Age has been cited as a factor affecting those with OHSS, with younger women more at risk. Additionally, women with allergies were seen to have a higher incidence of OHSS. It is important to note that at this point in time, there is no positive correlation between gonadotropin dose and OHSS.

Of the 0.5-5% of women affected with OHSS mentioned above, 2% of those women will require hospitalisation. As of 2011, it has been reported that the incidence of OHSS was '''increasing''', resulting in approximately 3 deaths per 100,000 women undergoing ovarian stimulation per year <ref name="PMID21828116"><pubmed>21828116</pubmed></ref>. This is particularly worrying as in 2008, in the United States alone, there were around 150,000 IVF cycles undertaken.

{|
|-bgcolor="F8E0F1"
|
'''With the field of Assisted Reproductive Technologies expanding and more women partaking in IVF treatments, the threat of women developing OHSS is an ongoing and increasing one''' <ref name="PMID21828116" />.
|}
{| class="wikitable mw-collapsible mw-collapsed"
! Characteristics of women by complication group <ref name="PMID19591989"><pubmed>19591989</pubmed></ref>
|-
! scope="col" width="100px" height="60px" style="text-align:center| '''Characteristic'''
! scope="col" width="100px" height="60px" style="text-align:center| '''No Complications
(N = 212,041)'''
! scope="col" width="100px" height="60px" style="text-align:center| '''Moderate OHSS
(N = 1,523)'''
! scope="col" width="100px" height="60px" style="text-align:center| '''Severe OHSS
(N = 655)'''
|-
|style="text-align:center; background: #FF99FF;"| '''Maternal Age (Mean ± SD)'''
|style="text-align:center; background: #F6CEEC;"| 35.6 ± 4.6
|style="text-align:center; background: #F6CEEC;"| 33.0 ± 4.3
|style="text-align:center; background: #F6CEEC;"| 33.1 ± 4.4
|-
|style="text-align:center; background: #FF99FF;"| '''Maternal Age (%)'''
|-
|style="text-align:left; background: #F6CEEC;"| <30 years
|style="text-align:center; background: #F6CEEC;"| 10 %
|style="text-align:center; background: #F6CEEC;"| 21.1 %
|style="text-align:center; background: #F6CEEC;"| 20.6 %
|-
|style="text-align:left; background: #F6CEEC;"| 30-34 years
|style="text-align:center; background: #F6CEEC;"| 30.4 %
|style="text-align:center; background: #F6CEEC;"| 43.2 %
|style="text-align:center; background: #F6CEEC;"| 40.5 %
|-
|style="text-align:left; background: #F6CEEC;"| 35-39 years
|style="text-align:center; background: #F6CEEC;"| 37.8 %
|style="text-align:center; background: #F6CEEC;"| 27.2 %
|style="text-align:center; background: #F6CEEC;"| 32.5 %
|-
|style="text-align:left; background: #F6CEEC;"| >40 years
|style="text-align:center; background: #F6CEEC;"| 21.8 %
|style="text-align:center; background: #F6CEEC;"| 8.4 %
|style="text-align:center; background: #F6CEEC;"| 6.4 %
|-
|style="text-align:center; background: #FF99FF;"| '''Nulligravida (%)'''
|style="text-align:center; background: #F6CEEC;"| 45.8 %
|style="text-align:center; background: #F6CEEC;"| 51.5 %
|style="text-align:center; background: #F6CEEC;"| 51.8 %
|-
|style="text-align:center; background: #FF99FF;"| '''Infertility Diagnosis (%)'''
|-
|style="text-align:left; background: #F6CEEC;"| Male factor
|style="text-align:center; background: #F6CEEC;"| 37.7 %
|style="text-align:center; background: #F6CEEC;"| 41.0 %
|style="text-align:center; background: #F6CEEC;"| 33.4 %
|-
|style="text-align:left; background: #F6CEEC;"| Endometriosis
|style="text-align:center; background: #F6CEEC;"| 13.5 %
|style="text-align:center; background: #F6CEEC;"| 13.5 %
|style="text-align:center; background: #F6CEEC;"| 10.7 %
|-
|style="text-align:left; background: #F6CEEC;"| Ovulation Disorders
|style="text-align:center; background: #F6CEEC;"| 14.0 %
|style="text-align:center; background: #F6CEEC;"| 29.5 %
|style="text-align:center; background: #F6CEEC;"| 22.4 %
|-
|style="text-align:left; background: #F6CEEC;"| Diminished ovarian reserve
|style="text-align:center; background: #F6CEEC;"| 16.9 %
|style="text-align:center; background: #F6CEEC;"| 3.2 %
|style="text-align:center; background: #F6CEEC;"| 2.4 %
|-
|style="text-align:left; background: #F6CEEC;"| Tubal factors
|style="text-align:center; background: #F6CEEC;"| 20.4 %
|style="text-align:center; background: #F6CEEC;"| 22.6 %
|style="text-align:center; background: #F6CEEC;"| 22.3 %
|-
|style="text-align:left; background: #F6CEEC;"| Uterine factors
|style="text-align:center; background: #F6CEEC;"| 5.1 %
|style="text-align:center; background: #F6CEEC;"| 4.3 %
|style="text-align:center; background: #F6CEEC;"| 3.1 %
|-
|style="text-align:left; background: #F6CEEC;"| Other factors
|style="text-align:center; background: #F6CEEC;"| 13.9 %
|style="text-align:center; background: #F6CEEC;"| 13.1 %
|style="text-align:center; background: #F6CEEC;"| 10.4 %
|-
|style="text-align:left; background: #F6CEEC;"| Unexplained factor
|style="text-align:center; background: #F6CEEC;"| 12.7 %
|style="text-align:center; background: #F6CEEC;"| 11.8 %
|style="text-align:center; background: #F6CEEC;"| 18.6 %
|-
|}
</div>

==Causative Agents==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

[[File:Follicular Development.jpeg|right|thumbnail|500px|Infertility treatments aim to facilitate follicular development and induce ovulation to improve chances of fertilisation <ref name="PMID24717179"><pubmed>24717179</pubmed></ref>]]

Normally a woman produces one egg per month from the ovaries, which travel down the Fallopian tube to be fertilized or be released from the body. In cases where women have difficulty falling pregnant, they are given medication which help them to produce and release eggs (as shown in the diagram to the right), further increasing their chances of fertilization and pregnancy <ref><pubmed>19573285</pubmed></ref>. Ovarian Hyper stimulation Syndrome generally occurs during infertility treatments when the ovaries are overstimulated by the fertility medication which causes the ovaries to swell and leak fluids into the belly and abdomen. The prevalence of OHSS onset is linked with excessive number of follicle development in response to the administration of injectable Follicle Stimulating Hormones (FSH) followed by the '''Human Chorionic Gonadotrophins''' (hCG) which triggers the release of the oocytes <ref><pubmed>26190539</pubmed></ref>.

'''Follicle Stimulating Hormones''' (FSH) <ref name="PMID9020850"><pubmed>9020850</pubmed></ref> are glycoprotein hormones that are produced and secreted from the Anterior Pituitary gland into the bloodstream, which regulate the developmental, growth, maturation and the reproductive processes within the body. In females, the Follicle Stimulating Hormones initiates the stages of growth and development of immature ovarian follicles within the ovaries before the release of an egg from a follicle at ovulation. When FSH is administered to a patient who is suffering from infertility, the increase FSH levels affect the rate of development and production, in turn increasing the amount of follicles which are ready to be released during ovulation.

</div>

==Symptoms==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

OHSS is classified based on a criteria from mild, moderate and severe <ref name="WikiOHSS" />:

'''Mild Symptoms'''- abdominal bloating, minimal weight gain, nausea, diarrhoea and a feeling of fullness.

'''Moderate Symptoms'''- Substantial weight gain (on average 2 or more pounds a day), increased abdominal girth, darkend urine and excessive thirst in addition to the mild symptoms.

'''Severe Symptoms'''- In addition to the symptoms associated with Mild and Moderate OHSS, in severe OHSS, you see shortness of breath, calf and chest pains and pleural effusion.

<span style="font-size:100%">'''Classifications of Ovarian Hyper-stimulation Syndrome:'''</span> <ref name="PMID22065820"><pubmed>22065820</pubmed></ref>
{| class="wikitable" style="text-align:center
|-
! scope="col" width="70px"| '''Classification'''
! scope="col" width="650px"| '''Symptoms'''
|-
|style="text-align:center; background: #F6CEEC;"| '''Mild'''
|style="height: 60px; background: #F6CEEC;"| '''Grade 1''' - Abdominal distention and discomfort
'''Grade 2''' - Abdominal distention, discomfort with nausea, vomiting and/or diarrhea and ovarian enlargement from 5~12cm
|-
|style="text-align:center; background: #F8E0F1;"| '''Moderate'''
|style="height: 60px; background: #F8E0F1;"| '''Grade 3''' - All features of Mild OHSS with ultrasonographic evidence of ascites
|-
|style="text-align:center; background: #F6CEEC;"| '''Severe'''
|style="height: 60px; background: #F6CEEC;"| '''Grade 4''' - All features of Moderate OHSS with the addition of clinical evidence of ascites and breathing difficulties present
'''Grade 5''' - All of the above symptoms along with a change in the blood volume, increased blood viscosity due to coagulation and diminished renal function
|}

</div>

==Diagnosis==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

Whilst symptoms of OHSS can occur as soon as 24 hours post hCG administration, they are usually seen in women 7-10 days post administration. Initially women with OHSS will present with abdominal bloating, as a result of fluid in the peritoneal cavity and an increase in ovary size. When women present with severe OHSS they are often dehydrated, due to increased vascular permeability, and have hemoconcentration. The above results in a decrease in intravascular volume, leading to '''oligouria''' <ref name="PMID22416285" />.

===History===

Initially a thorough history of the patient is taken during which the clinician looks for evidence of ovarian stimulation, followed by ovulation. During this history taking, the clinician will inquire into any weight gain noticed, urine output, and the woman's ability to maintain oral hydration. A key diagnostic tool for clinicians regarding women who are taking gonadotropins is to identify if they are at an increased risk of developing OHSS. Some risk factors include woman aged less than 30, women who have polycystic ovaries, woman with a previous history of OHSS and women who have had greater than 20 oocytes retrieved <ref name="PMID22416285" />.

===Physical Exam===
[[File:Vaginal_Ultrasonography_in_Sagittal_Plane.jpg|right|thumbnail|600px|Vaginal Ultrasonography in Sagittal plane <ref name="Wikiversity Journal of Medicine"> Häggström, Mikael. "Medical gallery of Mikael Häggström 2014". Wikiversity Journal of Medicine 1 (2). DOI:10.15347/wjm/2014.008. ISSN 20018762</ref>]]
After a history of the patient is taken, the next step is to perform a physical exam on the patient. Women who present with abdominal bloating will produce a shifting dullness upon abdominal percussion. Additionally the clinician will test the woman's vital signs, measure her abdominal girth, weight and will look for evidence of ascites or increase in calf size (usually unilateral)<ref name="PMID22416285" />.

===Investigations===

If the clinician further suspects a women of having OHSS, various investigations can be done such as an ultrasound.The intraperitoneal fluid is best imaged via vaginal ultrasound due to the enlarged ovaries making it difficult to image the pelvis using transabdominal ultrasound. The clinician can also order laboratory testing to look for urine specific gravity and and complete blood count to look for hemoconcentration with a hematocrit. Additionally, liver function tests can be ordered to look for elevated function. The clinician will also look for evidence of elevated D-dimers and fibrinogen and decreased levels of anti-thrombin 3 <ref name="SAHealth"> Government of South Australia Health [ http://www.sahealth.sa.gov.au/wps/wcm/connect/9b61ed004ee5348da663afd150ce4f37/Ovarian-hyperstimulation-syndrome-WCHN-PPG-17072012.pdf?MOD=AJPERES&CACHEID=9b61ed004ee5348da663afd150ce4f37 ], 'South Australian Paediatric Clinical Guidelines OHSS'</ref>.

====Ultrasound====

Typical appearances of the ultrasound include <ref name="Ultrasound"> Radiopaedia [ http://radiopaedia.org/articles/ovarian-hyperstimulation-syndrome-1 ], 'Ovarian Hyperstimulation Syndrome'</ref>:

*Bilaterally and symmetrically enlarged ovaries (>12cm)
* "Spoke-Wheel appearance" - presence of multiple cysts of varying size
*May also see ascites (fluid)

===Severity===

Once a clinician has deduced a women is suffering from OHSS, the severity of their condition needs to be established as either mild, moderate or severe. This is done by referring to the criteria under the sub-heading [[Symptoms]].The subsequent course of treatment for the woman will be based upon this evaluation.

{|
|-bgcolor="F6CEEC"
|
'''Further investigations''' can be done including a Chest X-ray to check for pleural effusions and oedema and USS with Doppler's to check for ascites or possible ovary torsion. <ref name="PMID22416285"><pubmed>22416285</pubmed></ref>
|}

===Differential Diagnosis===

Conditions presenting with similar symptoms or ultrasound images include <ref name="Ultrasound" />:

*Polycystic Ovaries (PO)
:: The difference is that with PO is that the cycts are typically smaller than OHSS cysts and there is no evidence of ascited or pleural effusion
*Mucinous Ovarian Malignancy
:: A type of Ovarian Epithelial tumour
*Ectopic Pregnancy <ref name="Casereport"> Australian Medical Student Journal [ http://www.amsj.org/wpcontent/uploads/files/articles/amsj_v2_i1/AMSJ_v2_i1_pg58-60.pdf ], 'Ovarian hyperstimulation syndrome'</ref>
::A pregnancy in which the foetus develops outside of the uterus e.g. in the fallopian tube

</div>

==Pathophysiology==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

[[File:Pathogenesis_of_OHSS.png|600px|thumb|Pathogenesis of OHSS <ref name="PMID20416867"><pubmed>20416867</pubmed></ref>]]

The definition of Ovarian Stimulation is enlarged ovaries with many luteinized cysts, that can present with secondary complications. What distinguishes Ovarian Stimulation from OHSS is the presence of vascular hyper-permeability that results in fluids being redirected elsewhere in the body.

The key process to OHSS appears to be caused by '''Vascular Endothelial Growth Factor''' (VEGF), that is released along with other cytokines, estrogen and progesterone, due to the ovary undergoing luteinization as a result of stimulation by hCG. VEGF increases vascular permeability and as a result the capillaries become more "leaky" to the fluids in them. These fluids can then escape the capillaries and accumulate in the pleural and abdominal cavities as ascites. The woman then becomes hypovolemic and is at an increased risk of circulatory, renal and respiratory issues such as arterial thromboembolism due to the thickening of the blood. Note, the blood is thickened as fluid is leaving the capillaries, leaving behind red blood cells and other cellular components of the blood <ref name="WikiOHSS" />.

The increase in expression of VEGF and VEGF Receptor 2 (VEGFR2) is attributed to the greatly increased amount of their mRNA present in the body after stimulation with hCG <ref name="PMID21082502"><pubmed>21082502</pubmed></ref>. VEGF interacts with VEGF2 and VEGF Receptor 1 (VEGFR1) to create a strong angiogenic effect. Both VEGFR2 and VEGFR1 belong to a family of receptors called tyrosine kinases. VEGF2 is involved in the regulation of angiogenesis and vascular permeability whilst VEGF1 has a slightly contradictory role in that is is involved in the maintenance of the tight junctions between endothelial cells in blood vessels. A study by Gómez ''et. al.'' <ref name="PMID21082502" /> showed that women experiencing OHSS had substantially higher plasma levels of VEGF and lower levels of VEGFR1.

</div>

==Complications==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

Ovarian torsion or rupture, renal insufficiency and thrombophlebitis can all complicate OHSS. If a pregnancy occurs, symptoms may persist longer than the usual 1 to 2 weeks and become more severe, however, even with severe OHSS, they do not extend past the first trimester <ref name="WikiOHSS" />.

<span style="color:#FA58D0"> '''1-2% of women who undergo ovarian stimulation develop a severe form of OHSS''' </span>. Complications from severe OHSS include:

*Fluid collection in the abdomen
*Electrolyte disturbances (sodium and potassium)
*Kidney failure
*Ovary twisting
*Rupture of a cyst in an ovary
*Breathing problems
*Blood clots in large vessels (most commonly the legs)
*Pregnancy loss from miscarriage or termination
*Rarely, death

A study by Nouri ''et. al.'' <ref name="PMID24996451"><pubmed>24996451</pubmed></ref> found that women with '''Polycystic Ovarian Syndrome''' (PCOS) and those that were induced with hCG experienced longer recovery times from severe OHSS than women who were not pregnant. They looked at a cohort of women hospitalised for the first time with severe OHSS and subject them to the same treatments. Based on a defined criteria, they established the recovery time of these women and compared the times between those that were pregnant to those that were not pregnant. They also found that whether a woman had PCOS or ovulation induction did not affect her risk of developing OHSS if she was not pregnant. It is only a risk factor for pregnant women.

===Thromboembolic events===

A frequent and deadly complication of OHSS are thromboembolic events due to increased blood clotting. This increase in blood clotting has been attributed to a variety of complications such as hemoconcentration (which thickens the blood), hypovolemia and an increase in the permeability of blood vessels as a result of increased vasoactive substances in the body of ovarian origin. Thromboembolic events include venous thromboses often in the upper extremities and arterial thromboses such as those in the cerebrovascular region. These events can lead to amputations of extremities, brain damage, miscarriage and death. To avoid this, anti-coagulants are given to pateitns with OHSS and they are fitted with compression stockings (see [[Treatment]]) <ref name="PMID23378404"><pubmed>23378404</pubmed></ref>.

{|
|-bgcolor="F8E0F1"
|
The risk of a woman developing OHSS is higher if she is having a '''twin pregnancy''', as she is exposed to higher concentration of hCG. <ref name="PMID9756273"><pubmed>9756273</pubmed></ref>
|}

</div>

==Treatment==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

'''General treatment
'''
*''Acetaminophen'' with or without a narcotic agent- used to treat abdominal discomfort
*Women are encouraged to drink 2-3 litres of water a day to prevent hemoconcentration
*Women are advised to avoid sexual intercourse and vigorous exercise at the risk of torsion or rupture of the ovaries
*NSAID's with anti-platelet properties should NOT be used as they may effect renal function in a women with OHSS
*Patients with significantly painful ascites or breathing problems may undergo ''Paracentesis'' (drainage of the ascites)
*''Culdocentesis'' (extraction of fluid from recto-uterine pouch) can be done to decrease the likelihood of a woman with moderate OHSS progressing to severe OHSS.<ref name="PMID22416285" />

===Mild to Moderate OHSS===

Mild OHSS can often resolve on its own, however, moderate OHSS may include treatments such as<ref name="WikiOHSS" />:

*Anti-nausea medication and prescription painkillers
*Regular physical examinations and ultrasounds
*Daily weigh-ins and waist measurements
*Measuring the amount of urine produced each day
*Frequent blood tests for monitoring dehydration and electrolyte imbalance
*Maintaining a high balance of fluids
*Drainage of excess abdominal fluid by inserting a needle in the abdominal cavity
*Wearing support stockings which help prevent blood clots/thrombosis

===Severe OHSS===

Severe OHSS requires hospital care in order for constant monitoring and treatment such as <ref name="WikiOHSS" />:

*Intravenous fluids with a crystalloid solution (100-150mL/hr)
*Intravenous Albumin is administered is IV fluids are insufficient (15-20mL/hr of 25% albumin for 4 hrs)
*In addition to Acetaminophen, ''Opioid analgesics'' can be administered for pain relief
*''Antiemetics'' can be used to subside nauseas and/or vomiting
*Woman administered to hospital of OHSS are considered at high risk of thromboembolic complications and are given low molecular weight ''heparin'', an anti-coagulant
*''Cabergoline''- lessens OHSS symptoms
*''GnRH agonist''- suppresses ovarian activity
**If at risk of OHSS, alternates include using a GnRH agonist instead of hCG however its effects on pregnancy rates are questionable. Using a GnRH agonist to replace the use of hCG for final oocyte stimulation will see a 6% decrease in delivery rate.

*Daily monitoring of creatine, urea, creatine clearance C-reactive protein (to rule out infection) are all required in combination with weekly tests such as liver and renal function tests and chest x-rays (to check for pleural effusion) <ref name="PMID12638783" />.

If there are serious complications then additional treatments are required:

*Surgery for a ruptured ovarian cyst
*Intensive care for the liver or lung complications

====Paracentesis====

For women with severe/grade 3 OHSS, paracentesis, the removal of fluid from the body using an aspiration needle, can be undertaken. It is a diagnostic and a therapeutic method that can be done trans-abdominally and trans-vaginally. It is used to relieve symptoms, improve haemodynamics e.g. Urinary output, and shorten the women's hospital stay. Complications of paracentesis include bleeding, infection and organ injury, however are note common <ref name="Paracentesis"> S. Monica Soni, HMS 3, Gillian Lieberman, MD [ http://eradiology.bidmc.harvard.edu/LearningLab/genito/Soni.pdf ], 'Ovarian Hyperstimulation Syndrome'</ref>.

{|
|-bgcolor="F8E0F1"
|
The most important aspect of treatment for any women with OHSS is close and constant '''monitoring''' with her healthcare professional. Counselling may also be provided to women and their partners or families in order to provide them with the best possible knowledge base to manage and treat their OHSS. It is important to note that there is '''no one cure or treatment''' for OHSS. Treatment involves managing and eliminating the symptoms until such time as the syndrome resolves itself <ref name="WikiOHSS" />.
|}

</div>

==Prevention==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

There are three key avenues through which the incidence of OHSS may be prevented. These include identifying risk factors to predict OHSS development, modifying treatment regimes on the basis of the identified risk factors and intervention to prevent progression to OHSS once the patient has undergone '''Controlled Ovarian Stimulation''' (COS).

=== Risk factors===

'''Primary risk factors'''

Pre-existing factors likely to exacerbate the ovarian stimulation response. Primary risk factors include <ref name="PMID26074966"><pubmed>26074966</pubmed></ref>:

*Young age
*Low body weight
*History of elevated response to gonadotropins
*Polycystic Ovary Syndrome (PCOS)
*Isolated PCOS characteristic
*A previous history of OHSS.
*High pretreatment basal Anti-Mullerian Hormone concentration
*Large Antral Follicle Count

'''Secondary risk factors'''

Secondary risk factors involve the monitoring of ovarian response parameters once COS has been initiated. These parameters are monitored for <ref name="PMID19007627"><pubmed>19007627</pubmed></ref>:

*rapidly rising E2 levels
*E2 concentration larger than 2500 pg/mL
*large number of developing follicles (10-14mm) on the day hCG is administered
*large number of oocytes retrieved

These factors in combination, act as a predictive tool to assess the likelihood of severe OHSS development, with a 83% sensitivity and 84% specificity. <ref name="PMID19007627"/>

=== Primary Prevention===

Primary Prevention involves the modification of treatment regimens on the basis of OHSS risk classifications, in order to prevent OHSS occurrence.

'''Ovulation Induction'''

Unifollicular Ovulation Induction through Ovulation Induction (OI) is a primary means of avoiding OHSS in women with Polycystic Ovarian Syndrome, who are at an increased risk. In order to promote unifollicular development, the ovaries are stimulated with a low starting dose of FSH (75 IU).<ref name="PMID20416867"><pubmed>20416867</pubmed></ref> Studies suggests that a minimum gonadotropin dose lowers OHSS risk and thus a step-up regimen is utilised to achieve an ovarian response, whereby the FSH dosage is increased every 7 days until follicular development of greater than 10mm is noted.<ref name="PMID26074966" /> Alternatively, a step-down regimen may be followed, whereby a high initial FSH dosage is lowered according to the ovarian response. Another method to increase FSH levels during OI, is through '''Aromatase Inhibitors''' which promote folliculogenesis by increasing pituitary secretion of FSH, and downregulate oestrogen production through a negative feedback loop. However, Aromatase Inhibitors have not been shown to reduce OHSS incidence in comparison to other methods of OI.<ref name="PMID26074966" /> During OI, a key objective is to prevent early cycle cancellation due to premature luteinisation from pituitary secretion of LH. In order to downregulate LH secretion, Gonadotropin-releasing hormone agonists '''GnRHa''' are administered in addition to gonadotropins. Alternatively, '''GnRH antagonists''' may be administered to downregulate endogenous LH secretion. Comparative studies have shown that the GnRH antagonist protocol has a greater effect in lowering the incidence of mild to severe OHSS. However due to the rare nature of OHSS, and insufficient sample sizes, the difference was not found to be significant. <ref name="PMID21082508"><pubmed>21082508</pubmed></ref>. Generally, the duration of exposure to gonadotropins and subsequent risk of OHSS may be minimised through mild stimulation protocols which administer FSH only in the mid to late follicular phase.<ref name="PMID20416867" />

'''Adjuvant Metformin Therapy'''

Adjuvant Metformin Therapy has been found to lower the risk of OHSS by 63%.<ref name="PMID25406011"><pubmed>25406011</pubmed></ref> It involves the administration of metformin at a daily dosage of 1000 to 2000mg, 2 months prior to Controlled Ovarian Stimulation <ref name="PMID26074966"/>. Metformin lowers the elevated insulin levels in PCOS which consequently reduce intraovarian androgen levels. This leads to a reduced sensitivity and expression of granulosa cell-follicle stimulating hormone receptors which result in a less exaggerated response to gonadotropins. Furthermore, it is suggested that Metformin prevents OHSS by controlling vascular permeability through the inhibition of various vasoactive molecules, including VEGF.

'''Avoiding hCG during Luteal Phase Support

Following Controlled Ovarian Stimulation, the steroid levels of E2 and P4 are reduced during the luteal phase due to the negative feedback on the pituitary. This leads to low endogenous LH levels, which consequently reduce endometrial receptivity as well as the luteal phase duration itself. As a result, implantation and pregnancy rates are reduced and early pregnancy loss rates are increased.<ref name="PMID20416867" /> Luteal Phase Support (LPS) serves to combat these adverse events with the use of hCG. However, hCG has been found to increase the risk of OHSS. Alternatively, the use of progesterone has been found to not only halve the risk of OHSS, but also induce similar improvements in pregnancy and miscarriage rates as hCG.<ref name="PMID26148507"><pubmed>26148507</pubmed></ref>

===Secondary Prevention===

Secondary Prevention aims to prevent progression to OHSS once COS has been initiated and the patient has been found to mount an exaggerated response. <ref name="PMID20416867" />

'''Coasting'''

Coasting is a first-line secondary preventative strategy. It consists of the withdrawal of gonadotrophins when a critical number of follicles and/or E2 concentration is reached. hCG is administered once the E2 concentration reduces to a safe level, before the process of oocyte retrieval commences. This preventative strategy is conducted for a period of less than 3 days in order to avoid compromising IVF outcomes.

'''Cryopreservation'''

Cryopreservation of embryos after oocyte retrieval is another avenue which may avert OHSS progression. The cryopreserved embryos are only reimplanted once the patient's hormone serum levels have normalised. Using oocyte vitrification, crystal formation within embryo tissue is avoided and so cryopreserved embryos have been found to produce better pregnancy rates with a 32% increase, than fresh embryo transfer. Recent studies suggest cryopreservation itself does not reduce OHSS rates, but must be followed by a GnRHa trigger to avert OHSS.

'''Cycle cancellation'''

Cycle cancellation is a guaranteed method to prevent early OHSS whereby hCG is withheld. This is a last resort strategy as it carries the risk of significant psychological distress and financial loss for the patient.

</div>

==Effect on the Newborn==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

</div>
Women who develop OHSS while undergoing Assisted Reproductive Technologies (ART) treatment are not only more likely to achieve a pregnancy, but have a live birth as the pregnancy outcome. This live birth is also more likely to be a multiple birth of two, three or more children. <ref name="PMID19591989"><pubmed>19591989</pubmed></ref> It has been postulated that a multifetal pregnancy leads to a more rapid increase in hCG levels, resulting in an increased risk of OHSS. However, the causal nature between multifetal pregnancy and OHSS development is disputed and further research is required to distinguish correlation from causation. <ref name="PMID19573292"><pubmed>19573292</pubmed></ref>

OHSS development is also associated with an increased risk of adverse outcomes including stillbirth, premature birth and low birthweight.<ref name="PMID19591989" /> Although the cause for the increased risk in adverse pregnancy outcomes is unknown, it is suggested that as the incidence of OHSS is reduced through various prevention strategies, the risk of such outcomes may be also be reduced.

==Genetics==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

Despite OHSS typically being of iatrogenic origin as a result of ovarian stimulation with gonadotropins, research has been conducted into the potential genetics behind OHSS as many sporadic and familial cases have been observed. '''Mutations''' in the receptor for hormones such as Follicle Simulating Hormone (FSH), Lutenizing Hormone (LH) and hCG have all been targets of OHSS genetics research. Interestingly, they too also arise from a common ancestral gene.

===Follicle Stimulating Hormome===

Dr. Botros Rizk, of the University of South Alabama College of Medicine <ref name="PMID19573286"><pubmed>19573286</pubmed></ref>, has written extensively regarding the genetics behind OHSS. In particular, he talks about '''FSH receptors''' (FSHR) and their role in the syndrome. He hypothesises that mutations in these receptors could be activating or inactivating, leading to an increased risk of developing OHSS or sterility respectively. Currently, 744 single nucleotide polymorphisms (a type of mutation) have been found in the gene encoding the FSHR, 8 of which are located in its exons (coding regions of the gene). How the ovary responds is resultant on the FSHR genotype. For example, Ser680Asn, a polymorphism in the FSHR gene has been shown to aid in predicting the severity of a woman's OHSS. Ordinarily FSH stimulates the growth of ovarian follicles, however, when mutated, it is stimulated by the hCG resulting in excessive follicle development.

Spontaneous OHSS, OHSS that arises and cannot be attributed to any form of ovarian stimulation or Assisted Reproductive Technology, has been linked to activating mutations in the FSHR <ref name="PMID23499866"><pubmed>23499866</pubmed></ref>. This familial disorder is an autosomal dominant one. In most cases the FSHR can be stimulated by the presence of Thyroid Stimulating Hormone (TSH) or hCG, in the absence of FSH (the ligand for FSHR).

===Lutenizing Hormome===

The '''Lutenizing Hormone Receptor''' (LHR) gene in humans is comprised of 11 exons. Animal studies have shown that many primates exhibit a similar gene which is comprised of only 10 exons, however a gene lacking the 10th exon has been identified and termed the type 2 LHR. Expression of the type 2 LHR has been seen in humans. The type 2 LHR, compared to the wild-type LHR appears to be repaired with regard to its function. Defects in the type 2 LHR include a decrease in efficiency of transport to the plasma membrane and irregularities in signal transduction. Inactivating mutations in the LHR have been seen to cause infertility in women as well as amenorrhoea. Activating LHR gene mutations are asymptomatic and are not associated with OHSS in women.

===Bone Morphogenic Protein===

An imporant growth factor, derived from oocytes called '''BMP-15''' (Bone Morphogenic Protein 15) is vital for female fertility. It belongs to the family of growth factors, Transforming Growth Factor β (TGF-β) and is heavily involved in folliculogenesis. It has been found that mutations in the BMP-15 gene caused infertility in female sheep. Conversely, it has also been indicated in enhanced fertility when BMP-15 is present is high amounts in follicular fluid <ref name="PMID19573286" />.

A case study done by Hanevik ''et. al.'' in 2013 <ref name="PMID21565556"><pubmed>21565556</pubmed></ref> found that a Single Nuclear Polymorphism (SNP) in the BMP-15 gene is responsible for a high response to ovarian hyper-stimulation. The aim of the study was to test the effect the SNP had on BMP-15 with regard to high and low responders buy taking blood from 53 high responders, 38 low responders and 100 non-responders (controls) and analysing 5 noted SNP's. Results from their study showed a correlation between a high response to ovarian hyper-stimulation and the BMP-15 9G allele. The article does state however, that further research is required into the molecular effects of SNP's on the function of BMP-15.

===Vascular Endothelial Growth Factor===

'''Vascular endothelial growth factor''' (VEGF) has been indicated as one of the key agents causing vascular permeability and subsequent ascites in OHSS. The gene, which is located on chromosome 12, is made up of 8 exons (coding regions), of which exons 6 and 7 do not always appear due to the exons being spliced out.The splicing of this gene allows for various isoforms of the gene to exist of which VEGF 121 and 165 appear to play a role in angiogenesis. There are two VEGF Receptors, VEGFR-1 and VEGFR-2 that belong to the tyrosine kinase family of receptors (for more information on VEGF see [[Pathophysiology]]). Because of its distinct role in OHSS, it has been targeted as an area for research for potential treatments. The idea is that if the genetic expression of VEGF and its receptors can be controlled, OHSS can be avoided or treated.<ref name="PMID19573286" />

A different study by Hanevik ''et. al.'' , <ref name="PMID22587628"><pubmed>22587628</pubmed></ref> done in 2012 involved analysing blood samples from 53 women with OHSS and 100 women without it (controls) and analysing 6 SNP's in the VEGFR2 gene to find any genetic variations. They found a correlation between women with the VEGF +405cc genotype and the development of OHSS indicating women that undergo controlled ovarian hyper-stimulation and posses his genotype, are at an increased risk of developing OHSS.

</div>

== Current Research on Animal Models==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">
{|
|-bgcolor="F8E0F1"
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<span style="font-size:120%">'''Inhibition of Cyclooxygenase-2 (COX-2) by Meloxican decreasing the incidence of OHSS in Rat Model'''</span> <ref name="PMID18166186"><pubmed>18166186</pubmed></ref>

Reasearch was carried out to investigate the effects of selective inhibition of the enzyme COX-2 on the Ovarian Hyperstimulation Syndrome (OHSS) using Female Wistar rates as the subjects. The research aimed to find results by measuring the number of antral and luteinized follicles, ovarian weight, vascualr endothelial growth factors and COX-2 immunohistochemistry. The rats being tested were all 22 days old and were divided into four equal groups;

'''Group 1 (Control group)''' was subject to a 0.1 ml of Intraperitoneal Saline from days 22 ~ 26

'''Group 2 (Mildly-stimulated group)''' subject to 10IU of pregnant mare serum gonadotrophin (PMSG) on day 24 and then 10IU of Human Chorionic Gonadotrophin (hCG) on day 26

'''Group 3 (OHSS positive group)''' was subject to 10IU of PMSG from days 22 ~ 26 and then administered 30IU of hCG on day 26 to induce OHSS

'''Group 4 (OHSS positive variant group)''' received 15mg/ml of Meloxicam 2 hours prior to administration of 10IU PMSG from days 22 ~ 26

Results showed there was no difference in ovarian weight in samples from Group 1 and Group 2, however Group 3 showed signs of significant ovarian weight increase which in group 4 was suppressed by the introduction of Meloxicam. No differences were observed in the number of antral follicles amongst the four test groups. Results from Group 2 and Group 3 showed that the granulosa cells of preovulatory follicles and the stromal cells were highly VEGF immunoreactive, however the Meloxicam treated Group 4 showed less immunoreactivity than Group 2 and Group 3 which indicated the correlation between Meloxicam and the diminished VEGF expression. Group 3 presented an increased COS-2 immunoreactivity which was highly diminished than in Group 4.

The research concluded that in a rat model, the enzyme Meloxicam has a beneficial effect on OHSS by reducing the increase of ovarian weight and the expression of VEGF associated with OHSS, the effects of which may be mediated by the inhibitory capacity of COX-2 on Meloxicam
|}

{|
|-bgcolor="FF99FF"
|
<span style="font-size:120%">'''Inhibition of Ovarian VEGF secretion by activation of Dopamine Receptor 2'''</span> <ref name="PMID25217874"><pubmed>25217874</pubmed></ref>

This research was carried out to investigate a possibility in whether a Dopamine Receptor 2 agonist '''(D2-ag)''' can assist in the prevention of Ovarian Hyperstimulation Syndrome, using rat models, by decreasing the ovarian vascular endothelial growth factor '''(VEGF)''' production. Using Immature Wistar rats (22 days old) as their animal model, the rats were initially stimulated with Gonadotrophins to mimic the onset and effects of OHSS and then subjected to treatment with a D2-agonist and/or a D2-antagonist (D2-ant). The vascular permeability was measured at the endpoint after day 26 by measuring the peritoneal extravasion of a previously injected dye and ovaries from all subjects were collected to assess the effects of D2-ag and D2-ant on the production of Ovarian VEGF. The expression of VEGF mRNA was measured by quantitative real time PCR and the levels of VEGF proteins were measured by Western Blots.

Results showed that the D2-ag caused a large reduction in the vascular permeability which was in turn associated with the great decreased in VEGF protein production in the OHSS rat ovaries, whereas the introduction of D2-ant showed opposite results with a increase in the vascular permeability leading to the increase of VEGF protein production in the ovaries. Ovarian VEGF mRNA levels were found to be unaffected by the introduction of these drugs in OHSS rat subjects. Conclusions were drawn on the fact that Dopamine Receptor 2 agonists prevent the increase of vascular permeability in subjects with OHSS by decreasing the ovarian production of VEGF and also that due to the dose-dependent inhibitory effect of the D2-ag on ovarian VEGF, current OHSS therapies used in humans can benefit by increasing the intraovarian concentration of D2-ag.
|}
</div>

==Glossary==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

'''Aromatase Inhibitor''' - A drug that inhibits enzyme aromatase, which in turn suppresses estrogen synthesis.

'''Ascites''' - An accumulation of fluid in the peritoneal cavity with resultant abdominal swelling.

'''Cabergoline''' - A dopamine receptor agonist used to treat hormone imbalance.

'''Controlled Ovarian Stimulation''' - female infertility treatment using medications to stimulate the ovaries to develop follicles.

'''Cryopreservation''' - Cooling and storing biological material at extremely low temperatures.

'''E2''' - Estradiol - Potent estrogen sex hormone.

'''FSH''' - Follicle Stimulating Hormone

'''Gonadotropin''' - Any hormone that has a stimulating effect on the gonads.

'''GnRH agonist''' - Gonadotropin Releasing Hormone - A class of compounds that mimic the effect of the natural Gonadotropin Releasing Hormone.

'''GnRH antagonist''' - Gonadotropin Releasing Hormone - A class of compounds that are similar in terms of the structure of natural Gonadotropin Releasing Hormone but has a antagonistic effect.

'''hCG'''- Human Chorionic Gonadotropin

'''Hemoconcentration''' - An increase in the concentration of circulating red blood cells in response to a decrease in blood plasma volume.

'''Hypovolemic''' - A decrease in circulating blood volume.

'''Iatrogenic''' - Illness caused as a result of a medical examination or treatment.

'''Intravenous fluids''' - Is the infusion of liquid substances directly into a vein.

'''IVF''' - In-vitro Fertilization

'''LH''' - Luteinizing Hormone

'''Metformin''' - A biguanide, antidiabetic drug used as an adjuvant to modify the effect of other agents.

'''NSAID''' - Non-steroidal Anti-Inflammatory Drug e.g. Ibuprofen

'''oocyte vitrification''' - technique for cryopreservation of oocytes.

'''OHSS''' - Ovarian Hyper-stimulation Syndrome

'''Oliguria'''- Decreased urine output/small amounts of urine produced.

'''P4''' - Progesterone - endogenous progestogen sex hormone.

'''PCOS''' - Polycystic Ovarian Syndrome. An endrocrine system disorder whereby the ovaries are enlarged with small collections of fluid.

</div>

==References==

2015 Group Project 2

2015-10-22T23:30:14Z

Z3372824: /* Risk factors */

{{ANAT2341Project2015header}}

==<span style="font-size:120%">'''Ovarian Hyper-stimulation Syndrome (OHSS)'''</span>==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

Ovarian Hyper stimulation Syndrome (OHSS) is an iatrogenic complication of '''Assisted Reproduction Technology''' (ART), in which women take medications to stimulate oocyte growth. It is generally identified by cystic enlargements of the ovaries and fluid accumulation in the peritoneal cavity due to the increased capillary permeability and ovarian neoangiogenesis <ref name="PMID22065820"><pubmed>22065820</pubmed></ref>. It is an occurrence which is dependent on the controlled stimulation of the ovaries in preparation for IVF i.e. administration of human Chorionic Gonadotropin (hCG).

OHSS was first described in 1943 as ''“syndrome d’hyperluteinisation massive
des ovaries”''. It was during this time that gonadotropins were prepared from animals such as sheep to bring on ovulation in women. The first recorded death as a result of OHSS occurred in 1951 and was due to renal failure as a result of oligouria, a complication of the syndrome <ref name="OHSS"> Marie M. Budev, DO, MPH; Alejandro C. Arroliga, MD; Tommaso Falcone, MD, [ http://utilis.net/Morning%20Topics/REI/Ovarian%20Hyperstimulation.pdf ], 'Ovarian Hyperstimulation Syndrome'</ref> <ref name="PMID12638783"><pubmed>12638783</pubmed></ref>.

<span style="color:#FA58D0">This wikipage aims to provide clear information on various areas surrounding OHSS such as diagnosis, prevention and complications and will look into the genetics behind the disorder and the various animals models used to research it.</span>

<html5media height="350" width="450">https://www.youtube.com/watch?v=aXmjJw234a4</html5media>

'''Overview of the Ovarian Hyperstimulation Syndrome''' <ref> Howcast (2013, August 27) Ovarian Hyperstimulation Syndrome | Infertility. Retrieved from https://www.youtube.com/watch?v=aXmjJw234a4</ref>

</div>

==Epidemiology==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

Ovarian Hyper-Stimulation Syndrome (OHSS) rarely occurs sporadically, and if it does, it is usually the result of an underlying genetic problem. The majority of OHSS is due to the ovaries being stimulated to mature and release an abundance of oocytes, in response to hormones Human Chorionic Gonadotropin (hCG) and Follicle Stimulating hormone (FSH), during IVF. Rarely, Clomifene Citrate therapy can cause OHSS.<ref name="WikiOHSS"> Wikipedia, [ https://en.wikipedia.org/wiki/Ovarian_hyperstimulation_syndrome ], 'Ovarian Hyperstimulation Syndrome'</ref>

OHSS only affects '''0.5-5%''' of women undergoing Ovarian Hyper-stimulation, but despite its small prevalence, it is a potentially fatal outcome of a non-vital procedure and remains a prevalent problem for fertility specialists <ref name="PMID12498425"><pubmed>12498425</pubmed></ref> <ref name="PMID12638783"><pubmed>12638783</pubmed></ref>. Age has been cited as a factor affecting those with OHSS, with younger women more at risk. Additionally, women with allergies were seen to have a higher incidence of OHSS. It is important to note that at this point in time, there is no positive correlation between gonadotropin dose and OHSS.

Of the 0.5-5% of women affected with OHSS mentioned above, 2% of those women will require hospitalisation. As of 2011, it has been reported that the incidence of OHSS was '''increasing''', resulting in approximately 3 deaths per 100,000 women undergoing ovarian stimulation per year <ref name="PMID21828116"><pubmed>21828116</pubmed></ref>. This is particularly worrying as in 2008, in the United States alone, there were around 150,000 IVF cycles undertaken.

{|
|-bgcolor="F8E0F1"
|
'''With the field of Assisted Reproductive Technologies expanding and more women partaking in IVF treatments, the threat of women developing OHSS is an ongoing and increasing one''' <ref name="PMID21828116" />.
|}
{| class="wikitable mw-collapsible mw-collapsed"
! Characteristics of women by complication group <ref name="PMID19591989"><pubmed>19591989</pubmed></ref>
|-
! scope="col" width="100px" height="60px" style="text-align:center| '''Characteristic'''
! scope="col" width="100px" height="60px" style="text-align:center| '''No Complications
(N = 212,041)'''
! scope="col" width="100px" height="60px" style="text-align:center| '''Moderate OHSS
(N = 1,523)'''
! scope="col" width="100px" height="60px" style="text-align:center| '''Severe OHSS
(N = 655)'''
|-
|style="text-align:center; background: #FF99FF;"| '''Maternal Age (Mean ± SD)'''
|style="text-align:center; background: #F6CEEC;"| 35.6 ± 4.6
|style="text-align:center; background: #F6CEEC;"| 33.0 ± 4.3
|style="text-align:center; background: #F6CEEC;"| 33.1 ± 4.4
|-
|style="text-align:center; background: #FF99FF;"| '''Maternal Age (%)'''
|-
|style="text-align:left; background: #F6CEEC;"| <30 years
|style="text-align:center; background: #F6CEEC;"| 10 %
|style="text-align:center; background: #F6CEEC;"| 21.1 %
|style="text-align:center; background: #F6CEEC;"| 20.6 %
|-
|style="text-align:left; background: #F6CEEC;"| 30-34 years
|style="text-align:center; background: #F6CEEC;"| 30.4 %
|style="text-align:center; background: #F6CEEC;"| 43.2 %
|style="text-align:center; background: #F6CEEC;"| 40.5 %
|-
|style="text-align:left; background: #F6CEEC;"| 35-39 years
|style="text-align:center; background: #F6CEEC;"| 37.8 %
|style="text-align:center; background: #F6CEEC;"| 27.2 %
|style="text-align:center; background: #F6CEEC;"| 32.5 %
|-
|style="text-align:left; background: #F6CEEC;"| >40 years
|style="text-align:center; background: #F6CEEC;"| 21.8 %
|style="text-align:center; background: #F6CEEC;"| 8.4 %
|style="text-align:center; background: #F6CEEC;"| 6.4 %
|-
|style="text-align:center; background: #FF99FF;"| '''Nulligravida (%)'''
|style="text-align:center; background: #F6CEEC;"| 45.8 %
|style="text-align:center; background: #F6CEEC;"| 51.5 %
|style="text-align:center; background: #F6CEEC;"| 51.8 %
|-
|style="text-align:center; background: #FF99FF;"| '''Infertility Diagnosis (%)'''
|-
|style="text-align:left; background: #F6CEEC;"| Male factor
|style="text-align:center; background: #F6CEEC;"| 37.7 %
|style="text-align:center; background: #F6CEEC;"| 41.0 %
|style="text-align:center; background: #F6CEEC;"| 33.4 %
|-
|style="text-align:left; background: #F6CEEC;"| Endometriosis
|style="text-align:center; background: #F6CEEC;"| 13.5 %
|style="text-align:center; background: #F6CEEC;"| 13.5 %
|style="text-align:center; background: #F6CEEC;"| 10.7 %
|-
|style="text-align:left; background: #F6CEEC;"| Ovulation Disorders
|style="text-align:center; background: #F6CEEC;"| 14.0 %
|style="text-align:center; background: #F6CEEC;"| 29.5 %
|style="text-align:center; background: #F6CEEC;"| 22.4 %
|-
|style="text-align:left; background: #F6CEEC;"| Diminished ovarian reserve
|style="text-align:center; background: #F6CEEC;"| 16.9 %
|style="text-align:center; background: #F6CEEC;"| 3.2 %
|style="text-align:center; background: #F6CEEC;"| 2.4 %
|-
|style="text-align:left; background: #F6CEEC;"| Tubal factors
|style="text-align:center; background: #F6CEEC;"| 20.4 %
|style="text-align:center; background: #F6CEEC;"| 22.6 %
|style="text-align:center; background: #F6CEEC;"| 22.3 %
|-
|style="text-align:left; background: #F6CEEC;"| Uterine factors
|style="text-align:center; background: #F6CEEC;"| 5.1 %
|style="text-align:center; background: #F6CEEC;"| 4.3 %
|style="text-align:center; background: #F6CEEC;"| 3.1 %
|-
|style="text-align:left; background: #F6CEEC;"| Other factors
|style="text-align:center; background: #F6CEEC;"| 13.9 %
|style="text-align:center; background: #F6CEEC;"| 13.1 %
|style="text-align:center; background: #F6CEEC;"| 10.4 %
|-
|style="text-align:left; background: #F6CEEC;"| Unexplained factor
|style="text-align:center; background: #F6CEEC;"| 12.7 %
|style="text-align:center; background: #F6CEEC;"| 11.8 %
|style="text-align:center; background: #F6CEEC;"| 18.6 %
|-
|}
</div>

==Causative Agents==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

[[File:Follicular Development.jpeg|right|thumbnail|500px|Infertility treatments aim to facilitate follicular development and induce ovulation to improve chances of fertilisation <ref name="PMID24717179"><pubmed>24717179</pubmed></ref>]]

Normally a woman produces one egg per month from the ovaries, which travel down the Fallopian tube to be fertilized or be released from the body. In cases where women have difficulty falling pregnant, they are given medication which help them to produce and release eggs (as shown in the diagram to the right), further increasing their chances of fertilization and pregnancy <ref><pubmed>19573285</pubmed></ref>. Ovarian Hyper stimulation Syndrome generally occurs during infertility treatments when the ovaries are overstimulated by the fertility medication which causes the ovaries to swell and leak fluids into the belly and abdomen. The prevalence of OHSS onset is linked with excessive number of follicle development in response to the administration of injectable Follicle Stimulating Hormones (FSH) followed by the '''Human Chorionic Gonadotrophins''' (hCG) which triggers the release of the oocytes <ref><pubmed>26190539</pubmed></ref>.

'''Follicle Stimulating Hormones''' (FSH) <ref name="PMID9020850"><pubmed>9020850</pubmed></ref> are glycoprotein hormones that are produced and secreted from the Anterior Pituitary gland into the bloodstream, which regulate the developmental, growth, maturation and the reproductive processes within the body. In females, the Follicle Stimulating Hormones initiates the stages of growth and development of immature ovarian follicles within the ovaries before the release of an egg from a follicle at ovulation. When FSH is administered to a patient who is suffering from infertility, the increase FSH levels affect the rate of development and production, in turn increasing the amount of follicles which are ready to be released during ovulation.

</div>

==Symptoms==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

OHSS is classified based on a criteria from mild, moderate and severe <ref name="WikiOHSS" />:

'''Mild Symptoms'''- abdominal bloating, minimal weight gain, nausea, diarrhoea and a feeling of fullness.

'''Moderate Symptoms'''- Substantial weight gain (on average 2 or more pounds a day), increased abdominal girth, darkend urine and excessive thirst in addition to the mild symptoms.

'''Severe Symptoms'''- In addition to the symptoms associated with Mild and Moderate OHSS, in severe OHSS, you see shortness of breath, calf and chest pains and pleural effusion.

<span style="font-size:100%">'''Classifications of Ovarian Hyper-stimulation Syndrome:'''</span> <ref name="PMID22065820"><pubmed>22065820</pubmed></ref>
{| class="wikitable" style="text-align:center
|-
! scope="col" width="70px"| '''Classification'''
! scope="col" width="650px"| '''Symptoms'''
|-
|style="text-align:center; background: #F6CEEC;"| '''Mild'''
|style="height: 60px; background: #F6CEEC;"| '''Grade 1''' - Abdominal distention and discomfort
'''Grade 2''' - Abdominal distention, discomfort with nausea, vomiting and/or diarrhea and ovarian enlargement from 5~12cm
|-
|style="text-align:center; background: #F8E0F1;"| '''Moderate'''
|style="height: 60px; background: #F8E0F1;"| '''Grade 3''' - All features of Mild OHSS with ultrasonographic evidence of ascites
|-
|style="text-align:center; background: #F6CEEC;"| '''Severe'''
|style="height: 60px; background: #F6CEEC;"| '''Grade 4''' - All features of Moderate OHSS with the addition of clinical evidence of ascites and breathing difficulties present
'''Grade 5''' - All of the above symptoms along with a change in the blood volume, increased blood viscosity due to coagulation and diminished renal function
|}

</div>

==Diagnosis==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

Whilst symptoms of OHSS can occur as soon as 24 hours post hCG administration, they are usually seen in women 7-10 days post administration. Initially women with OHSS will present with abdominal bloating, as a result of fluid in the peritoneal cavity and an increase in ovary size. When women present with severe OHSS they are often dehydrated, due to increased vascular permeability, and have hemoconcentration. The above results in a decrease in intravascular volume, leading to '''oligouria''' <ref name="PMID22416285" />.

===History===

Initially a thorough history of the patient is taken during which the clinician looks for evidence of ovarian stimulation, followed by ovulation. During this history taking, the clinician will inquire into any weight gain noticed, urine output, and the woman's ability to maintain oral hydration. A key diagnostic tool for clinicians regarding women who are taking gonadotropins is to identify if they are at an increased risk of developing OHSS. Some risk factors include woman aged less than 30, women who have polycystic ovaries, woman with a previous history of OHSS and women who have had greater than 20 oocytes retrieved <ref name="PMID22416285" />.

===Physical Exam===
[[File:Vaginal_Ultrasonography_in_Sagittal_Plane.jpg|right|thumbnail|600px|Vaginal Ultrasonography in Sagittal plane <ref name="Wikiversity Journal of Medicine"> Häggström, Mikael. "Medical gallery of Mikael Häggström 2014". Wikiversity Journal of Medicine 1 (2). DOI:10.15347/wjm/2014.008. ISSN 20018762</ref>]]
After a history of the patient is taken, the next step is to perform a physical exam on the patient. Women who present with abdominal bloating will produce a shifting dullness upon abdominal percussion. Additionally the clinician will test the woman's vital signs, measure her abdominal girth, weight and will look for evidence of ascites or increase in calf size (usually unilateral)<ref name="PMID22416285" />.

===Investigations===

If the clinician further suspects a women of having OHSS, various investigations can be done such as an ultrasound.The intraperitoneal fluid is best imaged via vaginal ultrasound due to the enlarged ovaries making it difficult to image the pelvis using transabdominal ultrasound. The clinician can also order laboratory testing to look for urine specific gravity and and complete blood count to look for hemoconcentration with a hematocrit. Additionally, liver function tests can be ordered to look for elevated function. The clinician will also look for evidence of elevated D-dimers and fibrinogen and decreased levels of anti-thrombin 3 <ref name="SAHealth"> Government of South Australia Health [ http://www.sahealth.sa.gov.au/wps/wcm/connect/9b61ed004ee5348da663afd150ce4f37/Ovarian-hyperstimulation-syndrome-WCHN-PPG-17072012.pdf?MOD=AJPERES&CACHEID=9b61ed004ee5348da663afd150ce4f37 ], 'South Australian Paediatric Clinical Guidelines OHSS'</ref>.

====Ultrasound====

Typical appearances of the ultrasound include <ref name="Ultrasound"> Radiopaedia [ http://radiopaedia.org/articles/ovarian-hyperstimulation-syndrome-1 ], 'Ovarian Hyperstimulation Syndrome'</ref>:

*Bilaterally and symmetrically enlarged ovaries (>12cm)
* "Spoke-Wheel appearance" - presence of multiple cysts of varying size
*May also see ascites (fluid)

===Severity===

Once a clinician has deduced a women is suffering from OHSS, the severity of their condition needs to be established as either mild, moderate or severe. This is done by referring to the criteria under the sub-heading [[Symptoms]].The subsequent course of treatment for the woman will be based upon this evaluation.

{|
|-bgcolor="F6CEEC"
|
'''Further investigations''' can be done including a Chest X-ray to check for pleural effusions and oedema and USS with Doppler's to check for ascites or possible ovary torsion. <ref name="PMID22416285"><pubmed>22416285</pubmed></ref>
|}

===Differential Diagnosis===

Conditions presenting with similar symptoms or ultrasound images include <ref name="Ultrasound" />:

*Polycystic Ovaries (PO)
:: The difference is that with PO is that the cycts are typically smaller than OHSS cysts and there is no evidence of ascited or pleural effusion
*Mucinous Ovarian Malignancy
:: A type of Ovarian Epithelial tumour
*Ectopic Pregnancy <ref name="Casereport"> Australian Medical Student Journal [ http://www.amsj.org/wpcontent/uploads/files/articles/amsj_v2_i1/AMSJ_v2_i1_pg58-60.pdf ], 'Ovarian hyperstimulation syndrome'</ref>
::A pregnancy in which the foetus develops outside of the uterus e.g. in the fallopian tube

</div>

==Pathophysiology==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

[[File:Pathogenesis_of_OHSS.png|600px|thumb|Pathogenesis of OHSS <ref name="PMID20416867"><pubmed>20416867</pubmed></ref>]]

The definition of Ovarian Stimulation is enlarged ovaries with many luteinized cysts, that can present with secondary complications. What distinguishes Ovarian Stimulation from OHSS is the presence of vascular hyper-permeability that results in fluids being redirected elsewhere in the body.

The key process to OHSS appears to be caused by '''Vascular Endothelial Growth Factor''' (VEGF), that is released along with other cytokines, estrogen and progesterone, due to the ovary undergoing luteinization as a result of stimulation by hCG. VEGF increases vascular permeability and as a result the capillaries become more "leaky" to the fluids in them. These fluids can then escape the capillaries and accumulate in the pleural and abdominal cavities as ascites. The woman then becomes hypovolemic and is at an increased risk of circulatory, renal and respiratory issues such as arterial thromboembolism due to the thickening of the blood. Note, the blood is thickened as fluid is leaving the capillaries, leaving behind red blood cells and other cellular components of the blood <ref name="WikiOHSS" />.

The increase in expression of VEGF and VEGF Receptor 2 (VEGFR2) is attributed to the greatly increased amount of their mRNA present in the body after stimulation with hCG <ref name="PMID21082502"><pubmed>21082502</pubmed></ref>. VEGF interacts with VEGF2 and VEGF Receptor 1 (VEGFR1) to create a strong angiogenic effect. Both VEGFR2 and VEGFR1 belong to a family of receptors called tyrosine kinases. VEGF2 is involved in the regulation of angiogenesis and vascular permeability whilst VEGF1 has a slightly contradictory role in that is is involved in the maintenance of the tight junctions between endothelial cells in blood vessels. A study by Gómez ''et. al.'' <ref name="PMID21082502" /> showed that women experiencing OHSS had substantially higher plasma levels of VEGF and lower levels of VEGFR1.

</div>

==Complications==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

Ovarian torsion or rupture, renal insufficiency and thrombophlebitis can all complicate OHSS. If a pregnancy occurs, symptoms may persist longer than the usual 1 to 2 weeks and become more severe, however, even with severe OHSS, they do not extend past the first trimester <ref name="WikiOHSS" />.

<span style="color:#FA58D0"> '''1-2% of women who undergo ovarian stimulation develop a severe form of OHSS''' </span>. Complications from severe OHSS include:

*Fluid collection in the abdomen
*Electrolyte disturbances (sodium and potassium)
*Kidney failure
*Ovary twisting
*Rupture of a cyst in an ovary
*Breathing problems
*Blood clots in large vessels (most commonly the legs)
*Pregnancy loss from miscarriage or termination
*Rarely, death

A study by Nouri ''et. al.'' <ref name="PMID24996451"><pubmed>24996451</pubmed></ref> found that women with '''Polycystic Ovarian Syndrome''' (PCOS) and those that were induced with hCG experienced longer recovery times from severe OHSS than women who were not pregnant. They looked at a cohort of women hospitalised for the first time with severe OHSS and subject them to the same treatments. Based on a defined criteria, they established the recovery time of these women and compared the times between those that were pregnant to those that were not pregnant. They also found that whether a woman had PCOS or ovulation induction did not affect her risk of developing OHSS if she was not pregnant. It is only a risk factor for pregnant women.

===Thromboembolic events===

A frequent and deadly complication of OHSS are thromboembolic events due to increased blood clotting. This increase in blood clotting has been attributed to a variety of complications such as hemoconcentration (which thickens the blood), hypovolemia and an increase in the permeability of blood vessels as a result of increased vasoactive substances in the body of ovarian origin. Thromboembolic events include venous thromboses often in the upper extremities and arterial thromboses such as those in the cerebrovascular region. These events can lead to amputations of extremities, brain damage, miscarriage and death. To avoid this, anti-coagulants are given to pateitns with OHSS and they are fitted with compression stockings (see [[Treatment]]) <ref name="PMID23378404"><pubmed>23378404</pubmed></ref>.

{|
|-bgcolor="F8E0F1"
|
The risk of a woman developing OHSS is higher if she is having a '''twin pregnancy''', as she is exposed to higher concentration of hCG. <ref name="PMID9756273"><pubmed>9756273</pubmed></ref>
|}

</div>

==Treatment==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

'''General treatment
'''
*''Acetaminophen'' with or without a narcotic agent- used to treat abdominal discomfort
*Women are encouraged to drink 2-3 litres of water a day to prevent hemoconcentration
*Women are advised to avoid sexual intercourse and vigorous exercise at the risk of torsion or rupture of the ovaries
*NSAID's with anti-platelet properties should NOT be used as they may effect renal function in a women with OHSS
*Patients with significantly painful ascites or breathing problems may undergo ''Paracentesis'' (drainage of the ascites)
*''Culdocentesis'' (extraction of fluid from recto-uterine pouch) can be done to decrease the likelihood of a woman with moderate OHSS progressing to severe OHSS.<ref name="PMID22416285" />

===Mild to Moderate OHSS===

Mild OHSS can often resolve on its own, however, moderate OHSS may include treatments such as<ref name="WikiOHSS" />:

*Anti-nausea medication and prescription painkillers
*Regular physical examinations and ultrasounds
*Daily weigh-ins and waist measurements
*Measuring the amount of urine produced each day
*Frequent blood tests for monitoring dehydration and electrolyte imbalance
*Maintaining a high balance of fluids
*Drainage of excess abdominal fluid by inserting a needle in the abdominal cavity
*Wearing support stockings which help prevent blood clots/thrombosis

===Severe OHSS===

Severe OHSS requires hospital care in order for constant monitoring and treatment such as <ref name="WikiOHSS" />:

*Intravenous fluids with a crystalloid solution (100-150mL/hr)
*Intravenous Albumin is administered is IV fluids are insufficient (15-20mL/hr of 25% albumin for 4 hrs)
*In addition to Acetaminophen, ''Opioid analgesics'' can be administered for pain relief
*''Antiemetics'' can be used to subside nauseas and/or vomiting
*Woman administered to hospital of OHSS are considered at high risk of thromboembolic complications and are given low molecular weight ''heparin'', an anti-coagulant
*''Cabergoline''- lessens OHSS symptoms
*''GnRH agonist''- suppresses ovarian activity
**If at risk of OHSS, alternates include using a GnRH agonist instead of hCG however its effects on pregnancy rates are questionable. Using a GnRH agonist to replace the use of hCG for final oocyte stimulation will see a 6% decrease in delivery rate.

*Daily monitoring of creatine, urea, creatine clearance C-reactive protein (to rule out infection) are all required in combination with weekly tests such as liver and renal function tests and chest x-rays (to check for pleural effusion) <ref name="PMID12638783" />.

If there are serious complications then additional treatments are required:

*Surgery for a ruptured ovarian cyst
*Intensive care for the liver or lung complications

====Paracentesis====

For women with severe/grade 3 OHSS, paracentesis, the removal of fluid from the body using an aspiration needle, can be undertaken. It is a diagnostic and a therapeutic method that can be done trans-abdominally and trans-vaginally. It is used to relieve symptoms, improve haemodynamics e.g. Urinary output, and shorten the women's hospital stay. Complications of paracentesis include bleeding, infection and organ injury, however are note common <ref name="Paracentesis"> S. Monica Soni, HMS 3, Gillian Lieberman, MD [ http://eradiology.bidmc.harvard.edu/LearningLab/genito/Soni.pdf ], 'Ovarian Hyperstimulation Syndrome'</ref>.

{|
|-bgcolor="F8E0F1"
|
The most important aspect of treatment for any women with OHSS is close and constant '''monitoring''' with her healthcare professional. Counselling may also be provided to women and their partners or families in order to provide them with the best possible knowledge base to manage and treat their OHSS. It is important to note that there is '''no one cure or treatment''' for OHSS. Treatment involves managing and eliminating the symptoms until such time as the syndrome resolves itself <ref name="WikiOHSS" />.
|}

</div>

==Prevention==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

There are three key avenues through which the incidence of OHSS may be prevented. These include identifying risk factors to predict OHSS development, modifying treatment regimes on the basis of the identified risk factors and intervention to prevent progression to OHSS once the patient has undergone '''Controlled Ovarian Stimulation''' (COS).

=== Risk factors===

'''Primary risk factors'''

Pre-existing factors likely to exacerbate the ovarian stimulation response. Primary risk factors include <ref name="PMID26074966"><pubmed>26074966</pubmed></ref>:

*Young age
*Low body weight
*History of elevated response to gonadotropins
*Polycystic Ovary Syndrome (PCOS)
*Isolated PCOS characteristic
*A previous history of OHSS.
*High pretreatment basal Anti-Mullerian Hormone concentration
*large Antral Follicle Count

'''Secondary risk factors'''

Secondary risk factors involve the monitoring of ovarian response parameters once COS has been initiated. These parameters are monitored for <ref name="PMID19007627"><pubmed>19007627</pubmed></ref>:

*rapidly rising E2 levels
*E2 concentration larger than 2500 pg/mL
*large number of developing follicles (10-14mm) on the day hCG is administered
*large number of oocytes retrieved

These factors in combination, act as a predictive tool to assess the likelihood of severe OHSS development, with a 83% sensitivity and 84% specificity. <ref name="PMID19007627"/>

=== Primary Prevention===

Primary Prevention involves the modification of treatment regimens on the basis of OHSS risk classifications, in order to prevent OHSS occurrence.

'''Ovulation Induction'''

Unifollicular Ovulation Induction through Ovulation Induction (OI) is a primary means of avoiding OHSS in women with Polycystic Ovarian Syndrome, who are at an increased risk. In order to promote unifollicular development, the ovaries are stimulated with a low starting dose of FSH (75 IU).<ref name="PMID20416867"><pubmed>20416867</pubmed></ref> Studies suggests that a minimum gonadotropin dose lowers OHSS risk and thus a step-up regimen is utilised to achieve an ovarian response, whereby the FSH dosage is increased every 7 days until follicular development of greater than 10mm is noted.<ref name="PMID26074966" /> Alternatively, a step-down regimen may be followed, whereby a high initial FSH dosage is lowered according to the ovarian response. Another method to increase FSH levels during OI, is through '''Aromatase Inhibitors''' which promote folliculogenesis by increasing pituitary secretion of FSH, and downregulate oestrogen production through a negative feedback loop. However, Aromatase Inhibitors have not been shown to reduce OHSS incidence in comparison to other methods of OI.<ref name="PMID26074966" /> During OI, a key objective is to prevent early cycle cancellation due to premature luteinisation from pituitary secretion of LH. In order to downregulate LH secretion, Gonadotropin-releasing hormone agonists '''GnRHa''' are administered in addition to gonadotropins. Alternatively, '''GnRH antagonists''' may be administered to downregulate endogenous LH secretion. Comparative studies have shown that the GnRH antagonist protocol has a greater effect in lowering the incidence of mild to severe OHSS. However due to the rare nature of OHSS, and insufficient sample sizes, the difference was not found to be significant. <ref name="PMID21082508"><pubmed>21082508</pubmed></ref>. Generally, the duration of exposure to gonadotropins and subsequent risk of OHSS may be minimised through mild stimulation protocols which administer FSH only in the mid to late follicular phase.<ref name="PMID20416867" />

'''Adjuvant Metformin Therapy'''

Adjuvant Metformin Therapy has been found to lower the risk of OHSS by 63%.<ref name="PMID25406011"><pubmed>25406011</pubmed></ref> It involves the administration of metformin at a daily dosage of 1000 to 2000mg, 2 months prior to Controlled Ovarian Stimulation <ref name="PMID26074966"/>. Metformin lowers the elevated insulin levels in PCOS which consequently reduce intraovarian androgen levels. This leads to a reduced sensitivity and expression of granulosa cell-follicle stimulating hormone receptors which result in a less exaggerated response to gonadotropins. Furthermore, it is suggested that Metformin prevents OHSS by controlling vascular permeability through the inhibition of various vasoactive molecules, including VEGF.

'''Avoiding hCG during Luteal Phase Support

Following Controlled Ovarian Stimulation, the steroid levels of E2 and P4 are reduced during the luteal phase due to the negative feedback on the pituitary. This leads to low endogenous LH levels, which consequently reduce endometrial receptivity as well as the luteal phase duration itself. As a result, implantation and pregnancy rates are reduced and early pregnancy loss rates are increased.<ref name="PMID20416867" /> Luteal Phase Support (LPS) serves to combat these adverse events with the use of hCG. However, hCG has been found to increase the risk of OHSS. Alternatively, the use of progesterone has been found to not only halve the risk of OHSS, but also induce similar improvements in pregnancy and miscarriage rates as hCG.<ref name="PMID26148507"><pubmed>26148507</pubmed></ref>

===Secondary Prevention===

Secondary Prevention aims to prevent progression to OHSS once COS has been initiated and the patient has been found to mount an exaggerated response. <ref name="PMID20416867" />

'''Coasting'''

Coasting is a first-line secondary preventative strategy. It consists of the withdrawal of gonadotrophins when a critical number of follicles and/or E2 concentration is reached. hCG is administered once the E2 concentration reduces to a safe level, before the process of oocyte retrieval commences. This preventative strategy is conducted for a period of less than 3 days in order to avoid compromising IVF outcomes.

'''Cryopreservation'''

Cryopreservation of embryos after oocyte retrieval is another avenue which may avert OHSS progression. The cryopreserved embryos are only reimplanted once the patient's hormone serum levels have normalised. Using oocyte vitrification, crystal formation within embryo tissue is avoided and so cryopreserved embryos have been found to produce better pregnancy rates with a 32% increase, than fresh embryo transfer. Recent studies suggest cryopreservation itself does not reduce OHSS rates, but must be followed by a GnRHa trigger to avert OHSS.

'''Cycle cancellation'''

Cycle cancellation is a guaranteed method to prevent early OHSS whereby hCG is withheld. This is a last resort strategy as it carries the risk of significant psychological distress and financial loss for the patient.

</div>

==Effect on the Newborn==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

</div>
Women who develop OHSS while undergoing Assisted Reproductive Technologies (ART) treatment are not only more likely to achieve a pregnancy, but have a live birth as the pregnancy outcome. This live birth is also more likely to be a multiple birth of two, three or more children. <ref name="PMID19591989"><pubmed>19591989</pubmed></ref> It has been postulated that a multifetal pregnancy leads to a more rapid increase in hCG levels, resulting in an increased risk of OHSS. However, the causal nature between multifetal pregnancy and OHSS development is disputed and further research is required to distinguish correlation from causation. <ref name="PMID19573292"><pubmed>19573292</pubmed></ref>

OHSS development is also associated with an increased risk of adverse outcomes including stillbirth, premature birth and low birthweight.<ref name="PMID19591989" /> Although the cause for the increased risk in adverse pregnancy outcomes is unknown, it is suggested that as the incidence of OHSS is reduced through various prevention strategies, the risk of such outcomes may be also be reduced.

==Genetics==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

Despite OHSS typically being of iatrogenic origin as a result of ovarian stimulation with gonadotropins, research has been conducted into the potential genetics behind OHSS as many sporadic and familial cases have been observed. '''Mutations''' in the receptor for hormones such as Follicle Simulating Hormone (FSH), Lutenizing Hormone (LH) and hCG have all been targets of OHSS genetics research. Interestingly, they too also arise from a common ancestral gene.

===Follicle Stimulating Hormome===

Dr. Botros Rizk, of the University of South Alabama College of Medicine <ref name="PMID19573286"><pubmed>19573286</pubmed></ref>, has written extensively regarding the genetics behind OHSS. In particular, he talks about '''FSH receptors''' (FSHR) and their role in the syndrome. He hypothesises that mutations in these receptors could be activating or inactivating, leading to an increased risk of developing OHSS or sterility respectively. Currently, 744 single nucleotide polymorphisms (a type of mutation) have been found in the gene encoding the FSHR, 8 of which are located in its exons (coding regions of the gene). How the ovary responds is resultant on the FSHR genotype. For example, Ser680Asn, a polymorphism in the FSHR gene has been shown to aid in predicting the severity of a woman's OHSS. Ordinarily FSH stimulates the growth of ovarian follicles, however, when mutated, it is stimulated by the hCG resulting in excessive follicle development.

Spontaneous OHSS, OHSS that arises and cannot be attributed to any form of ovarian stimulation or Assisted Reproductive Technology, has been linked to activating mutations in the FSHR <ref name="PMID23499866"><pubmed>23499866</pubmed></ref>. This familial disorder is an autosomal dominant one. In most cases the FSHR can be stimulated by the presence of Thyroid Stimulating Hormone (TSH) or hCG, in the absence of FSH (the ligand for FSHR).

===Lutenizing Hormome===

The '''Lutenizing Hormone Receptor''' (LHR) gene in humans is comprised of 11 exons. Animal studies have shown that many primates exhibit a similar gene which is comprised of only 10 exons, however a gene lacking the 10th exon has been identified and termed the type 2 LHR. Expression of the type 2 LHR has been seen in humans. The type 2 LHR, compared to the wild-type LHR appears to be repaired with regard to its function. Defects in the type 2 LHR include a decrease in efficiency of transport to the plasma membrane and irregularities in signal transduction. Inactivating mutations in the LHR have been seen to cause infertility in women as well as amenorrhoea. Activating LHR gene mutations are asymptomatic and are not associated with OHSS in women.

===Bone Morphogenic Protein===

An imporant growth factor, derived from oocytes called '''BMP-15''' (Bone Morphogenic Protein 15) is vital for female fertility. It belongs to the family of growth factors, Transforming Growth Factor β (TGF-β) and is heavily involved in folliculogenesis. It has been found that mutations in the BMP-15 gene caused infertility in female sheep. Conversely, it has also been indicated in enhanced fertility when BMP-15 is present is high amounts in follicular fluid <ref name="PMID19573286" />.

A case study done by Hanevik ''et. al.'' in 2013 <ref name="PMID21565556"><pubmed>21565556</pubmed></ref> found that a Single Nuclear Polymorphism (SNP) in the BMP-15 gene is responsible for a high response to ovarian hyper-stimulation. The aim of the study was to test the effect the SNP had on BMP-15 with regard to high and low responders buy taking blood from 53 high responders, 38 low responders and 100 non-responders (controls) and analysing 5 noted SNP's. Results from their study showed a correlation between a high response to ovarian hyper-stimulation and the BMP-15 9G allele. The article does state however, that further research is required into the molecular effects of SNP's on the function of BMP-15.

===Vascular Endothelial Growth Factor===

'''Vascular endothelial growth factor''' (VEGF) has been indicated as one of the key agents causing vascular permeability and subsequent ascites in OHSS. The gene, which is located on chromosome 12, is made up of 8 exons (coding regions), of which exons 6 and 7 do not always appear due to the exons being spliced out.The splicing of this gene allows for various isoforms of the gene to exist of which VEGF 121 and 165 appear to play a role in angiogenesis. There are two VEGF Receptors, VEGFR-1 and VEGFR-2 that belong to the tyrosine kinase family of receptors (for more information on VEGF see [[Pathophysiology]]). Because of its distinct role in OHSS, it has been targeted as an area for research for potential treatments. The idea is that if the genetic expression of VEGF and its receptors can be controlled, OHSS can be avoided or treated.<ref name="PMID19573286" />

A different study by Hanevik ''et. al.'' , <ref name="PMID22587628"><pubmed>22587628</pubmed></ref> done in 2012 involved analysing blood samples from 53 women with OHSS and 100 women without it (controls) and analysing 6 SNP's in the VEGFR2 gene to find any genetic variations. They found a correlation between women with the VEGF +405cc genotype and the development of OHSS indicating women that undergo controlled ovarian hyper-stimulation and posses his genotype, are at an increased risk of developing OHSS.

</div>

== Current Research on Animal Models==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">
{|
|-bgcolor="F8E0F1"
|
<span style="font-size:120%">'''Inhibition of Cyclooxygenase-2 (COX-2) by Meloxican decreasing the incidence of OHSS in Rat Model'''</span> <ref name="PMID18166186"><pubmed>18166186</pubmed></ref>

Reasearch was carried out to investigate the effects of selective inhibition of the enzyme COX-2 on the Ovarian Hyperstimulation Syndrome (OHSS) using Female Wistar rates as the subjects. The research aimed to find results by measuring the number of antral and luteinized follicles, ovarian weight, vascualr endothelial growth factors and COX-2 immunohistochemistry. The rats being tested were all 22 days old and were divided into four equal groups;

'''Group 1 (Control group)''' was subject to a 0.1 ml of Intraperitoneal Saline from days 22 ~ 26

'''Group 2 (Mildly-stimulated group)''' subject to 10IU of pregnant mare serum gonadotrophin (PMSG) on day 24 and then 10IU of Human Chorionic Gonadotrophin (hCG) on day 26

'''Group 3 (OHSS positive group)''' was subject to 10IU of PMSG from days 22 ~ 26 and then administered 30IU of hCG on day 26 to induce OHSS

'''Group 4 (OHSS positive variant group)''' received 15mg/ml of Meloxicam 2 hours prior to administration of 10IU PMSG from days 22 ~ 26

Results showed there was no difference in ovarian weight in samples from Group 1 and Group 2, however Group 3 showed signs of significant ovarian weight increase which in group 4 was suppressed by the introduction of Meloxicam. No differences were observed in the number of antral follicles amongst the four test groups. Results from Group 2 and Group 3 showed that the granulosa cells of preovulatory follicles and the stromal cells were highly VEGF immunoreactive, however the Meloxicam treated Group 4 showed less immunoreactivity than Group 2 and Group 3 which indicated the correlation between Meloxicam and the diminished VEGF expression. Group 3 presented an increased COS-2 immunoreactivity which was highly diminished than in Group 4.

The research concluded that in a rat model, the enzyme Meloxicam has a beneficial effect on OHSS by reducing the increase of ovarian weight and the expression of VEGF associated with OHSS, the effects of which may be mediated by the inhibitory capacity of COX-2 on Meloxicam
|}

{|
|-bgcolor="FF99FF"
|
<span style="font-size:120%">'''Inhibition of Ovarian VEGF secretion by activation of Dopamine Receptor 2'''</span> <ref name="PMID25217874"><pubmed>25217874</pubmed></ref>

This research was carried out to investigate a possibility in whether a Dopamine Receptor 2 agonist '''(D2-ag)''' can assist in the prevention of Ovarian Hyperstimulation Syndrome, using rat models, by decreasing the ovarian vascular endothelial growth factor '''(VEGF)''' production. Using Immature Wistar rats (22 days old) as their animal model, the rats were initially stimulated with Gonadotrophins to mimic the onset and effects of OHSS and then subjected to treatment with a D2-agonist and/or a D2-antagonist (D2-ant). The vascular permeability was measured at the endpoint after day 26 by measuring the peritoneal extravasion of a previously injected dye and ovaries from all subjects were collected to assess the effects of D2-ag and D2-ant on the production of Ovarian VEGF. The expression of VEGF mRNA was measured by quantitative real time PCR and the levels of VEGF proteins were measured by Western Blots.

Results showed that the D2-ag caused a large reduction in the vascular permeability which was in turn associated with the great decreased in VEGF protein production in the OHSS rat ovaries, whereas the introduction of D2-ant showed opposite results with a increase in the vascular permeability leading to the increase of VEGF protein production in the ovaries. Ovarian VEGF mRNA levels were found to be unaffected by the introduction of these drugs in OHSS rat subjects. Conclusions were drawn on the fact that Dopamine Receptor 2 agonists prevent the increase of vascular permeability in subjects with OHSS by decreasing the ovarian production of VEGF and also that due to the dose-dependent inhibitory effect of the D2-ag on ovarian VEGF, current OHSS therapies used in humans can benefit by increasing the intraovarian concentration of D2-ag.
|}
</div>

==Glossary==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

'''Aromatase Inhibitor''' - A drug that inhibits enzyme aromatase, which in turn suppresses estrogen synthesis.

'''Ascites''' - An accumulation of fluid in the peritoneal cavity with resultant abdominal swelling.

'''Cabergoline''' - A dopamine receptor agonist used to treat hormone imbalance.

'''Controlled Ovarian Stimulation''' - female infertility treatment using medications to stimulate the ovaries to develop follicles.

'''Cryopreservation''' - Cooling and storing biological material at extremely low temperatures.

'''E2''' - Estradiol - Potent estrogen sex hormone.

'''FSH''' - Follicle Stimulating Hormone

'''Gonadotropin''' - Any hormone that has a stimulating effect on the gonads.

'''GnRH agonist''' - Gonadotropin Releasing Hormone - A class of compounds that mimic the effect of the natural Gonadotropin Releasing Hormone.

'''GnRH antagonist''' - Gonadotropin Releasing Hormone - A class of compounds that are similar in terms of the structure of natural Gonadotropin Releasing Hormone but has a antagonistic effect.

'''hCG'''- Human Chorionic Gonadotropin

'''Hemoconcentration''' - An increase in the concentration of circulating red blood cells in response to a decrease in blood plasma volume.

'''Hypovolemic''' - A decrease in circulating blood volume.

'''Iatrogenic''' - Illness caused as a result of a medical examination or treatment.

'''Intravenous fluids''' - Is the infusion of liquid substances directly into a vein.

'''IVF''' - In-vitro Fertilization

'''LH''' - Luteinizing Hormone

'''Metformin''' - A biguanide, antidiabetic drug used as an adjuvant to modify the effect of other agents.

'''NSAID''' - Non-steroidal Anti-Inflammatory Drug e.g. Ibuprofen

'''oocyte vitrification''' - technique for cryopreservation of oocytes.

'''OHSS''' - Ovarian Hyper-stimulation Syndrome

'''Oliguria'''- Decreased urine output/small amounts of urine produced.

'''P4''' - Progesterone - endogenous progestogen sex hormone.

'''PCOS''' - Polycystic Ovarian Syndrome. An endrocrine system disorder whereby the ovaries are enlarged with small collections of fluid.

</div>

==References==

2015 Group Project 2

2015-10-22T22:52:20Z

Z3372824: /* Glossary */

{{ANAT2341Project2015header}}

==<span style="font-size:120%">'''Ovarian Hyper-stimulation Syndrome (OHSS)'''</span>==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

Ovarian Hyper stimulation Syndrome (OHSS) is an iatrogenic complication of '''Assisted Reproduction Technology''' (ART), in which women take medications to stimulate oocyte growth. It is generally identified by cystic enlargements of the ovaries and fluid accumulation in the peritoneal cavity due to the increased capillary permeability and ovarian neoangiogenesis <ref name="PMID22065820"><pubmed>22065820</pubmed></ref>. It is an occurrence which is dependent on the controlled stimulation of the ovaries in preparation for IVF i.e. administration of human Chorionic Gonadotropin (hCG).

OHSS was first described in 1943 as ''“syndrome d’hyperluteinisation massive
des ovaries”''. It was during this time that gonadotropins were prepared from animals such as sheep to bring on ovulation in women. The first recorded death as a result of OHSS occurred in 1951 and was due to renal failure as a result of oligouria, a complication of the syndrome <ref name="OHSS"> Marie M. Budev, DO, MPH; Alejandro C. Arroliga, MD; Tommaso Falcone, MD, [ http://utilis.net/Morning%20Topics/REI/Ovarian%20Hyperstimulation.pdf ], 'Ovarian Hyperstimulation Syndrome'</ref> <ref name="PMID12638783"><pubmed>12638783</pubmed></ref>.

<span style="color:#FA58D0">This wikipage aims to provide clear information on various areas surrounding OHSS such as diagnosis, prevention and complications and will look into the genetics behind the disorder and the various animals models used to research it.</span>

<html5media height="350" width="450">https://www.youtube.com/watch?v=aXmjJw234a4</html5media>

'''Overview of the Ovarian Hyperstimulation Syndrome''' <ref> Howcast (2013, August 27) Ovarian Hyperstimulation Syndrome | Infertility. Retrieved from https://www.youtube.com/watch?v=aXmjJw234a4</ref>

</div>

==Epidemiology==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

Ovarian Hyper-Stimulation Syndrome (OHSS) rarely occurs sporadically, and if it does, it is usually the result of an underlying genetic problem. The majority of OHSS is due to the ovaries being stimulated to mature and release an abundance of oocytes, in response to hormones Human Chorionic Gonadotropin (hCG) and Follicle Stimulating hormone (FSH), during IVF. Rarely, Clomifene Citrate therapy can cause OHSS.<ref name="WikiOHSS"> Wikipedia, [ https://en.wikipedia.org/wiki/Ovarian_hyperstimulation_syndrome ], 'Ovarian Hyperstimulation Syndrome'</ref>

OHSS only affects '''0.5-5%''' of women undergoing Ovarian Hyper-stimulation, but despite its small prevalence, it is a potentially fatal outcome of a non-vital procedure and remains a prevalent problem for fertility specialists <ref name="PMID12498425"><pubmed>12498425</pubmed></ref> <ref name="PMID12638783"><pubmed>12638783</pubmed></ref>. Age has been cited as a factor affecting those with OHSS, with younger women more at risk. Additionally, women with allergies were seen to have a higher incidence of OHSS. It is important to note that at this point in time, there is no positive correlation between gonadotropin dose and OHSS.

Of the 0.5-5% of women affected with OHSS mentioned above, 2% of those women will require hospitalisation. As of 2011, it has been reported that the incidence of OHSS was '''increasing''', resulting in approximately 3 deaths per 100,000 women undergoing ovarian stimulation per year <ref name="PMID21828116"><pubmed>21828116</pubmed></ref>. This is particularly worrying as in 2008, in the United States alone, there were around 150,000 IVF cycles undertaken.

{|
|-bgcolor="F8E0F1"
|
'''With the field of Assisted Reproductive Technologies expanding and more women partaking in IVF treatments, the threat of women developing OHSS is an ongoing and increasing one''' <ref name="PMID21828116" />.
|}
{| class="wikitable mw-collapsible mw-collapsed"
! Characteristics of women by complication group <ref name="PMID19591989"><pubmed>19591989</pubmed></ref>
|-
! scope="col" width="100px" height="60px" style="text-align:center| '''Characteristic'''
! scope="col" width="100px" height="60px" style="text-align:center| '''No Complications
(N = 212,041)'''
! scope="col" width="100px" height="60px" style="text-align:center| '''Moderate OHSS
(N = 1,523)'''
! scope="col" width="100px" height="60px" style="text-align:center| '''Severe OHSS
(N = 655)'''
|-
|style="text-align:center; background: #FF99FF;"| '''Maternal Age (Mean ± SD)'''
|style="text-align:center; background: #F6CEEC;"| 35.6 ± 4.6
|style="text-align:center; background: #F6CEEC;"| 33.0 ± 4.3
|style="text-align:center; background: #F6CEEC;"| 33.1 ± 4.4
|-
|style="text-align:center; background: #FF99FF;"| '''Maternal Age (%)'''
|-
|style="text-align:left; background: #F6CEEC;"| <30 years
|style="text-align:center; background: #F6CEEC;"| 10 %
|style="text-align:center; background: #F6CEEC;"| 21.1 %
|style="text-align:center; background: #F6CEEC;"| 20.6 %
|-
|style="text-align:left; background: #F6CEEC;"| 30-34 years
|style="text-align:center; background: #F6CEEC;"| 30.4 %
|style="text-align:center; background: #F6CEEC;"| 43.2 %
|style="text-align:center; background: #F6CEEC;"| 40.5 %
|-
|style="text-align:left; background: #F6CEEC;"| 35-39 years
|style="text-align:center; background: #F6CEEC;"| 37.8 %
|style="text-align:center; background: #F6CEEC;"| 27.2 %
|style="text-align:center; background: #F6CEEC;"| 32.5 %
|-
|style="text-align:left; background: #F6CEEC;"| >40 years
|style="text-align:center; background: #F6CEEC;"| 21.8 %
|style="text-align:center; background: #F6CEEC;"| 8.4 %
|style="text-align:center; background: #F6CEEC;"| 6.4 %
|-
|style="text-align:center; background: #FF99FF;"| '''Nulligravida (%)'''
|style="text-align:center; background: #F6CEEC;"| 45.8 %
|style="text-align:center; background: #F6CEEC;"| 51.5 %
|style="text-align:center; background: #F6CEEC;"| 51.8 %
|-
|style="text-align:center; background: #FF99FF;"| '''Infertility Diagnosis (%)'''
|-
|style="text-align:left; background: #F6CEEC;"| Male factor
|style="text-align:center; background: #F6CEEC;"| 37.7 %
|style="text-align:center; background: #F6CEEC;"| 41.0 %
|style="text-align:center; background: #F6CEEC;"| 33.4 %
|-
|style="text-align:left; background: #F6CEEC;"| Endometriosis
|style="text-align:center; background: #F6CEEC;"| 13.5 %
|style="text-align:center; background: #F6CEEC;"| 13.5 %
|style="text-align:center; background: #F6CEEC;"| 10.7 %
|-
|style="text-align:left; background: #F6CEEC;"| Ovulation Disorders
|style="text-align:center; background: #F6CEEC;"| 14.0 %
|style="text-align:center; background: #F6CEEC;"| 29.5 %
|style="text-align:center; background: #F6CEEC;"| 22.4 %
|-
|style="text-align:left; background: #F6CEEC;"| Diminished ovarian reserve
|style="text-align:center; background: #F6CEEC;"| 16.9 %
|style="text-align:center; background: #F6CEEC;"| 3.2 %
|style="text-align:center; background: #F6CEEC;"| 2.4 %
|-
|style="text-align:left; background: #F6CEEC;"| Tubal factors
|style="text-align:center; background: #F6CEEC;"| 20.4 %
|style="text-align:center; background: #F6CEEC;"| 22.6 %
|style="text-align:center; background: #F6CEEC;"| 22.3 %
|-
|style="text-align:left; background: #F6CEEC;"| Uterine factors
|style="text-align:center; background: #F6CEEC;"| 5.1 %
|style="text-align:center; background: #F6CEEC;"| 4.3 %
|style="text-align:center; background: #F6CEEC;"| 3.1 %
|-
|style="text-align:left; background: #F6CEEC;"| Other factors
|style="text-align:center; background: #F6CEEC;"| 13.9 %
|style="text-align:center; background: #F6CEEC;"| 13.1 %
|style="text-align:center; background: #F6CEEC;"| 10.4 %
|-
|style="text-align:left; background: #F6CEEC;"| Unexplained factor
|style="text-align:center; background: #F6CEEC;"| 12.7 %
|style="text-align:center; background: #F6CEEC;"| 11.8 %
|style="text-align:center; background: #F6CEEC;"| 18.6 %
|-
|}
</div>

==Causative Agents==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

[[File:Follicular Development.jpeg|right|thumbnail|500px|Infertility treatments aim to facilitate follicular development and induce ovulation to improve chances of fertilisation <ref name="PMID24717179"><pubmed>24717179</pubmed></ref>]]

Normally a woman produces one egg per month from the ovaries, which travel down the Fallopian tube to be fertilized or be released from the body. In cases where women have difficulty falling pregnant, they are given medication which help them to produce and release eggs (as shown in the diagram to the right), further increasing their chances of fertilization and pregnancy <ref><pubmed>19573285</pubmed></ref>. Ovarian Hyper stimulation Syndrome generally occurs during infertility treatments when the ovaries are overstimulated by the fertility medication which causes the ovaries to swell and leak fluids into the belly and abdomen. The prevalence of OHSS onset is linked with excessive number of follicle development in response to the administration of injectable Follicle Stimulating Hormones (FSH) followed by the '''Human Chorionic Gonadotrophins''' (hCG) which triggers the release of the oocytes <ref><pubmed>26190539</pubmed></ref>.

'''Follicle Stimulating Hormones''' (FSH) <ref name="PMID9020850"><pubmed>9020850</pubmed></ref> are glycoprotein hormones that are produced and secreted from the Anterior Pituitary gland into the bloodstream, which regulate the developmental, growth, maturation and the reproductive processes within the body. In females, the Follicle Stimulating Hormones initiates the stages of growth and development of immature ovarian follicles within the ovaries before the release of an egg from a follicle at ovulation. When FSH is administered to a patient who is suffering from infertility, the increase FSH levels affect the rate of development and production, in turn increasing the amount of follicles which are ready to be released during ovulation.

</div>

==Symptoms==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

OHSS is classified based on a criteria from mild, moderate and severe <ref name="WikiOHSS" />:

'''Mild Symptoms'''- abdominal bloating, minimal weight gain, nausea, diarrhoea and a feeling of fullness.

'''Moderate Symptoms'''- Substantial weight gain (on average 2 or more pounds a day), increased abdominal girth, darkend urine and excessive thirst in addition to the mild symptoms.

'''Severe Symptoms'''- In addition to the symptoms associated with Mild and Moderate OHSS, in severe OHSS, you see shortness of breath, calf and chest pains and pleural effusion.

<span style="font-size:100%">'''Classifications of Ovarian Hyper-stimulation Syndrome:'''</span> <ref name="PMID22065820"><pubmed>22065820</pubmed></ref>
{| class="wikitable" style="text-align:center
|-
! scope="col" width="70px"| '''Classification'''
! scope="col" width="650px"| '''Symptoms'''
|-
|style="text-align:center; background: #F6CEEC;"| '''Mild'''
|style="height: 60px; background: #F6CEEC;"| '''Grade 1''' - Abdominal distention and discomfort
'''Grade 2''' - Abdominal distention, discomfort with nausea, vomiting and/or diarrhea and ovarian enlargement from 5~12cm
|-
|style="text-align:center; background: #F8E0F1;"| '''Moderate'''
|style="height: 60px; background: #F8E0F1;"| '''Grade 3''' - All features of Mild OHSS with ultrasonographic evidence of ascites
|-
|style="text-align:center; background: #F6CEEC;"| '''Severe'''
|style="height: 60px; background: #F6CEEC;"| '''Grade 4''' - All features of Moderate OHSS with the addition of clinical evidence of ascites and breathing difficulties present
'''Grade 5''' - All of the above symptoms along with a change in the blood volume, increased blood viscosity due to coagulation and diminished renal function
|}

</div>

==Diagnosis==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

Whilst symptoms of OHSS can occur as soon as 24 hours post hCG administration, they are usually seen in women 7-10 days post administration. Initially women with OHSS will present with abdominal bloating, as a result of fluid in the peritoneal cavity and an increase in ovary size. When women present with severe OHSS they are often dehydrated, due to increased vascular permeability, and have hemoconcentration. The above results in a decrease in intravascular volume, leading to '''oligouria''' <ref name="PMID22416285" />.

===History===

Initially a thorough history of the patient is taken during which the clinician looks for evidence of ovarian stimulation, followed by ovulation. During this history taking, the clinician will inquire into any weight gain noticed, urine output, and the woman's ability to maintain oral hydration. A key diagnostic tool for clinicians regarding women who are taking gonadotropins is to identify if they are at an increased risk of developing OHSS. Some risk factors include woman aged less than 30, women who have polycystic ovaries, woman with a previous history of OHSS and women who have had greater than 20 oocytes retrieved <ref name="PMID22416285" />.

===Physical Exam===
[[File:Vaginal_Ultrasonography_in_Sagittal_Plane.jpg|right|thumbnail|600px|Vaginal Ultrasonography in Sagittal plane <ref name="Wikiversity Journal of Medicine"> Häggström, Mikael. "Medical gallery of Mikael Häggström 2014". Wikiversity Journal of Medicine 1 (2). DOI:10.15347/wjm/2014.008. ISSN 20018762</ref>]]
After a history of the patient is taken, the next step is to perform a physical exam on the patient. Women who present with abdominal bloating will produce a shifting dullness upon abdominal percussion. Additionally the clinician will test the woman's vital signs, measure her abdominal girth, weight and will look for evidence of ascites or increase in calf size (usually unilateral)<ref name="PMID22416285" />.

===Investigations===

If the clinician further suspects a women of having OHSS, various investigations can be done such as an ultrasound.The intraperitoneal fluid is best imaged via vaginal ultrasound due to the enlarged ovaries making it difficult to image the pelvis using transabdominal ultrasound. The clinician can also order laboratory testing to look for urine specific gravity and and complete blood count to look for hemoconcentration with a hematocrit. Additionally, liver function tests can be ordered to look for elevated function. The clinician will also look for evidence of elevated D-dimers and fibrinogen and decreased levels of anti-thrombin 3 <ref name="SAHealth"> Government of South Australia Health [ http://www.sahealth.sa.gov.au/wps/wcm/connect/9b61ed004ee5348da663afd150ce4f37/Ovarian-hyperstimulation-syndrome-WCHN-PPG-17072012.pdf?MOD=AJPERES&CACHEID=9b61ed004ee5348da663afd150ce4f37 ], 'South Australian Paediatric Clinical Guidelines OHSS'</ref>.

====Ultrasound====

Typical appearances of the ultrasound include <ref name="Ultrasound"> Radiopaedia [ http://radiopaedia.org/articles/ovarian-hyperstimulation-syndrome-1 ], 'Ovarian Hyperstimulation Syndrome'</ref>:

*Bilaterally and symmetrically enlarged ovaries (>12cm)
* "Spoke-Wheel appearance" - presence of multiple cysts of varying size
*May also see ascites (fluid)

===Severity===

Once a clinician has deduced a women is suffering from OHSS, the severity of their condition needs to be established as either mild, moderate or severe. This is done by referring to the criteria under the sub-heading [[Symptoms]].The subsequent course of treatment for the woman will be based upon this evaluation.

{|
|-bgcolor="F6CEEC"
|
'''Further investigations''' can be done including a Chest X-ray to check for pleural effusions and oedema and USS with Doppler's to check for ascites or possible ovary torsion. <ref name="PMID22416285"><pubmed>22416285</pubmed></ref>
|}

===Differential Diagnosis===

Conditions presenting with similar symptoms or ultrasound images include <ref name="Ultrasound" />:

*Polycystic Ovaries (PO)
:: The difference is that with PO is that the cycts are typically smaller than OHSS cysts and there is no evidence of ascited or pleural effusion
*Mucinous Ovarian Malignancy
:: A type of Ovarian Epithelial tumour
*Ectopic Pregnancy <ref name="Casereport"> Australian Medical Student Journal [ http://www.amsj.org/wpcontent/uploads/files/articles/amsj_v2_i1/AMSJ_v2_i1_pg58-60.pdf ], 'Ovarian hyperstimulation syndrome'</ref>
::A pregnancy in which the foetus develops outside of the uterus e.g. in the fallopian tube

</div>

==Pathophysiology==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

[[File:Pathogenesis_of_OHSS.png|600px|thumb|Pathogenesis of OHSS <ref name="PMID20416867"><pubmed>20416867</pubmed></ref>]]

The definition of Ovarian Stimulation is enlarged ovaries with many luteinized cysts, that can present with secondary complications. What distinguishes Ovarian Stimulation from OHSS is the presence of vascular hyper-permeability that results in fluids being redirected elsewhere in the body.

The key process to OHSS appears to be caused by '''Vascular Endothelial Growth Factor''' (VEGF), that is released along with other cytokines, estrogen and progesterone, due to the ovary undergoing luteinization as a result of stimulation by hCG. VEGF increases vascular permeability and as a result the capillaries become more "leaky" to the fluids in them. These fluids can then escape the capillaries and accumulate in the pleural and abdominal cavities as ascites. The woman then becomes hypovolemic and is at an increased risk of circulatory, renal and respiratory issues such as arterial thromboembolism due to the thickening of the blood. Note, the blood is thickened as fluid is leaving the capillaries, leaving behind red blood cells and other cellular components of the blood <ref name="WikiOHSS" />.

The increase in expression of VEGF and VEGF Receptor 2 (VEGFR2) is attributed to the greatly increased amount of their mRNA present in the body after stimulation with hCG <ref name="PMID21082502"><pubmed>21082502</pubmed></ref>. VEGF interacts with VEGF2 and VEGF Receptor 1 (VEGFR1) to create a strong angiogenic effect. Both VEGFR2 and VEGFR1 belong to a family of receptors called tyrosine kinases. VEGF2 is involved in the regulation of angiogenesis and vascular permeability whilst VEGF1 has a slightly contradictory role in that is is involved in the maintenance of the tight junctions between endothelial cells in blood vessels. A study by Gómez ''et. al.'' <ref name="PMID21082502" /> showed that women experiencing OHSS had substantially higher plasma levels of VEGF and lower levels of VEGFR1.

</div>

==Complications==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

Ovarian torsion or rupture, renal insufficiency and thrombophlebitis can all complicate OHSS. If a pregnancy occurs, symptoms may persist longer than the usual 1 to 2 weeks and become more severe, however, even with severe OHSS, they do not extend past the first trimester <ref name="WikiOHSS" />.

<span style="color:#FA58D0"> '''1-2% of women who undergo ovarian stimulation develop a severe form of OHSS''' </span>. Complications from severe OHSS include:

*Fluid collection in the abdomen
*Electrolyte disturbances (sodium and potassium)
*Kidney failure
*Ovary twisting
*Rupture of a cyst in an ovary
*Breathing problems
*Blood clots in large vessels (most commonly the legs)
*Pregnancy loss from miscarriage or termination
*Rarely, death

A study by Nouri ''et. al.'' <ref name="PMID24996451"><pubmed>24996451</pubmed></ref> found that women with '''Polycystic Ovarian Syndrome''' (PCOS) and those that were induced with hCG experienced longer recovery times from severe OHSS than women who were not pregnant. They looked at a cohort of women hospitalised for the first time with severe OHSS and subject them to the same treatments. Based on a defined criteria, they established the recovery time of these women and compared the times between those that were pregnant to those that were not pregnant. They also found that whether a woman had PCOS or ovulation induction did not affect her risk of developing OHSS if she was not pregnant. It is only a risk factor for pregnant women.

===Thromboembolic events===

A frequent and deadly complication of OHSS are thromboembolic events due to increased blood clotting. This increase in blood clotting has been attributed to a variety of complications such as hemoconcentration (which thickens the blood), hypovolemia and an increase in the permeability of blood vessels as a result of increased vasoactive substances in the body of ovarian origin. Thromboembolic events include venous thromboses often in the upper extremities and arterial thromboses such as those in the cerebrovascular region. These events can lead to amputations of extremities, brain damage, miscarriage and death. To avoid this, anti-coagulants are given to pateitns with OHSS and they are fitted with compression stockings (see [[Treatment]]) <ref name="PMID23378404"><pubmed>23378404</pubmed></ref>.

{|
|-bgcolor="F8E0F1"
|
The risk of a woman developing OHSS is higher if she is having a '''twin pregnancy''', as she is exposed to higher concentration of hCG. <ref name="PMID9756273"><pubmed>9756273</pubmed></ref>
|}

</div>

==Treatment==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

'''General treatment
'''
*''Acetaminophen'' with or without a narcotic agent- used to treat abdominal discomfort
*Women are encouraged to drink 2-3 litres of water a day to prevent hemoconcentration
*Women are advised to avoid sexual intercourse and vigorous exercise at the risk of torsion or rupture of the ovaries
*NSAID's with anti-platelet properties should NOT be used as they may effect renal function in a women with OHSS
*Patients with significantly painful ascites or breathing problems may undergo ''Paracentesis'' (drainage of the ascites)
*''Culdocentesis'' (extraction of fluid from recto-uterine pouch) can be done to decrease the likelihood of a woman with moderate OHSS progressing to severe OHSS.<ref name="PMID22416285" />

===Mild to Moderate OHSS===

Mild OHSS can often resolve on its own, however, moderate OHSS may include treatments such as<ref name="WikiOHSS" />:

*Anti-nausea medication and prescription painkillers
*Regular physical examinations and ultrasounds
*Daily weigh-ins and waist measurements
*Measuring the amount of urine produced each day
*Frequent blood tests for monitoring dehydration and electrolyte imbalance
*Maintaining a high balance of fluids
*Drainage of excess abdominal fluid by inserting a needle in the abdominal cavity
*Wearing support stockings which help prevent blood clots/thrombosis

===Severe OHSS===

Severe OHSS requires hospital care in order for constant monitoring and treatment such as <ref name="WikiOHSS" />:

*Intravenous fluids with a crystalloid solution (100-150mL/hr)
*Intravenous Albumin is administered is IV fluids are insufficient (15-20mL/hr of 25% albumin for 4 hrs)
*In addition to Acetaminophen, ''Opioid analgesics'' can be administered for pain relief
*''Antiemetics'' can be used to subside nauseas and/or vomiting
*Woman administered to hospital of OHSS are considered at high risk of thromboembolic complications and are given low molecular weight ''heparin'', an anti-coagulant
*''Cabergoline''- lessens OHSS symptoms
*''GnRH agonist''- suppresses ovarian activity
**If at risk of OHSS, alternates include using a GnRH agonist instead of hCG however its effects on pregnancy rates are questionable. Using a GnRH agonist to replace the use of hCG for final oocyte stimulation will see a 6% decrease in delivery rate.

*Daily monitoring of creatine, urea, creatine clearance C-reactive protein (to rule out infection) are all required in combination with weekly tests such as liver and renal function tests and chest x-rays (to check for pleural effusion) <ref name="PMID12638783" />.

If there are serious complications then additional treatments are required:

*Surgery for a ruptured ovarian cyst
*Intensive care for the liver or lung complications

====Paracentesis====

For women with severe/grade 3 OHSS, paracentesis, the removal of fluid from the body using an aspiration needle, can be undertaken. It is a diagnostic and a therapeutic method that can be done trans-abdominally and trans-vaginally. It is used to relieve symptoms, improve haemodynamics e.g. Urinary output, and shorten the women's hospital stay. Complications of paracentesis include bleeding, infection and organ injury, however are note common <ref name="Paracentesis"> S. Monica Soni, HMS 3, Gillian Lieberman, MD [ http://eradiology.bidmc.harvard.edu/LearningLab/genito/Soni.pdf ], 'Ovarian Hyperstimulation Syndrome'</ref>.

{|
|-bgcolor="F8E0F1"
|
The most important aspect of treatment for any women with OHSS is close and constant '''monitoring''' with her healthcare professional. Counselling may also be provided to women and their partners or families in order to provide them with the best possible knowledge base to manage and treat their OHSS. It is important to note that there is '''no one cure or treatment''' for OHSS. Treatment involves managing and eliminating the symptoms until such time as the syndrome resolves itself <ref name="WikiOHSS" />.
|}

</div>

==Prevention==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

There are three key avenues through which the incidence of OHSS may be prevented. These include identifying risk factors to predict OHSS development, modifying treatment regimes on the basis of the identified risk factors and intervention to prevent progression to OHSS once the patient has undergone '''Controlled Ovarian Stimulation''' (COS).

=== Risk factors===

'''Primary risk factors'''

Pre-existing factors likely to exacerbate the ovarian stimulation response. Primary risk factors include <ref name="PMID26074966"><pubmed>26074966</pubmed></ref>:

*Young age
*Low body weight
*History of elevated response to gonadotropins
*Polycystic Ovary Syndrome (PCOS)
*Isolated PCOS characteristic
*A previous history of OHSS.
*Hormonal markers (e.g. Anti-Mullerian Hormone markers)
*Ultrasonographic markers (e.g. Antral Follicle Count)

'''Secondary risk factors'''

Secondary risk factors involve the monitoring of ovarian response parameters once COS has been initiated. These parameters are monitored for <ref name="PMID19007627"><pubmed>19007627</pubmed></ref>:

*rapidly rising E2 levels
*E2 concentration larger than 2500 pg/mL
*large number of developing follicles (10-14mm) on the day hCG is administered
*large number of oocytes retrieved

These factors in combination, act as a predictive tool to assess the likelihood of severe OHSS development, with a 83% sensitivity and 84% specificity. <ref name="PMID19007627"/>

=== Primary Prevention===

Primary Prevention involves the modification of treatment regimens on the basis of OHSS risk classifications, in order to prevent OHSS occurrence.

'''Ovulation Induction'''

Unifollicular Ovulation Induction through Ovulation Induction (OI) is a primary means of avoiding OHSS in women with Polycystic Ovarian Syndrome, who are at an increased risk. In order to promote unifollicular development, the ovaries are stimulated with a low starting dose of FSH (75 IU).<ref name="PMID20416867"><pubmed>20416867</pubmed></ref> Studies suggests that a minimum gonadotropin dose lowers OHSS risk and thus a step-up regimen is utilised to achieve an ovarian response, whereby the FSH dosage is increased every 7 days until follicular development of greater than 10mm is noted.<ref name="PMID26074966" /> Alternatively, a step-down regimen may be followed, whereby a high initial FSH dosage is lowered according to the ovarian response. Another method to increase FSH levels during OI, is through '''Aromatase Inhibitors''' which promote folliculogenesis by increasing pituitary secretion of FSH, and downregulate oestrogen production through a negative feedback loop. However, Aromatase Inhibitors have not been shown to reduce OHSS incidence in comparison to other methods of OI.<ref name="PMID26074966" /> During OI, a key objective is to prevent early cycle cancellation due to premature luteinisation from pituitary secretion of LH. In order to downregulate LH secretion, Gonadotropin-releasing hormone agonists '''GnRHa''' are administered in addition to gonadotropins. Alternatively, '''GnRH antagonists''' may be administered to downregulate endogenous LH secretion. Comparative studies have shown that the GnRH antagonist protocol has a greater effect in lowering the incidence of mild to severe OHSS. However due to the rare nature of OHSS, and insufficient sample sizes, the difference was not found to be significant. <ref name="PMID21082508"><pubmed>21082508</pubmed></ref>. Generally, the duration of exposure to gonadotropins and subsequent risk of OHSS may be minimised through mild stimulation protocols which administer FSH only in the mid to late follicular phase.<ref name="PMID20416867" />

'''Adjuvant Metformin Therapy'''

Adjuvant Metformin Therapy has been found to lower the risk of OHSS by 63%.<ref name="PMID25406011"><pubmed>25406011</pubmed></ref> It involves the administration of metformin at a daily dosage of 1000 to 2000mg, 2 months prior to Controlled Ovarian Stimulation <ref name="PMID26074966"/>. Metformin lowers the elevated insulin levels in PCOS which consequently reduce intraovarian androgen levels. This leads to a reduced sensitivity and expression of granulosa cell-follicle stimulating hormone receptors which result in a less exaggerated response to gonadotropins. Furthermore, it is suggested that Metformin prevents OHSS by controlling vascular permeability through the inhibition of various vasoactive molecules, including VEGF.

'''Avoiding hCG during Luteal Phase Support

Following Controlled Ovarian Stimulation, the steroid levels of E2 and P4 are reduced during the luteal phase due to the negative feedback on the pituitary. This leads to low endogenous LH levels, which consequently reduce endometrial receptivity as well as the luteal phase duration itself. As a result, implantation and pregnancy rates are reduced and early pregnancy loss rates are increased.<ref name="PMID20416867" /> Luteal Phase Support (LPS) serves to combat these adverse events with the use of hCG. However, hCG has been found to increase the risk of OHSS. Alternatively, the use of progesterone has been found to not only halve the risk of OHSS, but also induce similar improvements in pregnancy and miscarriage rates as hCG.<ref name="PMID26148507"><pubmed>26148507</pubmed></ref>

===Secondary Prevention===

Secondary Prevention aims to prevent progression to OHSS once COS has been initiated and the patient has been found to mount an exaggerated response. <ref name="PMID20416867" />

'''Coasting'''

Coasting is a first-line secondary preventative strategy. It consists of the withdrawal of gonadotrophins when a critical number of follicles and/or E2 concentration is reached. hCG is administered once the E2 concentration reduces to a safe level, before the process of oocyte retrieval commences. This preventative strategy is conducted for a period of less than 3 days in order to avoid compromising IVF outcomes.

'''Cryopreservation'''

Cryopreservation of embryos after oocyte retrieval is another avenue which may avert OHSS progression. The cryopreserved embryos are only reimplanted once the patient's hormone serum levels have normalised. Using oocyte vitrification, crystal formation within embryo tissue is avoided and so cryopreserved embryos have been found to produce better pregnancy rates with a 32% increase, than fresh embryo transfer. Recent studies suggest cryopreservation itself does not reduce OHSS rates, but must be followed by a GnRHa trigger to avert OHSS.

'''Cycle cancellation'''

Cycle cancellation is a guaranteed method to prevent early OHSS whereby hCG is withheld. This is a last resort strategy as it carries the risk of significant psychological distress and financial loss for the patient.

</div>

==Effect on the Newborn==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

</div>
Women who develop OHSS while undergoing Assisted Reproductive Technologies (ART) treatment are not only more likely to achieve a pregnancy, but have a live birth as the pregnancy outcome. This live birth is also more likely to be a multiple birth of two, three or more children. <ref name="PMID19591989"><pubmed>19591989</pubmed></ref> It has been postulated that a multifetal pregnancy leads to a more rapid increase in hCG levels, resulting in an increased risk of OHSS. However, the causal nature between multifetal pregnancy and OHSS development is disputed and further research is required to distinguish correlation from causation. <ref name="PMID19573292"><pubmed>19573292</pubmed></ref>

OHSS development is also associated with an increased risk of adverse outcomes including stillbirth, premature birth and low birthweight.<ref name="PMID19591989" /> Although the cause for the increased risk in adverse pregnancy outcomes is unknown, it is suggested that as the incidence of OHSS is reduced through various prevention strategies, the risk of such outcomes may be also be reduced.

==Genetics==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

Despite OHSS typically being of iatrogenic origin as a result of ovarian stimulation with gonadotropins, research has been conducted into the potential genetics behind OHSS as many sporadic and familial cases have been observed. '''Mutations''' in the receptor for hormones such as Follicle Simulating Hormone (FSH), Lutenizing Hormone (LH) and hCG have all been targets of OHSS genetics research. Interestingly, they too also arise from a common ancestral gene.

===Follicle Stimulating Hormome===

Dr. Botros Rizk, of the University of South Alabama College of Medicine <ref name="PMID19573286"><pubmed>19573286</pubmed></ref>, has written extensively regarding the genetics behind OHSS. In particular, he talks about '''FSH receptors''' (FSHR) and their role in the syndrome. He hypothesises that mutations in these receptors could be activating or inactivating, leading to an increased risk of developing OHSS or sterility respectively. Currently, 744 single nucleotide polymorphisms (a type of mutation) have been found in the gene encoding the FSHR, 8 of which are located in its exons (coding regions of the gene). How the ovary responds is resultant on the FSHR genotype. For example, Ser680Asn, a polymorphism in the FSHR gene has been shown to aid in predicting the severity of a woman's OHSS. Ordinarily FSH stimulates the growth of ovarian follicles, however, when mutated, it is stimulated by the hCG resulting in excessive follicle development.

Spontaneous OHSS, OHSS that arises and cannot be attributed to any form of ovarian stimulation or Assisted Reproductive Technology, has been linked to activating mutations in the FSHR <ref name="PMID23499866"><pubmed>23499866</pubmed></ref>. This familial disorder is an autosomal dominant one. In most cases the FSHR can be stimulated by the presence of Thyroid Stimulating Hormone (TSH) or hCG, in the absence of FSH (the ligand for FSHR).

===Lutenizing Hormome===

The '''Lutenizing Hormone Receptor''' (LHR) gene in humans is comprised of 11 exons. Animal studies have shown that many primates exhibit a similar gene which is comprised of only 10 exons, however a gene lacking the 10th exon has been identified and termed the type 2 LHR. Expression of the type 2 LHR has been seen in humans. The type 2 LHR, compared to the wild-type LHR appears to be repaired with regard to its function. Defects in the type 2 LHR include a decrease in efficiency of transport to the plasma membrane and irregularities in signal transduction. Inactivating mutations in the LHR have been seen to cause infertility in women as well as amenorrhoea. Activating LHR gene mutations are asymptomatic and are not associated with OHSS in women.

===Bone Morphogenic Protein===

An imporant growth factor, derived from oocytes called '''BMP-15''' (Bone Morphogenic Protein 15) is vital for female fertility. It belongs to the family of growth factors, Transforming Growth Factor β (TGF-β) and is heavily involved in folliculogenesis. It has been found that mutations in the BMP-15 gene caused infertility in female sheep. Conversely, it has also been indicated in enhanced fertility when BMP-15 is present is high amounts in follicular fluid <ref name="PMID19573286" />.

A case study done by Hanevik ''et. al.'' in 2013 <ref name="PMID21565556"><pubmed>21565556</pubmed></ref> found that a Single Nuclear Polymorphism (SNP) in the BMP-15 gene is responsible for a high response to ovarian hyper-stimulation. The aim of the study was to test the effect the SNP had on BMP-15 with regard to high and low responders buy taking blood from 53 high responders, 38 low responders and 100 non-responders (controls) and analysing 5 noted SNP's. Results from their study showed a correlation between a high response to ovarian hyper-stimulation and the BMP-15 9G allele. The article does state however, that further research is required into the molecular effects of SNP's on the function of BMP-15.

===Vascular Endothelial Growth Factor===

'''Vascular endothelial growth factor''' (VEGF) has been indicated as one of the key agents causing vascular permeability and subsequent ascites in OHSS. The gene, which is located on chromosome 12, is made up of 8 exons (coding regions), of which exons 6 and 7 do not always appear due to the exons being spliced out.The splicing of this gene allows for various isoforms of the gene to exist of which VEGF 121 and 165 appear to play a role in angiogenesis. There are two VEGF Receptors, VEGFR-1 and VEGFR-2 that belong to the tyrosine kinase family of receptors (for more information on VEGF see [[Pathophysiology]]). Because of its distinct role in OHSS, it has been targeted as an area for research for potential treatments. The idea is that if the genetic expression of VEGF and its receptors can be controlled, OHSS can be avoided or treated.<ref name="PMID19573286" />

A different study by Hanevik ''et. al.'' , <ref name="PMID22587628"><pubmed>22587628</pubmed></ref> done in 2012 involved analysing blood samples from 53 women with OHSS and 100 women without it (controls) and analysing 6 SNP's in the VEGFR2 gene to find any genetic variations. They found a correlation between women with the VEGF +405cc genotype and the development of OHSS indicating women that undergo controlled ovarian hyper-stimulation and posses his genotype, are at an increased risk of developing OHSS.

</div>

== Current Research on Animal Models==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">
{|
|-bgcolor="F8E0F1"
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<span style="font-size:120%">'''Inhibition of Cyclooxygenase-2 (COX-2) by Meloxican decreasing the incidence of OHSS in Rat Model'''</span> <ref name="PMID18166186"><pubmed>18166186</pubmed></ref>

Reasearch was carried out to investigate the effects of selective inhibition of the enzyme COX-2 on the Ovarian Hyperstimulation Syndrome (OHSS) using Female Wistar rates as the subjects. The research aimed to find results by measuring the number of antral and luteinized follicles, ovarian weight, vascualr endothelial growth factors and COX-2 immunohistochemistry. The rats being tested were all 22 days old and were divided into four equal groups;

'''Group 1 (Control group)''' was subject to a 0.1 ml of Intraperitoneal Saline from days 22 ~ 26

'''Group 2 (Mildly-stimulated group)''' subject to 10IU of pregnant mare serum gonadotrophin (PMSG) on day 24 and then 10IU of Human Chorionic Gonadotrophin (hCG) on day 26

'''Group 3 (OHSS positive group)''' was subject to 10IU of PMSG from days 22 ~ 26 and then administered 30IU of hCG on day 26 to induce OHSS

'''Group 4 (OHSS positive variant group)''' received 15mg/ml of Meloxicam 2 hours prior to administration of 10IU PMSG from days 22 ~ 26

Results showed there was no difference in ovarian weight in samples from Group 1 and Group 2, however Group 3 showed signs of significant ovarian weight increase which in group 4 was suppressed by the introduction of Meloxicam. No differences were observed in the number of antral follicles amongst the four test groups. Results from Group 2 and Group 3 showed that the granulosa cells of preovulatory follicles and the stromal cells were highly VEGF immunoreactive, however the Meloxicam treated Group 4 showed less immunoreactivity than Group 2 and Group 3 which indicated the correlation between Meloxicam and the diminished VEGF expression. Group 3 presented an increased COS-2 immunoreactivity which was highly diminished than in Group 4.

The research concluded that in a rat model, the enzyme Meloxicam has a beneficial effect on OHSS by reducing the increase of ovarian weight and the expression of VEGF associated with OHSS, the effects of which may be mediated by the inhibitory capacity of COX-2 on Meloxicam
|}

{|
|-bgcolor="FF99FF"
|
<span style="font-size:120%">'''Inhibition of Ovarian VEGF secretion by activation of Dopamine Receptor 2'''</span> <ref name="PMID25217874"><pubmed>25217874</pubmed></ref>

This research was carried out to investigate a possibility in whether a Dopamine Receptor 2 agonist '''(D2-ag)''' can assist in the prevention of Ovarian Hyperstimulation Syndrome, using rat models, by decreasing the ovarian vascular endothelial growth factor '''(VEGF)''' production. Using Immature Wistar rats (22 days old) as their animal model, the rats were initially stimulated with Gonadotrophins to mimic the onset and effects of OHSS and then subjected to treatment with a D2-agonist and/or a D2-antagonist (D2-ant). The vascular permeability was measured at the endpoint after day 26 by measuring the peritoneal extravasion of a previously injected dye and ovaries from all subjects were collected to assess the effects of D2-ag and D2-ant on the production of Ovarian VEGF. The expression of VEGF mRNA was measured by quantitative real time PCR and the levels of VEGF proteins were measured by Western Blots.

Results showed that the D2-ag caused a large reduction in the vascular permeability which was in turn associated with the great decreased in VEGF protein production in the OHSS rat ovaries, whereas the introduction of D2-ant showed opposite results with a increase in the vascular permeability leading to the increase of VEGF protein production in the ovaries. Ovarian VEGF mRNA levels were found to be unaffected by the introduction of these drugs in OHSS rat subjects. Conclusions were drawn on the fact that Dopamine Receptor 2 agonists prevent the increase of vascular permeability in subjects with OHSS by decreasing the ovarian production of VEGF and also that due to the dose-dependent inhibitory effect of the D2-ag on ovarian VEGF, current OHSS therapies used in humans can benefit by increasing the intraovarian concentration of D2-ag.
|}
</div>

==Glossary==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

'''Aromatase Inhibitor''' - A drug that inhibits enzyme aromatase, which in turn suppresses estrogen synthesis.

'''Ascites''' - An accumulation of fluid in the peritoneal cavity with resultant abdominal swelling.

'''Cabergoline''' - A dopamine receptor agonist used to treat hormone imbalance.

'''Controlled Ovarian Stimulation''' - female infertility treatment using medications to stimulate the ovaries to develop follicles.

'''Cryopreservation''' - Cooling and storing biological material at extremely low temperatures.

'''E2''' - Estradiol - Potent estrogen sex hormone.

'''FSH''' - Follicle Stimulating Hormone

'''Gonadotropin''' - Any hormone that has a stimulating effect on the gonads.

'''GnRH agonist''' - Gonadotropin Releasing Hormone - A class of compounds that mimic the effect of the natural Gonadotropin Releasing Hormone.

'''GnRH antagonist''' - Gonadotropin Releasing Hormone - A class of compounds that are similar in terms of the structure of natural Gonadotropin Releasing Hormone but has a antagonistic effect.

'''hCG'''- Human Chorionic Gonadotropin

'''Hemoconcentration''' - An increase in the concentration of circulating red blood cells in response to a decrease in blood plasma volume.

'''Hypovolemic''' - A decrease in circulating blood volume.

'''Iatrogenic''' - Illness caused as a result of a medical examination or treatment.

'''Intravenous fluids''' - Is the infusion of liquid substances directly into a vein.

'''IVF''' - In-vitro Fertilization

'''LH''' - Luteinizing Hormone

'''Metformin''' - A biguanide, antidiabetic drug used as an adjuvant to modify the effect of other agents.

'''NSAID''' - Non-steroidal Anti-Inflammatory Drug e.g. Ibuprofen

'''oocyte vitrification''' - technique for cryopreservation of oocytes.

'''OHSS''' - Ovarian Hyper-stimulation Syndrome

'''Oliguria'''- Decreased urine output/small amounts of urine produced.

'''P4''' - Progesterone - endogenous progestogen sex hormone.

'''PCOS''' - Polycystic Ovarian Syndrome. An endrocrine system disorder whereby the ovaries are enlarged with small collections of fluid.

</div>

==References==

2015 Group Project 2

2015-10-22T22:46:52Z

Z3372824: /* Glossary */

{{ANAT2341Project2015header}}

==<span style="font-size:120%">'''Ovarian Hyper-stimulation Syndrome (OHSS)'''</span>==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

Ovarian Hyper stimulation Syndrome (OHSS) is an iatrogenic complication of '''Assisted Reproduction Technology''' (ART), in which women take medications to stimulate oocyte growth. It is generally identified by cystic enlargements of the ovaries and fluid accumulation in the peritoneal cavity due to the increased capillary permeability and ovarian neoangiogenesis <ref name="PMID22065820"><pubmed>22065820</pubmed></ref>. It is an occurrence which is dependent on the controlled stimulation of the ovaries in preparation for IVF i.e. administration of human Chorionic Gonadotropin (hCG).

OHSS was first described in 1943 as ''“syndrome d’hyperluteinisation massive
des ovaries”''. It was during this time that gonadotropins were prepared from animals such as sheep to bring on ovulation in women. The first recorded death as a result of OHSS occurred in 1951 and was due to renal failure as a result of oligouria, a complication of the syndrome <ref name="OHSS"> Marie M. Budev, DO, MPH; Alejandro C. Arroliga, MD; Tommaso Falcone, MD, [ http://utilis.net/Morning%20Topics/REI/Ovarian%20Hyperstimulation.pdf ], 'Ovarian Hyperstimulation Syndrome'</ref> <ref name="PMID12638783"><pubmed>12638783</pubmed></ref>.

<span style="color:#FA58D0">This wikipage aims to provide clear information on various areas surrounding OHSS such as diagnosis, prevention and complications and will look into the genetics behind the disorder and the various animals models used to research it.</span>

<html5media height="350" width="450">https://www.youtube.com/watch?v=aXmjJw234a4</html5media>

'''Overview of the Ovarian Hyperstimulation Syndrome''' <ref> Howcast (2013, August 27) Ovarian Hyperstimulation Syndrome | Infertility. Retrieved from https://www.youtube.com/watch?v=aXmjJw234a4</ref>

</div>

==Epidemiology==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

Ovarian Hyper-Stimulation Syndrome (OHSS) rarely occurs sporadically, and if it does, it is usually the result of an underlying genetic problem. The majority of OHSS is due to the ovaries being stimulated to mature and release an abundance of oocytes, in response to hormones Human Chorionic Gonadotropin (hCG) and Follicle Stimulating hormone (FSH), during IVF. Rarely, Clomifene Citrate therapy can cause OHSS.<ref name="WikiOHSS"> Wikipedia, [ https://en.wikipedia.org/wiki/Ovarian_hyperstimulation_syndrome ], 'Ovarian Hyperstimulation Syndrome'</ref>

OHSS only affects '''0.5-5%''' of women undergoing Ovarian Hyper-stimulation, but despite its small prevalence, it is a potentially fatal outcome of a non-vital procedure and remains a prevalent problem for fertility specialists <ref name="PMID12498425"><pubmed>12498425</pubmed></ref> <ref name="PMID12638783"><pubmed>12638783</pubmed></ref>. Age has been cited as a factor affecting those with OHSS, with younger women more at risk. Additionally, women with allergies were seen to have a higher incidence of OHSS. It is important to note that at this point in time, there is no positive correlation between gonadotropin dose and OHSS.

Of the 0.5-5% of women affected with OHSS mentioned above, 2% of those women will require hospitalisation. As of 2011, it has been reported that the incidence of OHSS was '''increasing''', resulting in approximately 3 deaths per 100,000 women undergoing ovarian stimulation per year <ref name="PMID21828116"><pubmed>21828116</pubmed></ref>. This is particularly worrying as in 2008, in the United States alone, there were around 150,000 IVF cycles undertaken.

{|
|-bgcolor="F8E0F1"
|
'''With the field of Assisted Reproductive Technologies expanding and more women partaking in IVF treatments, the threat of women developing OHSS is an ongoing and increasing one''' <ref name="PMID21828116" />.
|}
{| class="wikitable mw-collapsible mw-collapsed"
! Characteristics of women by complication group <ref name="PMID19591989"><pubmed>19591989</pubmed></ref>
|-
! scope="col" width="100px" height="60px" style="text-align:center| '''Characteristic'''
! scope="col" width="100px" height="60px" style="text-align:center| '''No Complications
(N = 212,041)'''
! scope="col" width="100px" height="60px" style="text-align:center| '''Moderate OHSS
(N = 1,523)'''
! scope="col" width="100px" height="60px" style="text-align:center| '''Severe OHSS
(N = 655)'''
|-
|style="text-align:center; background: #FF99FF;"| '''Maternal Age (Mean ± SD)'''
|style="text-align:center; background: #F6CEEC;"| 35.6 ± 4.6
|style="text-align:center; background: #F6CEEC;"| 33.0 ± 4.3
|style="text-align:center; background: #F6CEEC;"| 33.1 ± 4.4
|-
|style="text-align:center; background: #FF99FF;"| '''Maternal Age (%)'''
|-
|style="text-align:left; background: #F6CEEC;"| <30 years
|style="text-align:center; background: #F6CEEC;"| 10 %
|style="text-align:center; background: #F6CEEC;"| 21.1 %
|style="text-align:center; background: #F6CEEC;"| 20.6 %
|-
|style="text-align:left; background: #F6CEEC;"| 30-34 years
|style="text-align:center; background: #F6CEEC;"| 30.4 %
|style="text-align:center; background: #F6CEEC;"| 43.2 %
|style="text-align:center; background: #F6CEEC;"| 40.5 %
|-
|style="text-align:left; background: #F6CEEC;"| 35-39 years
|style="text-align:center; background: #F6CEEC;"| 37.8 %
|style="text-align:center; background: #F6CEEC;"| 27.2 %
|style="text-align:center; background: #F6CEEC;"| 32.5 %
|-
|style="text-align:left; background: #F6CEEC;"| >40 years
|style="text-align:center; background: #F6CEEC;"| 21.8 %
|style="text-align:center; background: #F6CEEC;"| 8.4 %
|style="text-align:center; background: #F6CEEC;"| 6.4 %
|-
|style="text-align:center; background: #FF99FF;"| '''Nulligravida (%)'''
|style="text-align:center; background: #F6CEEC;"| 45.8 %
|style="text-align:center; background: #F6CEEC;"| 51.5 %
|style="text-align:center; background: #F6CEEC;"| 51.8 %
|-
|style="text-align:center; background: #FF99FF;"| '''Infertility Diagnosis (%)'''
|-
|style="text-align:left; background: #F6CEEC;"| Male factor
|style="text-align:center; background: #F6CEEC;"| 37.7 %
|style="text-align:center; background: #F6CEEC;"| 41.0 %
|style="text-align:center; background: #F6CEEC;"| 33.4 %
|-
|style="text-align:left; background: #F6CEEC;"| Endometriosis
|style="text-align:center; background: #F6CEEC;"| 13.5 %
|style="text-align:center; background: #F6CEEC;"| 13.5 %
|style="text-align:center; background: #F6CEEC;"| 10.7 %
|-
|style="text-align:left; background: #F6CEEC;"| Ovulation Disorders
|style="text-align:center; background: #F6CEEC;"| 14.0 %
|style="text-align:center; background: #F6CEEC;"| 29.5 %
|style="text-align:center; background: #F6CEEC;"| 22.4 %
|-
|style="text-align:left; background: #F6CEEC;"| Diminished ovarian reserve
|style="text-align:center; background: #F6CEEC;"| 16.9 %
|style="text-align:center; background: #F6CEEC;"| 3.2 %
|style="text-align:center; background: #F6CEEC;"| 2.4 %
|-
|style="text-align:left; background: #F6CEEC;"| Tubal factors
|style="text-align:center; background: #F6CEEC;"| 20.4 %
|style="text-align:center; background: #F6CEEC;"| 22.6 %
|style="text-align:center; background: #F6CEEC;"| 22.3 %
|-
|style="text-align:left; background: #F6CEEC;"| Uterine factors
|style="text-align:center; background: #F6CEEC;"| 5.1 %
|style="text-align:center; background: #F6CEEC;"| 4.3 %
|style="text-align:center; background: #F6CEEC;"| 3.1 %
|-
|style="text-align:left; background: #F6CEEC;"| Other factors
|style="text-align:center; background: #F6CEEC;"| 13.9 %
|style="text-align:center; background: #F6CEEC;"| 13.1 %
|style="text-align:center; background: #F6CEEC;"| 10.4 %
|-
|style="text-align:left; background: #F6CEEC;"| Unexplained factor
|style="text-align:center; background: #F6CEEC;"| 12.7 %
|style="text-align:center; background: #F6CEEC;"| 11.8 %
|style="text-align:center; background: #F6CEEC;"| 18.6 %
|-
|}
</div>

==Causative Agents==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

[[File:Follicular Development.jpeg|right|thumbnail|500px|Infertility treatments aim to facilitate follicular development and induce ovulation to improve chances of fertilisation <ref name="PMID24717179"><pubmed>24717179</pubmed></ref>]]

Normally a woman produces one egg per month from the ovaries, which travel down the Fallopian tube to be fertilized or be released from the body. In cases where women have difficulty falling pregnant, they are given medication which help them to produce and release eggs (as shown in the diagram to the right), further increasing their chances of fertilization and pregnancy <ref><pubmed>19573285</pubmed></ref>. Ovarian Hyper stimulation Syndrome generally occurs during infertility treatments when the ovaries are overstimulated by the fertility medication which causes the ovaries to swell and leak fluids into the belly and abdomen. The prevalence of OHSS onset is linked with excessive number of follicle development in response to the administration of injectable Follicle Stimulating Hormones (FSH) followed by the '''Human Chorionic Gonadotrophins''' (hCG) which triggers the release of the oocytes <ref><pubmed>26190539</pubmed></ref>.

'''Follicle Stimulating Hormones''' (FSH) <ref name="PMID9020850"><pubmed>9020850</pubmed></ref> are glycoprotein hormones that are produced and secreted from the Anterior Pituitary gland into the bloodstream, which regulate the developmental, growth, maturation and the reproductive processes within the body. In females, the Follicle Stimulating Hormones initiates the stages of growth and development of immature ovarian follicles within the ovaries before the release of an egg from a follicle at ovulation. When FSH is administered to a patient who is suffering from infertility, the increase FSH levels affect the rate of development and production, in turn increasing the amount of follicles which are ready to be released during ovulation.

</div>

==Symptoms==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

OHSS is classified based on a criteria from mild, moderate and severe <ref name="WikiOHSS" />:

'''Mild Symptoms'''- abdominal bloating, minimal weight gain, nausea, diarrhoea and a feeling of fullness.

'''Moderate Symptoms'''- Substantial weight gain (on average 2 or more pounds a day), increased abdominal girth, darkend urine and excessive thirst in addition to the mild symptoms.

'''Severe Symptoms'''- In addition to the symptoms associated with Mild and Moderate OHSS, in severe OHSS, you see shortness of breath, calf and chest pains and pleural effusion.

<span style="font-size:100%">'''Classifications of Ovarian Hyper-stimulation Syndrome:'''</span> <ref name="PMID22065820"><pubmed>22065820</pubmed></ref>
{| class="wikitable" style="text-align:center
|-
! scope="col" width="70px"| '''Classification'''
! scope="col" width="650px"| '''Symptoms'''
|-
|style="text-align:center; background: #F6CEEC;"| '''Mild'''
|style="height: 60px; background: #F6CEEC;"| '''Grade 1''' - Abdominal distention and discomfort
'''Grade 2''' - Abdominal distention, discomfort with nausea, vomiting and/or diarrhea and ovarian enlargement from 5~12cm
|-
|style="text-align:center; background: #F8E0F1;"| '''Moderate'''
|style="height: 60px; background: #F8E0F1;"| '''Grade 3''' - All features of Mild OHSS with ultrasonographic evidence of ascites
|-
|style="text-align:center; background: #F6CEEC;"| '''Severe'''
|style="height: 60px; background: #F6CEEC;"| '''Grade 4''' - All features of Moderate OHSS with the addition of clinical evidence of ascites and breathing difficulties present
'''Grade 5''' - All of the above symptoms along with a change in the blood volume, increased blood viscosity due to coagulation and diminished renal function
|}

</div>

==Diagnosis==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

Whilst symptoms of OHSS can occur as soon as 24 hours post hCG administration, they are usually seen in women 7-10 days post administration. Initially women with OHSS will present with abdominal bloating, as a result of fluid in the peritoneal cavity and an increase in ovary size. When women present with severe OHSS they are often dehydrated, due to increased vascular permeability, and have hemoconcentration. The above results in a decrease in intravascular volume, leading to '''oligouria''' <ref name="PMID22416285" />.

===History===

Initially a thorough history of the patient is taken during which the clinician looks for evidence of ovarian stimulation, followed by ovulation. During this history taking, the clinician will inquire into any weight gain noticed, urine output, and the woman's ability to maintain oral hydration. A key diagnostic tool for clinicians regarding women who are taking gonadotropins is to identify if they are at an increased risk of developing OHSS. Some risk factors include woman aged less than 30, women who have polycystic ovaries, woman with a previous history of OHSS and women who have had greater than 20 oocytes retrieved <ref name="PMID22416285" />.

===Physical Exam===
[[File:Vaginal_Ultrasonography_in_Sagittal_Plane.jpg|right|thumbnail|600px|Vaginal Ultrasonography in Sagittal plane <ref name="Wikiversity Journal of Medicine"> Häggström, Mikael. "Medical gallery of Mikael Häggström 2014". Wikiversity Journal of Medicine 1 (2). DOI:10.15347/wjm/2014.008. ISSN 20018762</ref>]]
After a history of the patient is taken, the next step is to perform a physical exam on the patient. Women who present with abdominal bloating will produce a shifting dullness upon abdominal percussion. Additionally the clinician will test the woman's vital signs, measure her abdominal girth, weight and will look for evidence of ascites or increase in calf size (usually unilateral)<ref name="PMID22416285" />.

===Investigations===

If the clinician further suspects a women of having OHSS, various investigations can be done such as an ultrasound.The intraperitoneal fluid is best imaged via vaginal ultrasound due to the enlarged ovaries making it difficult to image the pelvis using transabdominal ultrasound. The clinician can also order laboratory testing to look for urine specific gravity and and complete blood count to look for hemoconcentration with a hematocrit. Additionally, liver function tests can be ordered to look for elevated function. The clinician will also look for evidence of elevated D-dimers and fibrinogen and decreased levels of anti-thrombin 3 <ref name="SAHealth"> Government of South Australia Health [ http://www.sahealth.sa.gov.au/wps/wcm/connect/9b61ed004ee5348da663afd150ce4f37/Ovarian-hyperstimulation-syndrome-WCHN-PPG-17072012.pdf?MOD=AJPERES&CACHEID=9b61ed004ee5348da663afd150ce4f37 ], 'South Australian Paediatric Clinical Guidelines OHSS'</ref>.

====Ultrasound====

Typical appearances of the ultrasound include <ref name="Ultrasound"> Radiopaedia [ http://radiopaedia.org/articles/ovarian-hyperstimulation-syndrome-1 ], 'Ovarian Hyperstimulation Syndrome'</ref>:

*Bilaterally and symmetrically enlarged ovaries (>12cm)
* "Spoke-Wheel appearance" - presence of multiple cysts of varying size
*May also see ascites (fluid)

===Severity===

Once a clinician has deduced a women is suffering from OHSS, the severity of their condition needs to be established as either mild, moderate or severe. This is done by referring to the criteria under the sub-heading [[Symptoms]].The subsequent course of treatment for the woman will be based upon this evaluation.

{|
|-bgcolor="F6CEEC"
|
'''Further investigations''' can be done including a Chest X-ray to check for pleural effusions and oedema and USS with Doppler's to check for ascites or possible ovary torsion. <ref name="PMID22416285"><pubmed>22416285</pubmed></ref>
|}

===Differential Diagnosis===

Conditions presenting with similar symptoms or ultrasound images include <ref name="Ultrasound" />:

*Polycystic Ovaries (PO)
:: The difference is that with PO is that the cycts are typically smaller than OHSS cysts and there is no evidence of ascited or pleural effusion
*Mucinous Ovarian Malignancy
:: A type of Ovarian Epithelial tumour
*Ectopic Pregnancy <ref name="Casereport"> Australian Medical Student Journal [ http://www.amsj.org/wpcontent/uploads/files/articles/amsj_v2_i1/AMSJ_v2_i1_pg58-60.pdf ], 'Ovarian hyperstimulation syndrome'</ref>
::A pregnancy in which the foetus develops outside of the uterus e.g. in the fallopian tube

</div>

==Pathophysiology==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

[[File:Pathogenesis_of_OHSS.png|600px|thumb|Pathogenesis of OHSS <ref name="PMID20416867"><pubmed>20416867</pubmed></ref>]]

The definition of Ovarian Stimulation is enlarged ovaries with many luteinized cysts, that can present with secondary complications. What distinguishes Ovarian Stimulation from OHSS is the presence of vascular hyper-permeability that results in fluids being redirected elsewhere in the body.

The key process to OHSS appears to be caused by '''Vascular Endothelial Growth Factor''' (VEGF), that is released along with other cytokines, estrogen and progesterone, due to the ovary undergoing luteinization as a result of stimulation by hCG. VEGF increases vascular permeability and as a result the capillaries become more "leaky" to the fluids in them. These fluids can then escape the capillaries and accumulate in the pleural and abdominal cavities as ascites. The woman then becomes hypovolemic and is at an increased risk of circulatory, renal and respiratory issues such as arterial thromboembolism due to the thickening of the blood. Note, the blood is thickened as fluid is leaving the capillaries, leaving behind red blood cells and other cellular components of the blood <ref name="WikiOHSS" />.

The increase in expression of VEGF and VEGF Receptor 2 (VEGFR2) is attributed to the greatly increased amount of their mRNA present in the body after stimulation with hCG <ref name="PMID21082502"><pubmed>21082502</pubmed></ref>. VEGF interacts with VEGF2 and VEGF Receptor 1 (VEGFR1) to create a strong angiogenic effect. Both VEGFR2 and VEGFR1 belong to a family of receptors called tyrosine kinases. VEGF2 is involved in the regulation of angiogenesis and vascular permeability whilst VEGF1 has a slightly contradictory role in that is is involved in the maintenance of the tight junctions between endothelial cells in blood vessels. A study by Gómez ''et. al.'' <ref name="PMID21082502" /> showed that women experiencing OHSS had substantially higher plasma levels of VEGF and lower levels of VEGFR1.

</div>

==Complications==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

Ovarian torsion or rupture, renal insufficiency and thrombophlebitis can all complicate OHSS. If a pregnancy occurs, symptoms may persist longer than the usual 1 to 2 weeks and become more severe, however, even with severe OHSS, they do not extend past the first trimester <ref name="WikiOHSS" />.

<span style="color:#FA58D0"> '''1-2% of women who undergo ovarian stimulation develop a severe form of OHSS''' </span>. Complications from severe OHSS include:

*Fluid collection in the abdomen
*Electrolyte disturbances (sodium and potassium)
*Kidney failure
*Ovary twisting
*Rupture of a cyst in an ovary
*Breathing problems
*Blood clots in large vessels (most commonly the legs)
*Pregnancy loss from miscarriage or termination
*Rarely, death

A study by Nouri ''et. al.'' <ref name="PMID24996451"><pubmed>24996451</pubmed></ref> found that women with '''Polycystic Ovarian Syndrome''' (PCOS) and those that were induced with hCG experienced longer recovery times from severe OHSS than women who were not pregnant. They looked at a cohort of women hospitalised for the first time with severe OHSS and subject them to the same treatments. Based on a defined criteria, they established the recovery time of these women and compared the times between those that were pregnant to those that were not pregnant. They also found that whether a woman had PCOS or ovulation induction did not affect her risk of developing OHSS if she was not pregnant. It is only a risk factor for pregnant women.

===Thromboembolic events===

A frequent and deadly complication of OHSS are thromboembolic events due to increased blood clotting. This increase in blood clotting has been attributed to a variety of complications such as hemoconcentration (which thickens the blood), hypovolemia and an increase in the permeability of blood vessels as a result of increased vasoactive substances in the body of ovarian origin. Thromboembolic events include venous thromboses often in the upper extremities and arterial thromboses such as those in the cerebrovascular region. These events can lead to amputations of extremities, brain damage, miscarriage and death. To avoid this, anti-coagulants are given to pateitns with OHSS and they are fitted with compression stockings (see [[Treatment]]) <ref name="PMID23378404"><pubmed>23378404</pubmed></ref>.

{|
|-bgcolor="F8E0F1"
|
The risk of a woman developing OHSS is higher if she is having a '''twin pregnancy''', as she is exposed to higher concentration of hCG. <ref name="PMID9756273"><pubmed>9756273</pubmed></ref>
|}

</div>

==Treatment==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

'''General treatment
'''
*''Acetaminophen'' with or without a narcotic agent- used to treat abdominal discomfort
*Women are encouraged to drink 2-3 litres of water a day to prevent hemoconcentration
*Women are advised to avoid sexual intercourse and vigorous exercise at the risk of torsion or rupture of the ovaries
*NSAID's with anti-platelet properties should NOT be used as they may effect renal function in a women with OHSS
*Patients with significantly painful ascites or breathing problems may undergo ''Paracentesis'' (drainage of the ascites)
*''Culdocentesis'' (extraction of fluid from recto-uterine pouch) can be done to decrease the likelihood of a woman with moderate OHSS progressing to severe OHSS.<ref name="PMID22416285" />

===Mild to Moderate OHSS===

Mild OHSS can often resolve on its own, however, moderate OHSS may include treatments such as<ref name="WikiOHSS" />:

*Anti-nausea medication and prescription painkillers
*Regular physical examinations and ultrasounds
*Daily weigh-ins and waist measurements
*Measuring the amount of urine produced each day
*Frequent blood tests for monitoring dehydration and electrolyte imbalance
*Maintaining a high balance of fluids
*Drainage of excess abdominal fluid by inserting a needle in the abdominal cavity
*Wearing support stockings which help prevent blood clots/thrombosis

===Severe OHSS===

Severe OHSS requires hospital care in order for constant monitoring and treatment such as <ref name="WikiOHSS" />:

*Intravenous fluids with a crystalloid solution (100-150mL/hr)
*Intravenous Albumin is administered is IV fluids are insufficient (15-20mL/hr of 25% albumin for 4 hrs)
*In addition to Acetaminophen, ''Opioid analgesics'' can be administered for pain relief
*''Antiemetics'' can be used to subside nauseas and/or vomiting
*Woman administered to hospital of OHSS are considered at high risk of thromboembolic complications and are given low molecular weight ''heparin'', an anti-coagulant
*''Cabergoline''- lessens OHSS symptoms
*''GnRH agonist''- suppresses ovarian activity
**If at risk of OHSS, alternates include using a GnRH agonist instead of hCG however its effects on pregnancy rates are questionable. Using a GnRH agonist to replace the use of hCG for final oocyte stimulation will see a 6% decrease in delivery rate.

*Daily monitoring of creatine, urea, creatine clearance C-reactive protein (to rule out infection) are all required in combination with weekly tests such as liver and renal function tests and chest x-rays (to check for pleural effusion) <ref name="PMID12638783" />.

If there are serious complications then additional treatments are required:

*Surgery for a ruptured ovarian cyst
*Intensive care for the liver or lung complications

====Paracentesis====

For women with severe/grade 3 OHSS, paracentesis, the removal of fluid from the body using an aspiration needle, can be undertaken. It is a diagnostic and a therapeutic method that can be done trans-abdominally and trans-vaginally. It is used to relieve symptoms, improve haemodynamics e.g. Urinary output, and shorten the women's hospital stay. Complications of paracentesis include bleeding, infection and organ injury, however are note common <ref name="Paracentesis"> S. Monica Soni, HMS 3, Gillian Lieberman, MD [ http://eradiology.bidmc.harvard.edu/LearningLab/genito/Soni.pdf ], 'Ovarian Hyperstimulation Syndrome'</ref>.

{|
|-bgcolor="F8E0F1"
|
The most important aspect of treatment for any women with OHSS is close and constant '''monitoring''' with her healthcare professional. Counselling may also be provided to women and their partners or families in order to provide them with the best possible knowledge base to manage and treat their OHSS. It is important to note that there is '''no one cure or treatment''' for OHSS. Treatment involves managing and eliminating the symptoms until such time as the syndrome resolves itself <ref name="WikiOHSS" />.
|}

</div>

==Prevention==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

There are three key avenues through which the incidence of OHSS may be prevented. These include identifying risk factors to predict OHSS development, modifying treatment regimes on the basis of the identified risk factors and intervention to prevent progression to OHSS once the patient has undergone '''Controlled Ovarian Stimulation''' (COS).

=== Risk factors===

'''Primary risk factors'''

Pre-existing factors likely to exacerbate the ovarian stimulation response. Primary risk factors include <ref name="PMID26074966"><pubmed>26074966</pubmed></ref>:

*Young age
*Low body weight
*History of elevated response to gonadotropins
*Polycystic Ovary Syndrome (PCOS)
*Isolated PCOS characteristic
*A previous history of OHSS.
*Hormonal markers (e.g. Anti-Mullerian Hormone markers)
*Ultrasonographic markers (e.g. Antral Follicle Count)

'''Secondary risk factors'''

Secondary risk factors involve the monitoring of ovarian response parameters once COS has been initiated. These parameters are monitored for <ref name="PMID19007627"><pubmed>19007627</pubmed></ref>:

*rapidly rising E2 levels
*E2 concentration larger than 2500 pg/mL
*large number of developing follicles (10-14mm) on the day hCG is administered
*large number of oocytes retrieved

These factors in combination, act as a predictive tool to assess the likelihood of severe OHSS development, with a 83% sensitivity and 84% specificity. <ref name="PMID19007627"/>

=== Primary Prevention===

Primary Prevention involves the modification of treatment regimens on the basis of OHSS risk classifications, in order to prevent OHSS occurrence.

'''Ovulation Induction'''

Unifollicular Ovulation Induction through Ovulation Induction (OI) is a primary means of avoiding OHSS in women with Polycystic Ovarian Syndrome, who are at an increased risk. In order to promote unifollicular development, the ovaries are stimulated with a low starting dose of FSH (75 IU).<ref name="PMID20416867"><pubmed>20416867</pubmed></ref> Studies suggests that a minimum gonadotropin dose lowers OHSS risk and thus a step-up regimen is utilised to achieve an ovarian response, whereby the FSH dosage is increased every 7 days until follicular development of greater than 10mm is noted.<ref name="PMID26074966" /> Alternatively, a step-down regimen may be followed, whereby a high initial FSH dosage is lowered according to the ovarian response. Another method to increase FSH levels during OI, is through '''Aromatase Inhibitors''' which promote folliculogenesis by increasing pituitary secretion of FSH, and downregulate oestrogen production through a negative feedback loop. However, Aromatase Inhibitors have not been shown to reduce OHSS incidence in comparison to other methods of OI.<ref name="PMID26074966" /> During OI, a key objective is to prevent early cycle cancellation due to premature luteinisation from pituitary secretion of LH. In order to downregulate LH secretion, Gonadotropin-releasing hormone agonists '''GnRHa''' are administered in addition to gonadotropins. Alternatively, '''GnRH antagonists''' may be administered to downregulate endogenous LH secretion. Comparative studies have shown that the GnRH antagonist protocol has a greater effect in lowering the incidence of mild to severe OHSS. However due to the rare nature of OHSS, and insufficient sample sizes, the difference was not found to be significant. <ref name="PMID21082508"><pubmed>21082508</pubmed></ref>. Generally, the duration of exposure to gonadotropins and subsequent risk of OHSS may be minimised through mild stimulation protocols which administer FSH only in the mid to late follicular phase.<ref name="PMID20416867" />

'''Adjuvant Metformin Therapy'''

Adjuvant Metformin Therapy has been found to lower the risk of OHSS by 63%.<ref name="PMID25406011"><pubmed>25406011</pubmed></ref> It involves the administration of metformin at a daily dosage of 1000 to 2000mg, 2 months prior to Controlled Ovarian Stimulation <ref name="PMID26074966"/>. Metformin lowers the elevated insulin levels in PCOS which consequently reduce intraovarian androgen levels. This leads to a reduced sensitivity and expression of granulosa cell-follicle stimulating hormone receptors which result in a less exaggerated response to gonadotropins. Furthermore, it is suggested that Metformin prevents OHSS by controlling vascular permeability through the inhibition of various vasoactive molecules, including VEGF.

'''Avoiding hCG during Luteal Phase Support

Following Controlled Ovarian Stimulation, the steroid levels of E2 and P4 are reduced during the luteal phase due to the negative feedback on the pituitary. This leads to low endogenous LH levels, which consequently reduce endometrial receptivity as well as the luteal phase duration itself. As a result, implantation and pregnancy rates are reduced and early pregnancy loss rates are increased.<ref name="PMID20416867" /> Luteal Phase Support (LPS) serves to combat these adverse events with the use of hCG. However, hCG has been found to increase the risk of OHSS. Alternatively, the use of progesterone has been found to not only halve the risk of OHSS, but also induce similar improvements in pregnancy and miscarriage rates as hCG.<ref name="PMID26148507"><pubmed>26148507</pubmed></ref>

===Secondary Prevention===

Secondary Prevention aims to prevent progression to OHSS once COS has been initiated and the patient has been found to mount an exaggerated response. <ref name="PMID20416867" />

'''Coasting'''

Coasting is a first-line secondary preventative strategy. It consists of the withdrawal of gonadotrophins when a critical number of follicles and/or E2 concentration is reached. hCG is administered once the E2 concentration reduces to a safe level, before the process of oocyte retrieval commences. This preventative strategy is conducted for a period of less than 3 days in order to avoid compromising IVF outcomes.

'''Cryopreservation'''

Cryopreservation of embryos after oocyte retrieval is another avenue which may avert OHSS progression. The cryopreserved embryos are only reimplanted once the patient's hormone serum levels have normalised. Using oocyte vitrification, crystal formation within embryo tissue is avoided and so cryopreserved embryos have been found to produce better pregnancy rates with a 32% increase, than fresh embryo transfer. Recent studies suggest cryopreservation itself does not reduce OHSS rates, but must be followed by a GnRHa trigger to avert OHSS.

'''Cycle cancellation'''

Cycle cancellation is a guaranteed method to prevent early OHSS whereby hCG is withheld. This is a last resort strategy as it carries the risk of significant psychological distress and financial loss for the patient.

</div>

==Effect on the Newborn==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

</div>
Women who develop OHSS while undergoing Assisted Reproductive Technologies (ART) treatment are not only more likely to achieve a pregnancy, but have a live birth as the pregnancy outcome. This live birth is also more likely to be a multiple birth of two, three or more children. <ref name="PMID19591989"><pubmed>19591989</pubmed></ref> It has been postulated that a multifetal pregnancy leads to a more rapid increase in hCG levels, resulting in an increased risk of OHSS. However, the causal nature between multifetal pregnancy and OHSS development is disputed and further research is required to distinguish correlation from causation. <ref name="PMID19573292"><pubmed>19573292</pubmed></ref>

OHSS development is also associated with an increased risk of adverse outcomes including stillbirth, premature birth and low birthweight.<ref name="PMID19591989" /> Although the cause for the increased risk in adverse pregnancy outcomes is unknown, it is suggested that as the incidence of OHSS is reduced through various prevention strategies, the risk of such outcomes may be also be reduced.

==Genetics==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

Despite OHSS typically being of iatrogenic origin as a result of ovarian stimulation with gonadotropins, research has been conducted into the potential genetics behind OHSS as many sporadic and familial cases have been observed. '''Mutations''' in the receptor for hormones such as Follicle Simulating Hormone (FSH), Lutenizing Hormone (LH) and hCG have all been targets of OHSS genetics research. Interestingly, they too also arise from a common ancestral gene.

===Follicle Stimulating Hormome===

Dr. Botros Rizk, of the University of South Alabama College of Medicine <ref name="PMID19573286"><pubmed>19573286</pubmed></ref>, has written extensively regarding the genetics behind OHSS. In particular, he talks about '''FSH receptors''' (FSHR) and their role in the syndrome. He hypothesises that mutations in these receptors could be activating or inactivating, leading to an increased risk of developing OHSS or sterility respectively. Currently, 744 single nucleotide polymorphisms (a type of mutation) have been found in the gene encoding the FSHR, 8 of which are located in its exons (coding regions of the gene). How the ovary responds is resultant on the FSHR genotype. For example, Ser680Asn, a polymorphism in the FSHR gene has been shown to aid in predicting the severity of a woman's OHSS. Ordinarily FSH stimulates the growth of ovarian follicles, however, when mutated, it is stimulated by the hCG resulting in excessive follicle development.

Spontaneous OHSS, OHSS that arises and cannot be attributed to any form of ovarian stimulation or Assisted Reproductive Technology, has been linked to activating mutations in the FSHR <ref name="PMID23499866"><pubmed>23499866</pubmed></ref>. This familial disorder is an autosomal dominant one. In most cases the FSHR can be stimulated by the presence of Thyroid Stimulating Hormone (TSH) or hCG, in the absence of FSH (the ligand for FSHR).

===Lutenizing Hormome===

The '''Lutenizing Hormone Receptor''' (LHR) gene in humans is comprised of 11 exons. Animal studies have shown that many primates exhibit a similar gene which is comprised of only 10 exons, however a gene lacking the 10th exon has been identified and termed the type 2 LHR. Expression of the type 2 LHR has been seen in humans. The type 2 LHR, compared to the wild-type LHR appears to be repaired with regard to its function. Defects in the type 2 LHR include a decrease in efficiency of transport to the plasma membrane and irregularities in signal transduction. Inactivating mutations in the LHR have been seen to cause infertility in women as well as amenorrhoea. Activating LHR gene mutations are asymptomatic and are not associated with OHSS in women.

===Bone Morphogenic Protein===

An imporant growth factor, derived from oocytes called '''BMP-15''' (Bone Morphogenic Protein 15) is vital for female fertility. It belongs to the family of growth factors, Transforming Growth Factor β (TGF-β) and is heavily involved in folliculogenesis. It has been found that mutations in the BMP-15 gene caused infertility in female sheep. Conversely, it has also been indicated in enhanced fertility when BMP-15 is present is high amounts in follicular fluid <ref name="PMID19573286" />.

A case study done by Hanevik ''et. al.'' in 2013 <ref name="PMID21565556"><pubmed>21565556</pubmed></ref> found that a Single Nuclear Polymorphism (SNP) in the BMP-15 gene is responsible for a high response to ovarian hyper-stimulation. The aim of the study was to test the effect the SNP had on BMP-15 with regard to high and low responders buy taking blood from 53 high responders, 38 low responders and 100 non-responders (controls) and analysing 5 noted SNP's. Results from their study showed a correlation between a high response to ovarian hyper-stimulation and the BMP-15 9G allele. The article does state however, that further research is required into the molecular effects of SNP's on the function of BMP-15.

===Vascular Endothelial Growth Factor===

'''Vascular endothelial growth factor''' (VEGF) has been indicated as one of the key agents causing vascular permeability and subsequent ascites in OHSS. The gene, which is located on chromosome 12, is made up of 8 exons (coding regions), of which exons 6 and 7 do not always appear due to the exons being spliced out.The splicing of this gene allows for various isoforms of the gene to exist of which VEGF 121 and 165 appear to play a role in angiogenesis. There are two VEGF Receptors, VEGFR-1 and VEGFR-2 that belong to the tyrosine kinase family of receptors (for more information on VEGF see [[Pathophysiology]]). Because of its distinct role in OHSS, it has been targeted as an area for research for potential treatments. The idea is that if the genetic expression of VEGF and its receptors can be controlled, OHSS can be avoided or treated.<ref name="PMID19573286" />

A different study by Hanevik ''et. al.'' , <ref name="PMID22587628"><pubmed>22587628</pubmed></ref> done in 2012 involved analysing blood samples from 53 women with OHSS and 100 women without it (controls) and analysing 6 SNP's in the VEGFR2 gene to find any genetic variations. They found a correlation between women with the VEGF +405cc genotype and the development of OHSS indicating women that undergo controlled ovarian hyper-stimulation and posses his genotype, are at an increased risk of developing OHSS.

</div>

== Current Research on Animal Models==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">
{|
|-bgcolor="F8E0F1"
|
<span style="font-size:120%">'''Inhibition of Cyclooxygenase-2 (COX-2) by Meloxican decreasing the incidence of OHSS in Rat Model'''</span> <ref name="PMID18166186"><pubmed>18166186</pubmed></ref>

Reasearch was carried out to investigate the effects of selective inhibition of the enzyme COX-2 on the Ovarian Hyperstimulation Syndrome (OHSS) using Female Wistar rates as the subjects. The research aimed to find results by measuring the number of antral and luteinized follicles, ovarian weight, vascualr endothelial growth factors and COX-2 immunohistochemistry. The rats being tested were all 22 days old and were divided into four equal groups;

'''Group 1 (Control group)''' was subject to a 0.1 ml of Intraperitoneal Saline from days 22 ~ 26

'''Group 2 (Mildly-stimulated group)''' subject to 10IU of pregnant mare serum gonadotrophin (PMSG) on day 24 and then 10IU of Human Chorionic Gonadotrophin (hCG) on day 26

'''Group 3 (OHSS positive group)''' was subject to 10IU of PMSG from days 22 ~ 26 and then administered 30IU of hCG on day 26 to induce OHSS

'''Group 4 (OHSS positive variant group)''' received 15mg/ml of Meloxicam 2 hours prior to administration of 10IU PMSG from days 22 ~ 26

Results showed there was no difference in ovarian weight in samples from Group 1 and Group 2, however Group 3 showed signs of significant ovarian weight increase which in group 4 was suppressed by the introduction of Meloxicam. No differences were observed in the number of antral follicles amongst the four test groups. Results from Group 2 and Group 3 showed that the granulosa cells of preovulatory follicles and the stromal cells were highly VEGF immunoreactive, however the Meloxicam treated Group 4 showed less immunoreactivity than Group 2 and Group 3 which indicated the correlation between Meloxicam and the diminished VEGF expression. Group 3 presented an increased COS-2 immunoreactivity which was highly diminished than in Group 4.

The research concluded that in a rat model, the enzyme Meloxicam has a beneficial effect on OHSS by reducing the increase of ovarian weight and the expression of VEGF associated with OHSS, the effects of which may be mediated by the inhibitory capacity of COX-2 on Meloxicam
|}

{|
|-bgcolor="FF99FF"
|
<span style="font-size:120%">'''Inhibition of Ovarian VEGF secretion by activation of Dopamine Receptor 2'''</span> <ref name="PMID25217874"><pubmed>25217874</pubmed></ref>

This research was carried out to investigate a possibility in whether a Dopamine Receptor 2 agonist '''(D2-ag)''' can assist in the prevention of Ovarian Hyperstimulation Syndrome, using rat models, by decreasing the ovarian vascular endothelial growth factor '''(VEGF)''' production. Using Immature Wistar rats (22 days old) as their animal model, the rats were initially stimulated with Gonadotrophins to mimic the onset and effects of OHSS and then subjected to treatment with a D2-agonist and/or a D2-antagonist (D2-ant). The vascular permeability was measured at the endpoint after day 26 by measuring the peritoneal extravasion of a previously injected dye and ovaries from all subjects were collected to assess the effects of D2-ag and D2-ant on the production of Ovarian VEGF. The expression of VEGF mRNA was measured by quantitative real time PCR and the levels of VEGF proteins were measured by Western Blots.

Results showed that the D2-ag caused a large reduction in the vascular permeability which was in turn associated with the great decreased in VEGF protein production in the OHSS rat ovaries, whereas the introduction of D2-ant showed opposite results with a increase in the vascular permeability leading to the increase of VEGF protein production in the ovaries. Ovarian VEGF mRNA levels were found to be unaffected by the introduction of these drugs in OHSS rat subjects. Conclusions were drawn on the fact that Dopamine Receptor 2 agonists prevent the increase of vascular permeability in subjects with OHSS by decreasing the ovarian production of VEGF and also that due to the dose-dependent inhibitory effect of the D2-ag on ovarian VEGF, current OHSS therapies used in humans can benefit by increasing the intraovarian concentration of D2-ag.
|}
</div>

==Glossary==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

'''Aromatase Inhibitor''' - A drug that inhibits enzyme aromatase, which in turn suppresses estrogen synthesis.

'''Ascites''' - An accumulation of fluid in the peritoneal cavity with resultant abdominal swelling.

'''Cabergoline''' - A dopamine receptor agonist used to treat hormone imbalance.

'''Controlled Ovarian Stimulation''' - female infertility treatment using medications to stimulate the ovaries to develop follicles.

'''E2''' - Estradiol - Potent estrogen sex hormone.

'''Gonadotropin''' - Any hormone that has a stimulating effect on the gonads.

'''GnRH agonist''' - Gonadotropin Releasing Hormone - A class of compounds that mimic the effect of the natural Gonadotropin Releasing Hormone.

'''GnRH antagonist''' - Gonadotropin Releasing Hormone - A class of compounds that are similar in terms of the structure of natural Gonadotropin Releasing Hormone but has a antagonistic effect.

'''hCG'''- Human Chorionic Gonadotropin

'''Hemoconcentration''' - An increase in the concentration of circulating red blood cells in response to a decrease in blood plasma volume.

'''Hypovolemic''' - A decrease in circulating blood volume.

'''Iatrogenic''' - Illness caused as a result of a medical examination or treatment.

'''Intravenous fluids''' - Is the infusion of liquid substances directly into a vein.

'''IVF''' - In-vitro Fertilization

'''Metformin''' - A biguanide, antidiabetic drug used as an adjuvant to modify the effect of other agents.

'''NSAID''' - Non-steroidal Anti-Inflammatory Drug e.g. Ibuprofen

'''OHSS''' - Ovarian Hyper-stimulation Syndrome

'''P4''' - Progesterone - endogenous progestogen sex hormone.

'''PCOS''' - Polycystic Ovarian Syndrome. An endrocrine system disorder whereby the ovaries are enlarged with small collections of fluid.

'''FSH''' - Follicle Stimulating Hormone

'''LH''' - Luteinizing Hormone

'''Oliguria'''- Decreased urine output/small amounts of urine produced.

</div>

==References==

2015 Group Project 2

2015-10-22T22:41:19Z

Z3372824: /* Primary Prevention */

{{ANAT2341Project2015header}}

==<span style="font-size:120%">'''Ovarian Hyper-stimulation Syndrome (OHSS)'''</span>==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

Ovarian Hyper stimulation Syndrome (OHSS) is an iatrogenic complication of '''Assisted Reproduction Technology''' (ART), in which women take medications to stimulate oocyte growth. It is generally identified by cystic enlargements of the ovaries and fluid accumulation in the peritoneal cavity due to the increased capillary permeability and ovarian neoangiogenesis <ref name="PMID22065820"><pubmed>22065820</pubmed></ref>. It is an occurrence which is dependent on the controlled stimulation of the ovaries in preparation for IVF i.e. administration of human Chorionic Gonadotropin (hCG).

OHSS was first described in 1943 as ''“syndrome d’hyperluteinisation massive
des ovaries”''. It was during this time that gonadotropins were prepared from animals such as sheep to bring on ovulation in women. The first recorded death as a result of OHSS occurred in 1951 and was due to renal failure as a result of oligouria, a complication of the syndrome <ref name="OHSS"> Marie M. Budev, DO, MPH; Alejandro C. Arroliga, MD; Tommaso Falcone, MD, [ http://utilis.net/Morning%20Topics/REI/Ovarian%20Hyperstimulation.pdf ], 'Ovarian Hyperstimulation Syndrome'</ref> <ref name="PMID12638783"><pubmed>12638783</pubmed></ref>.

<span style="color:#FA58D0">This wikipage aims to provide clear information on various areas surrounding OHSS such as diagnosis, prevention and complications and will look into the genetics behind the disorder and the various animals models used to research it.</span>

<html5media height="350" width="450">https://www.youtube.com/watch?v=aXmjJw234a4</html5media>

'''Overview of the Ovarian Hyperstimulation Syndrome''' <ref> Howcast (2013, August 27) Ovarian Hyperstimulation Syndrome | Infertility. Retrieved from https://www.youtube.com/watch?v=aXmjJw234a4</ref>

</div>

==Epidemiology==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

Ovarian Hyper-Stimulation Syndrome (OHSS) rarely occurs sporadically, and if it does, it is usually the result of an underlying genetic problem. The majority of OHSS is due to the ovaries being stimulated to mature and release an abundance of oocytes, in response to hormones Human Chorionic Gonadotropin (hCG) and Follicle Stimulating hormone (FSH), during IVF. Rarely, Clomifene Citrate therapy can cause OHSS.<ref name="WikiOHSS"> Wikipedia, [ https://en.wikipedia.org/wiki/Ovarian_hyperstimulation_syndrome ], 'Ovarian Hyperstimulation Syndrome'</ref>

OHSS only affects '''0.5-5%''' of women undergoing Ovarian Hyper-stimulation, but despite its small prevalence, it is a potentially fatal outcome of a non-vital procedure and remains a prevalent problem for fertility specialists <ref name="PMID12498425"><pubmed>12498425</pubmed></ref> <ref name="PMID12638783"><pubmed>12638783</pubmed></ref>. Age has been cited as a factor affecting those with OHSS, with younger women more at risk. Additionally, women with allergies were seen to have a higher incidence of OHSS. It is important to note that at this point in time, there is no positive correlation between gonadotropin dose and OHSS.

Of the 0.5-5% of women affected with OHSS mentioned above, 2% of those women will require hospitalisation. As of 2011, it has been reported that the incidence of OHSS was '''increasing''', resulting in approximately 3 deaths per 100,000 women undergoing ovarian stimulation per year <ref name="PMID21828116"><pubmed>21828116</pubmed></ref>. This is particularly worrying as in 2008, in the United States alone, there were around 150,000 IVF cycles undertaken.

{|
|-bgcolor="F8E0F1"
|
'''With the field of Assisted Reproductive Technologies expanding and more women partaking in IVF treatments, the threat of women developing OHSS is an ongoing and increasing one''' <ref name="PMID21828116" />.
|}
{| class="wikitable mw-collapsible mw-collapsed"
! Characteristics of women by complication group <ref name="PMID19591989"><pubmed>19591989</pubmed></ref>
|-
! scope="col" width="100px" height="60px" style="text-align:center| '''Characteristic'''
! scope="col" width="100px" height="60px" style="text-align:center| '''No Complications
(N = 212,041)'''
! scope="col" width="100px" height="60px" style="text-align:center| '''Moderate OHSS
(N = 1,523)'''
! scope="col" width="100px" height="60px" style="text-align:center| '''Severe OHSS
(N = 655)'''
|-
|style="text-align:center; background: #FF99FF;"| '''Maternal Age (Mean ± SD)'''
|style="text-align:center; background: #F6CEEC;"| 35.6 ± 4.6
|style="text-align:center; background: #F6CEEC;"| 33.0 ± 4.3
|style="text-align:center; background: #F6CEEC;"| 33.1 ± 4.4
|-
|style="text-align:center; background: #FF99FF;"| '''Maternal Age (%)'''
|-
|style="text-align:left; background: #F6CEEC;"| <30 years
|style="text-align:center; background: #F6CEEC;"| 10 %
|style="text-align:center; background: #F6CEEC;"| 21.1 %
|style="text-align:center; background: #F6CEEC;"| 20.6 %
|-
|style="text-align:left; background: #F6CEEC;"| 30-34 years
|style="text-align:center; background: #F6CEEC;"| 30.4 %
|style="text-align:center; background: #F6CEEC;"| 43.2 %
|style="text-align:center; background: #F6CEEC;"| 40.5 %
|-
|style="text-align:left; background: #F6CEEC;"| 35-39 years
|style="text-align:center; background: #F6CEEC;"| 37.8 %
|style="text-align:center; background: #F6CEEC;"| 27.2 %
|style="text-align:center; background: #F6CEEC;"| 32.5 %
|-
|style="text-align:left; background: #F6CEEC;"| >40 years
|style="text-align:center; background: #F6CEEC;"| 21.8 %
|style="text-align:center; background: #F6CEEC;"| 8.4 %
|style="text-align:center; background: #F6CEEC;"| 6.4 %
|-
|style="text-align:center; background: #FF99FF;"| '''Nulligravida (%)'''
|style="text-align:center; background: #F6CEEC;"| 45.8 %
|style="text-align:center; background: #F6CEEC;"| 51.5 %
|style="text-align:center; background: #F6CEEC;"| 51.8 %
|-
|style="text-align:center; background: #FF99FF;"| '''Infertility Diagnosis (%)'''
|-
|style="text-align:left; background: #F6CEEC;"| Male factor
|style="text-align:center; background: #F6CEEC;"| 37.7 %
|style="text-align:center; background: #F6CEEC;"| 41.0 %
|style="text-align:center; background: #F6CEEC;"| 33.4 %
|-
|style="text-align:left; background: #F6CEEC;"| Endometriosis
|style="text-align:center; background: #F6CEEC;"| 13.5 %
|style="text-align:center; background: #F6CEEC;"| 13.5 %
|style="text-align:center; background: #F6CEEC;"| 10.7 %
|-
|style="text-align:left; background: #F6CEEC;"| Ovulation Disorders
|style="text-align:center; background: #F6CEEC;"| 14.0 %
|style="text-align:center; background: #F6CEEC;"| 29.5 %
|style="text-align:center; background: #F6CEEC;"| 22.4 %
|-
|style="text-align:left; background: #F6CEEC;"| Diminished ovarian reserve
|style="text-align:center; background: #F6CEEC;"| 16.9 %
|style="text-align:center; background: #F6CEEC;"| 3.2 %
|style="text-align:center; background: #F6CEEC;"| 2.4 %
|-
|style="text-align:left; background: #F6CEEC;"| Tubal factors
|style="text-align:center; background: #F6CEEC;"| 20.4 %
|style="text-align:center; background: #F6CEEC;"| 22.6 %
|style="text-align:center; background: #F6CEEC;"| 22.3 %
|-
|style="text-align:left; background: #F6CEEC;"| Uterine factors
|style="text-align:center; background: #F6CEEC;"| 5.1 %
|style="text-align:center; background: #F6CEEC;"| 4.3 %
|style="text-align:center; background: #F6CEEC;"| 3.1 %
|-
|style="text-align:left; background: #F6CEEC;"| Other factors
|style="text-align:center; background: #F6CEEC;"| 13.9 %
|style="text-align:center; background: #F6CEEC;"| 13.1 %
|style="text-align:center; background: #F6CEEC;"| 10.4 %
|-
|style="text-align:left; background: #F6CEEC;"| Unexplained factor
|style="text-align:center; background: #F6CEEC;"| 12.7 %
|style="text-align:center; background: #F6CEEC;"| 11.8 %
|style="text-align:center; background: #F6CEEC;"| 18.6 %
|-
|}
</div>

==Causative Agents==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

[[File:Follicular Development.jpeg|right|thumbnail|500px|Infertility treatments aim to facilitate follicular development and induce ovulation to improve chances of fertilisation <ref name="PMID24717179"><pubmed>24717179</pubmed></ref>]]

Normally a woman produces one egg per month from the ovaries, which travel down the Fallopian tube to be fertilized or be released from the body. In cases where women have difficulty falling pregnant, they are given medication which help them to produce and release eggs (as shown in the diagram to the right), further increasing their chances of fertilization and pregnancy <ref><pubmed>19573285</pubmed></ref>. Ovarian Hyper stimulation Syndrome generally occurs during infertility treatments when the ovaries are overstimulated by the fertility medication which causes the ovaries to swell and leak fluids into the belly and abdomen. The prevalence of OHSS onset is linked with excessive number of follicle development in response to the administration of injectable Follicle Stimulating Hormones (FSH) followed by the '''Human Chorionic Gonadotrophins''' (hCG) which triggers the release of the oocytes <ref><pubmed>26190539</pubmed></ref>.

'''Follicle Stimulating Hormones''' (FSH) <ref name="PMID9020850"><pubmed>9020850</pubmed></ref> are glycoprotein hormones that are produced and secreted from the Anterior Pituitary gland into the bloodstream, which regulate the developmental, growth, maturation and the reproductive processes within the body. In females, the Follicle Stimulating Hormones initiates the stages of growth and development of immature ovarian follicles within the ovaries before the release of an egg from a follicle at ovulation. When FSH is administered to a patient who is suffering from infertility, the increase FSH levels affect the rate of development and production, in turn increasing the amount of follicles which are ready to be released during ovulation.

</div>

==Symptoms==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

OHSS is classified based on a criteria from mild, moderate and severe <ref name="WikiOHSS" />:

'''Mild Symptoms'''- abdominal bloating, minimal weight gain, nausea, diarrhoea and a feeling of fullness.

'''Moderate Symptoms'''- Substantial weight gain (on average 2 or more pounds a day), increased abdominal girth, darkend urine and excessive thirst in addition to the mild symptoms.

'''Severe Symptoms'''- In addition to the symptoms associated with Mild and Moderate OHSS, in severe OHSS, you see shortness of breath, calf and chest pains and pleural effusion.

<span style="font-size:100%">'''Classifications of Ovarian Hyper-stimulation Syndrome:'''</span> <ref name="PMID22065820"><pubmed>22065820</pubmed></ref>
{| class="wikitable" style="text-align:center
|-
! scope="col" width="70px"| '''Classification'''
! scope="col" width="650px"| '''Symptoms'''
|-
|style="text-align:center; background: #F6CEEC;"| '''Mild'''
|style="height: 60px; background: #F6CEEC;"| '''Grade 1''' - Abdominal distention and discomfort
'''Grade 2''' - Abdominal distention, discomfort with nausea, vomiting and/or diarrhea and ovarian enlargement from 5~12cm
|-
|style="text-align:center; background: #F8E0F1;"| '''Moderate'''
|style="height: 60px; background: #F8E0F1;"| '''Grade 3''' - All features of Mild OHSS with ultrasonographic evidence of ascites
|-
|style="text-align:center; background: #F6CEEC;"| '''Severe'''
|style="height: 60px; background: #F6CEEC;"| '''Grade 4''' - All features of Moderate OHSS with the addition of clinical evidence of ascites and breathing difficulties present
'''Grade 5''' - All of the above symptoms along with a change in the blood volume, increased blood viscosity due to coagulation and diminished renal function
|}

</div>

==Diagnosis==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

Whilst symptoms of OHSS can occur as soon as 24 hours post hCG administration, they are usually seen in women 7-10 days post administration. Initially women with OHSS will present with abdominal bloating, as a result of fluid in the peritoneal cavity and an increase in ovary size. When women present with severe OHSS they are often dehydrated, due to increased vascular permeability, and have hemoconcentration. The above results in a decrease in intravascular volume, leading to '''oligouria''' <ref name="PMID22416285" />.

===History===

Initially a thorough history of the patient is taken during which the clinician looks for evidence of ovarian stimulation, followed by ovulation. During this history taking, the clinician will inquire into any weight gain noticed, urine output, and the woman's ability to maintain oral hydration. A key diagnostic tool for clinicians regarding women who are taking gonadotropins is to identify if they are at an increased risk of developing OHSS. Some risk factors include woman aged less than 30, women who have polycystic ovaries, woman with a previous history of OHSS and women who have had greater than 20 oocytes retrieved <ref name="PMID22416285" />.

===Physical Exam===
[[File:Vaginal_Ultrasonography_in_Sagittal_Plane.jpg|right|thumbnail|600px|Vaginal Ultrasonography in Sagittal plane <ref name="Wikiversity Journal of Medicine"> Häggström, Mikael. "Medical gallery of Mikael Häggström 2014". Wikiversity Journal of Medicine 1 (2). DOI:10.15347/wjm/2014.008. ISSN 20018762</ref>]]
After a history of the patient is taken, the next step is to perform a physical exam on the patient. Women who present with abdominal bloating will produce a shifting dullness upon abdominal percussion. Additionally the clinician will test the woman's vital signs, measure her abdominal girth, weight and will look for evidence of ascites or increase in calf size (usually unilateral)<ref name="PMID22416285" />.

===Investigations===

If the clinician further suspects a women of having OHSS, various investigations can be done such as an ultrasound.The intraperitoneal fluid is best imaged via vaginal ultrasound due to the enlarged ovaries making it difficult to image the pelvis using transabdominal ultrasound. The clinician can also order laboratory testing to look for urine specific gravity and and complete blood count to look for hemoconcentration with a hematocrit. Additionally, liver function tests can be ordered to look for elevated function. The clinician will also look for evidence of elevated D-dimers and fibrinogen and decreased levels of anti-thrombin 3 <ref name="SAHealth"> Government of South Australia Health [ http://www.sahealth.sa.gov.au/wps/wcm/connect/9b61ed004ee5348da663afd150ce4f37/Ovarian-hyperstimulation-syndrome-WCHN-PPG-17072012.pdf?MOD=AJPERES&CACHEID=9b61ed004ee5348da663afd150ce4f37 ], 'South Australian Paediatric Clinical Guidelines OHSS'</ref>.

====Ultrasound====

Typical appearances of the ultrasound include <ref name="Ultrasound"> Radiopaedia [ http://radiopaedia.org/articles/ovarian-hyperstimulation-syndrome-1 ], 'Ovarian Hyperstimulation Syndrome'</ref>:

*Bilaterally and symmetrically enlarged ovaries (>12cm)
* "Spoke-Wheel appearance" - presence of multiple cysts of varying size
*May also see ascites (fluid)

===Severity===

Once a clinician has deduced a women is suffering from OHSS, the severity of their condition needs to be established as either mild, moderate or severe. This is done by referring to the criteria under the sub-heading [[Symptoms]].The subsequent course of treatment for the woman will be based upon this evaluation.

{|
|-bgcolor="F6CEEC"
|
'''Further investigations''' can be done including a Chest X-ray to check for pleural effusions and oedema and USS with Doppler's to check for ascites or possible ovary torsion. <ref name="PMID22416285"><pubmed>22416285</pubmed></ref>
|}

===Differential Diagnosis===

Conditions presenting with similar symptoms or ultrasound images include <ref name="Ultrasound" />:

*Polycystic Ovaries (PO)
:: The difference is that with PO is that the cycts are typically smaller than OHSS cysts and there is no evidence of ascited or pleural effusion
*Mucinous Ovarian Malignancy
:: A type of Ovarian Epithelial tumour
*Ectopic Pregnancy <ref name="Casereport"> Australian Medical Student Journal [ http://www.amsj.org/wpcontent/uploads/files/articles/amsj_v2_i1/AMSJ_v2_i1_pg58-60.pdf ], 'Ovarian hyperstimulation syndrome'</ref>
::A pregnancy in which the foetus develops outside of the uterus e.g. in the fallopian tube

</div>

==Pathophysiology==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

[[File:Pathogenesis_of_OHSS.png|600px|thumb|Pathogenesis of OHSS <ref name="PMID20416867"><pubmed>20416867</pubmed></ref>]]

The definition of Ovarian Stimulation is enlarged ovaries with many luteinized cysts, that can present with secondary complications. What distinguishes Ovarian Stimulation from OHSS is the presence of vascular hyper-permeability that results in fluids being redirected elsewhere in the body.

The key process to OHSS appears to be caused by '''Vascular Endothelial Growth Factor''' (VEGF), that is released along with other cytokines, estrogen and progesterone, due to the ovary undergoing luteinization as a result of stimulation by hCG. VEGF increases vascular permeability and as a result the capillaries become more "leaky" to the fluids in them. These fluids can then escape the capillaries and accumulate in the pleural and abdominal cavities as ascites. The woman then becomes hypovolemic and is at an increased risk of circulatory, renal and respiratory issues such as arterial thromboembolism due to the thickening of the blood. Note, the blood is thickened as fluid is leaving the capillaries, leaving behind red blood cells and other cellular components of the blood <ref name="WikiOHSS" />.

The increase in expression of VEGF and VEGF Receptor 2 (VEGFR2) is attributed to the greatly increased amount of their mRNA present in the body after stimulation with hCG <ref name="PMID21082502"><pubmed>21082502</pubmed></ref>. VEGF interacts with VEGF2 and VEGF Receptor 1 (VEGFR1) to create a strong angiogenic effect. Both VEGFR2 and VEGFR1 belong to a family of receptors called tyrosine kinases. VEGF2 is involved in the regulation of angiogenesis and vascular permeability whilst VEGF1 has a slightly contradictory role in that is is involved in the maintenance of the tight junctions between endothelial cells in blood vessels. A study by Gómez ''et. al.'' <ref name="PMID21082502" /> showed that women experiencing OHSS had substantially higher plasma levels of VEGF and lower levels of VEGFR1.

</div>

==Complications==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

Ovarian torsion or rupture, renal insufficiency and thrombophlebitis can all complicate OHSS. If a pregnancy occurs, symptoms may persist longer than the usual 1 to 2 weeks and become more severe, however, even with severe OHSS, they do not extend past the first trimester <ref name="WikiOHSS" />.

<span style="color:#FA58D0"> '''1-2% of women who undergo ovarian stimulation develop a severe form of OHSS''' </span>. Complications from severe OHSS include:

*Fluid collection in the abdomen
*Electrolyte disturbances (sodium and potassium)
*Kidney failure
*Ovary twisting
*Rupture of a cyst in an ovary
*Breathing problems
*Blood clots in large vessels (most commonly the legs)
*Pregnancy loss from miscarriage or termination
*Rarely, death

A study by Nouri ''et. al.'' <ref name="PMID24996451"><pubmed>24996451</pubmed></ref> found that women with '''Polycystic Ovarian Syndrome''' (PCOS) and those that were induced with hCG experienced longer recovery times from severe OHSS than women who were not pregnant. They looked at a cohort of women hospitalised for the first time with severe OHSS and subject them to the same treatments. Based on a defined criteria, they established the recovery time of these women and compared the times between those that were pregnant to those that were not pregnant. They also found that whether a woman had PCOS or ovulation induction did not affect her risk of developing OHSS if she was not pregnant. It is only a risk factor for pregnant women.

===Thromboembolic events===

A frequent and deadly complication of OHSS are thromboembolic events due to increased blood clotting. This increase in blood clotting has been attributed to a variety of complications such as hemoconcentration (which thickens the blood), hypovolemia and an increase in the permeability of blood vessels as a result of increased vasoactive substances in the body of ovarian origin. Thromboembolic events include venous thromboses often in the upper extremities and arterial thromboses such as those in the cerebrovascular region. These events can lead to amputations of extremities, brain damage, miscarriage and death. To avoid this, anti-coagulants are given to pateitns with OHSS and they are fitted with compression stockings (see [[Treatment]]) <ref name="PMID23378404"><pubmed>23378404</pubmed></ref>.

{|
|-bgcolor="F8E0F1"
|
The risk of a woman developing OHSS is higher if she is having a '''twin pregnancy''', as she is exposed to higher concentration of hCG. <ref name="PMID9756273"><pubmed>9756273</pubmed></ref>
|}

</div>

==Treatment==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

'''General treatment
'''
*''Acetaminophen'' with or without a narcotic agent- used to treat abdominal discomfort
*Women are encouraged to drink 2-3 litres of water a day to prevent hemoconcentration
*Women are advised to avoid sexual intercourse and vigorous exercise at the risk of torsion or rupture of the ovaries
*NSAID's with anti-platelet properties should NOT be used as they may effect renal function in a women with OHSS
*Patients with significantly painful ascites or breathing problems may undergo ''Paracentesis'' (drainage of the ascites)
*''Culdocentesis'' (extraction of fluid from recto-uterine pouch) can be done to decrease the likelihood of a woman with moderate OHSS progressing to severe OHSS.<ref name="PMID22416285" />

===Mild to Moderate OHSS===

Mild OHSS can often resolve on its own, however, moderate OHSS may include treatments such as<ref name="WikiOHSS" />:

*Anti-nausea medication and prescription painkillers
*Regular physical examinations and ultrasounds
*Daily weigh-ins and waist measurements
*Measuring the amount of urine produced each day
*Frequent blood tests for monitoring dehydration and electrolyte imbalance
*Maintaining a high balance of fluids
*Drainage of excess abdominal fluid by inserting a needle in the abdominal cavity
*Wearing support stockings which help prevent blood clots/thrombosis

===Severe OHSS===

Severe OHSS requires hospital care in order for constant monitoring and treatment such as <ref name="WikiOHSS" />:

*Intravenous fluids with a crystalloid solution (100-150mL/hr)
*Intravenous Albumin is administered is IV fluids are insufficient (15-20mL/hr of 25% albumin for 4 hrs)
*In addition to Acetaminophen, ''Opioid analgesics'' can be administered for pain relief
*''Antiemetics'' can be used to subside nauseas and/or vomiting
*Woman administered to hospital of OHSS are considered at high risk of thromboembolic complications and are given low molecular weight ''heparin'', an anti-coagulant
*''Cabergoline''- lessens OHSS symptoms
*''GnRH agonist''- suppresses ovarian activity
**If at risk of OHSS, alternates include using a GnRH agonist instead of hCG however its effects on pregnancy rates are questionable. Using a GnRH agonist to replace the use of hCG for final oocyte stimulation will see a 6% decrease in delivery rate.

*Daily monitoring of creatine, urea, creatine clearance C-reactive protein (to rule out infection) are all required in combination with weekly tests such as liver and renal function tests and chest x-rays (to check for pleural effusion) <ref name="PMID12638783" />.

If there are serious complications then additional treatments are required:

*Surgery for a ruptured ovarian cyst
*Intensive care for the liver or lung complications

====Paracentesis====

For women with severe/grade 3 OHSS, paracentesis, the removal of fluid from the body using an aspiration needle, can be undertaken. It is a diagnostic and a therapeutic method that can be done trans-abdominally and trans-vaginally. It is used to relieve symptoms, improve haemodynamics e.g. Urinary output, and shorten the women's hospital stay. Complications of paracentesis include bleeding, infection and organ injury, however are note common <ref name="Paracentesis"> S. Monica Soni, HMS 3, Gillian Lieberman, MD [ http://eradiology.bidmc.harvard.edu/LearningLab/genito/Soni.pdf ], 'Ovarian Hyperstimulation Syndrome'</ref>.

{|
|-bgcolor="F8E0F1"
|
The most important aspect of treatment for any women with OHSS is close and constant '''monitoring''' with her healthcare professional. Counselling may also be provided to women and their partners or families in order to provide them with the best possible knowledge base to manage and treat their OHSS. It is important to note that there is '''no one cure or treatment''' for OHSS. Treatment involves managing and eliminating the symptoms until such time as the syndrome resolves itself <ref name="WikiOHSS" />.
|}

</div>

==Prevention==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

There are three key avenues through which the incidence of OHSS may be prevented. These include identifying risk factors to predict OHSS development, modifying treatment regimes on the basis of the identified risk factors and intervention to prevent progression to OHSS once the patient has undergone '''Controlled Ovarian Stimulation''' (COS).

=== Risk factors===

'''Primary risk factors'''

Pre-existing factors likely to exacerbate the ovarian stimulation response. Primary risk factors include <ref name="PMID26074966"><pubmed>26074966</pubmed></ref>:

*Young age
*Low body weight
*History of elevated response to gonadotropins
*Polycystic Ovary Syndrome (PCOS)
*Isolated PCOS characteristic
*A previous history of OHSS.
*Hormonal markers (e.g. Anti-Mullerian Hormone markers)
*Ultrasonographic markers (e.g. Antral Follicle Count)

'''Secondary risk factors'''

Secondary risk factors involve the monitoring of ovarian response parameters once COS has been initiated. These parameters are monitored for <ref name="PMID19007627"><pubmed>19007627</pubmed></ref>:

*rapidly rising E2 levels
*E2 concentration larger than 2500 pg/mL
*large number of developing follicles (10-14mm) on the day hCG is administered
*large number of oocytes retrieved

These factors in combination, act as a predictive tool to assess the likelihood of severe OHSS development, with a 83% sensitivity and 84% specificity. <ref name="PMID19007627"/>

=== Primary Prevention===

Primary Prevention involves the modification of treatment regimens on the basis of OHSS risk classifications, in order to prevent OHSS occurrence.

'''Ovulation Induction'''

Unifollicular Ovulation Induction through Ovulation Induction (OI) is a primary means of avoiding OHSS in women with Polycystic Ovarian Syndrome, who are at an increased risk. In order to promote unifollicular development, the ovaries are stimulated with a low starting dose of FSH (75 IU).<ref name="PMID20416867"><pubmed>20416867</pubmed></ref> Studies suggests that a minimum gonadotropin dose lowers OHSS risk and thus a step-up regimen is utilised to achieve an ovarian response, whereby the FSH dosage is increased every 7 days until follicular development of greater than 10mm is noted.<ref name="PMID26074966" /> Alternatively, a step-down regimen may be followed, whereby a high initial FSH dosage is lowered according to the ovarian response. Another method to increase FSH levels during OI, is through '''Aromatase Inhibitors''' which promote folliculogenesis by increasing pituitary secretion of FSH, and downregulate oestrogen production through a negative feedback loop. However, Aromatase Inhibitors have not been shown to reduce OHSS incidence in comparison to other methods of OI.<ref name="PMID26074966" /> During OI, a key objective is to prevent early cycle cancellation due to premature luteinisation from pituitary secretion of LH. In order to downregulate LH secretion, Gonadotropin-releasing hormone agonists '''GnRHa''' are administered in addition to gonadotropins. Alternatively, '''GnRH antagonists''' may be administered to downregulate endogenous LH secretion. Comparative studies have shown that the GnRH antagonist protocol has a greater effect in lowering the incidence of mild to severe OHSS. However due to the rare nature of OHSS, and insufficient sample sizes, the difference was not found to be significant. <ref name="PMID21082508"><pubmed>21082508</pubmed></ref>. Generally, the duration of exposure to gonadotropins and subsequent risk of OHSS may be minimised through mild stimulation protocols which administer FSH only in the mid to late follicular phase.<ref name="PMID20416867" />

'''Adjuvant Metformin Therapy'''

Adjuvant Metformin Therapy has been found to lower the risk of OHSS by 63%.<ref name="PMID25406011"><pubmed>25406011</pubmed></ref> It involves the administration of metformin at a daily dosage of 1000 to 2000mg, 2 months prior to Controlled Ovarian Stimulation <ref name="PMID26074966"/>. Metformin lowers the elevated insulin levels in PCOS which consequently reduce intraovarian androgen levels. This leads to a reduced sensitivity and expression of granulosa cell-follicle stimulating hormone receptors which result in a less exaggerated response to gonadotropins. Furthermore, it is suggested that Metformin prevents OHSS by controlling vascular permeability through the inhibition of various vasoactive molecules, including VEGF.

'''Avoiding hCG during Luteal Phase Support

Following Controlled Ovarian Stimulation, the steroid levels of E2 and P4 are reduced during the luteal phase due to the negative feedback on the pituitary. This leads to low endogenous LH levels, which consequently reduce endometrial receptivity as well as the luteal phase duration itself. As a result, implantation and pregnancy rates are reduced and early pregnancy loss rates are increased.<ref name="PMID20416867" /> Luteal Phase Support (LPS) serves to combat these adverse events with the use of hCG. However, hCG has been found to increase the risk of OHSS. Alternatively, the use of progesterone has been found to not only halve the risk of OHSS, but also induce similar improvements in pregnancy and miscarriage rates as hCG.<ref name="PMID26148507"><pubmed>26148507</pubmed></ref>

===Secondary Prevention===

Secondary Prevention aims to prevent progression to OHSS once COS has been initiated and the patient has been found to mount an exaggerated response. <ref name="PMID20416867" />

'''Coasting'''

Coasting is a first-line secondary preventative strategy. It consists of the withdrawal of gonadotrophins when a critical number of follicles and/or E2 concentration is reached. hCG is administered once the E2 concentration reduces to a safe level, before the process of oocyte retrieval commences. This preventative strategy is conducted for a period of less than 3 days in order to avoid compromising IVF outcomes.

'''Cryopreservation'''

Cryopreservation of embryos after oocyte retrieval is another avenue which may avert OHSS progression. The cryopreserved embryos are only reimplanted once the patient's hormone serum levels have normalised. Using oocyte vitrification, crystal formation within embryo tissue is avoided and so cryopreserved embryos have been found to produce better pregnancy rates with a 32% increase, than fresh embryo transfer. Recent studies suggest cryopreservation itself does not reduce OHSS rates, but must be followed by a GnRHa trigger to avert OHSS.

'''Cycle cancellation'''

Cycle cancellation is a guaranteed method to prevent early OHSS whereby hCG is withheld. This is a last resort strategy as it carries the risk of significant psychological distress and financial loss for the patient.

</div>

==Effect on the Newborn==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

</div>
Women who develop OHSS while undergoing Assisted Reproductive Technologies (ART) treatment are not only more likely to achieve a pregnancy, but have a live birth as the pregnancy outcome. This live birth is also more likely to be a multiple birth of two, three or more children. <ref name="PMID19591989"><pubmed>19591989</pubmed></ref> It has been postulated that a multifetal pregnancy leads to a more rapid increase in hCG levels, resulting in an increased risk of OHSS. However, the causal nature between multifetal pregnancy and OHSS development is disputed and further research is required to distinguish correlation from causation. <ref name="PMID19573292"><pubmed>19573292</pubmed></ref>

OHSS development is also associated with an increased risk of adverse outcomes including stillbirth, premature birth and low birthweight.<ref name="PMID19591989" /> Although the cause for the increased risk in adverse pregnancy outcomes is unknown, it is suggested that as the incidence of OHSS is reduced through various prevention strategies, the risk of such outcomes may be also be reduced.

==Genetics==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

Despite OHSS typically being of iatrogenic origin as a result of ovarian stimulation with gonadotropins, research has been conducted into the potential genetics behind OHSS as many sporadic and familial cases have been observed. '''Mutations''' in the receptor for hormones such as Follicle Simulating Hormone (FSH), Lutenizing Hormone (LH) and hCG have all been targets of OHSS genetics research. Interestingly, they too also arise from a common ancestral gene.

===Follicle Stimulating Hormome===

Dr. Botros Rizk, of the University of South Alabama College of Medicine <ref name="PMID19573286"><pubmed>19573286</pubmed></ref>, has written extensively regarding the genetics behind OHSS. In particular, he talks about '''FSH receptors''' (FSHR) and their role in the syndrome. He hypothesises that mutations in these receptors could be activating or inactivating, leading to an increased risk of developing OHSS or sterility respectively. Currently, 744 single nucleotide polymorphisms (a type of mutation) have been found in the gene encoding the FSHR, 8 of which are located in its exons (coding regions of the gene). How the ovary responds is resultant on the FSHR genotype. For example, Ser680Asn, a polymorphism in the FSHR gene has been shown to aid in predicting the severity of a woman's OHSS. Ordinarily FSH stimulates the growth of ovarian follicles, however, when mutated, it is stimulated by the hCG resulting in excessive follicle development.

Spontaneous OHSS, OHSS that arises and cannot be attributed to any form of ovarian stimulation or Assisted Reproductive Technology, has been linked to activating mutations in the FSHR <ref name="PMID23499866"><pubmed>23499866</pubmed></ref>. This familial disorder is an autosomal dominant one. In most cases the FSHR can be stimulated by the presence of Thyroid Stimulating Hormone (TSH) or hCG, in the absence of FSH (the ligand for FSHR).

===Lutenizing Hormome===

The '''Lutenizing Hormone Receptor''' (LHR) gene in humans is comprised of 11 exons. Animal studies have shown that many primates exhibit a similar gene which is comprised of only 10 exons, however a gene lacking the 10th exon has been identified and termed the type 2 LHR. Expression of the type 2 LHR has been seen in humans. The type 2 LHR, compared to the wild-type LHR appears to be repaired with regard to its function. Defects in the type 2 LHR include a decrease in efficiency of transport to the plasma membrane and irregularities in signal transduction. Inactivating mutations in the LHR have been seen to cause infertility in women as well as amenorrhoea. Activating LHR gene mutations are asymptomatic and are not associated with OHSS in women.

===Bone Morphogenic Protein===

An imporant growth factor, derived from oocytes called '''BMP-15''' (Bone Morphogenic Protein 15) is vital for female fertility. It belongs to the family of growth factors, Transforming Growth Factor β (TGF-β) and is heavily involved in folliculogenesis. It has been found that mutations in the BMP-15 gene caused infertility in female sheep. Conversely, it has also been indicated in enhanced fertility when BMP-15 is present is high amounts in follicular fluid <ref name="PMID19573286" />.

A case study done by Hanevik ''et. al.'' in 2013 <ref name="PMID21565556"><pubmed>21565556</pubmed></ref> found that a Single Nuclear Polymorphism (SNP) in the BMP-15 gene is responsible for a high response to ovarian hyper-stimulation. The aim of the study was to test the effect the SNP had on BMP-15 with regard to high and low responders buy taking blood from 53 high responders, 38 low responders and 100 non-responders (controls) and analysing 5 noted SNP's. Results from their study showed a correlation between a high response to ovarian hyper-stimulation and the BMP-15 9G allele. The article does state however, that further research is required into the molecular effects of SNP's on the function of BMP-15.

===Vascular Endothelial Growth Factor===

'''Vascular endothelial growth factor''' (VEGF) has been indicated as one of the key agents causing vascular permeability and subsequent ascites in OHSS. The gene, which is located on chromosome 12, is made up of 8 exons (coding regions), of which exons 6 and 7 do not always appear due to the exons being spliced out.The splicing of this gene allows for various isoforms of the gene to exist of which VEGF 121 and 165 appear to play a role in angiogenesis. There are two VEGF Receptors, VEGFR-1 and VEGFR-2 that belong to the tyrosine kinase family of receptors (for more information on VEGF see [[Pathophysiology]]). Because of its distinct role in OHSS, it has been targeted as an area for research for potential treatments. The idea is that if the genetic expression of VEGF and its receptors can be controlled, OHSS can be avoided or treated.<ref name="PMID19573286" />

A different study by Hanevik ''et. al.'' , <ref name="PMID22587628"><pubmed>22587628</pubmed></ref> done in 2012 involved analysing blood samples from 53 women with OHSS and 100 women without it (controls) and analysing 6 SNP's in the VEGFR2 gene to find any genetic variations. They found a correlation between women with the VEGF +405cc genotype and the development of OHSS indicating women that undergo controlled ovarian hyper-stimulation and posses his genotype, are at an increased risk of developing OHSS.

</div>

== Current Research on Animal Models==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">
{|
|-bgcolor="F8E0F1"
|
<span style="font-size:120%">'''Inhibition of Cyclooxygenase-2 (COX-2) by Meloxican decreasing the incidence of OHSS in Rat Model'''</span> <ref name="PMID18166186"><pubmed>18166186</pubmed></ref>

Reasearch was carried out to investigate the effects of selective inhibition of the enzyme COX-2 on the Ovarian Hyperstimulation Syndrome (OHSS) using Female Wistar rates as the subjects. The research aimed to find results by measuring the number of antral and luteinized follicles, ovarian weight, vascualr endothelial growth factors and COX-2 immunohistochemistry. The rats being tested were all 22 days old and were divided into four equal groups;

'''Group 1 (Control group)''' was subject to a 0.1 ml of Intraperitoneal Saline from days 22 ~ 26

'''Group 2 (Mildly-stimulated group)''' subject to 10IU of pregnant mare serum gonadotrophin (PMSG) on day 24 and then 10IU of Human Chorionic Gonadotrophin (hCG) on day 26

'''Group 3 (OHSS positive group)''' was subject to 10IU of PMSG from days 22 ~ 26 and then administered 30IU of hCG on day 26 to induce OHSS

'''Group 4 (OHSS positive variant group)''' received 15mg/ml of Meloxicam 2 hours prior to administration of 10IU PMSG from days 22 ~ 26

Results showed there was no difference in ovarian weight in samples from Group 1 and Group 2, however Group 3 showed signs of significant ovarian weight increase which in group 4 was suppressed by the introduction of Meloxicam. No differences were observed in the number of antral follicles amongst the four test groups. Results from Group 2 and Group 3 showed that the granulosa cells of preovulatory follicles and the stromal cells were highly VEGF immunoreactive, however the Meloxicam treated Group 4 showed less immunoreactivity than Group 2 and Group 3 which indicated the correlation between Meloxicam and the diminished VEGF expression. Group 3 presented an increased COS-2 immunoreactivity which was highly diminished than in Group 4.

The research concluded that in a rat model, the enzyme Meloxicam has a beneficial effect on OHSS by reducing the increase of ovarian weight and the expression of VEGF associated with OHSS, the effects of which may be mediated by the inhibitory capacity of COX-2 on Meloxicam
|}

{|
|-bgcolor="FF99FF"
|
<span style="font-size:120%">'''Inhibition of Ovarian VEGF secretion by activation of Dopamine Receptor 2'''</span> <ref name="PMID25217874"><pubmed>25217874</pubmed></ref>

This research was carried out to investigate a possibility in whether a Dopamine Receptor 2 agonist '''(D2-ag)''' can assist in the prevention of Ovarian Hyperstimulation Syndrome, using rat models, by decreasing the ovarian vascular endothelial growth factor '''(VEGF)''' production. Using Immature Wistar rats (22 days old) as their animal model, the rats were initially stimulated with Gonadotrophins to mimic the onset and effects of OHSS and then subjected to treatment with a D2-agonist and/or a D2-antagonist (D2-ant). The vascular permeability was measured at the endpoint after day 26 by measuring the peritoneal extravasion of a previously injected dye and ovaries from all subjects were collected to assess the effects of D2-ag and D2-ant on the production of Ovarian VEGF. The expression of VEGF mRNA was measured by quantitative real time PCR and the levels of VEGF proteins were measured by Western Blots.

Results showed that the D2-ag caused a large reduction in the vascular permeability which was in turn associated with the great decreased in VEGF protein production in the OHSS rat ovaries, whereas the introduction of D2-ant showed opposite results with a increase in the vascular permeability leading to the increase of VEGF protein production in the ovaries. Ovarian VEGF mRNA levels were found to be unaffected by the introduction of these drugs in OHSS rat subjects. Conclusions were drawn on the fact that Dopamine Receptor 2 agonists prevent the increase of vascular permeability in subjects with OHSS by decreasing the ovarian production of VEGF and also that due to the dose-dependent inhibitory effect of the D2-ag on ovarian VEGF, current OHSS therapies used in humans can benefit by increasing the intraovarian concentration of D2-ag.
|}
</div>

==Glossary==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

'''Aromatase Inhibitor''' - A drug that inhibits enzyme aromatase, which in turn suppresses estrogen synthesis.

'''Ascites''' - An accumulation of fluid in the peritoneal cavity with resultant abdominal swelling.

'''Cabergoline''' - A dopamine receptor agonist used to treat hormone imbalance.

'''Controlled Ovarian Stimulation''' - female infertility treatment using medications to stimulate the ovaries to develop follicles.

'''E2''' - Estradiol - Potent estrogen sex hormone.

'''Gonadotropin''' - Any hormone that has a stimulating effect on the gonads.

'''GnRH agonist''' - Gonadotropin Releasing Hormone - A class of compounds that mimic the effect of the natural Gonadotropin Releasing Hormone.

'''GnRH antagonist''' - Gonadotropin Releasing Hormone - A class of compounds that are similar in terms of the structure of natural Gonadotropin Releasing Hormone but has a antagonistic effect.

'''hCG'''- Human Chorionic Gonadotropin

'''Hemoconcentration''' - An increase in the concentration of circulating red blood cells in response to a decrease in blood plasma volume.

'''Hypovolemic''' - A decrease in circulating blood volume.

'''Iatrogenic''' - Illness caused as a result of a medical examination or treatment.

'''Intravenous fluids''' - Is the infusion of liquid substances directly into a vein.

'''IVF''' - In-vitro Fertilization

'''NSAID''' - Non-steroidal Anti-Inflammatory Drug e.g. Ibuprofen

'''OHSS''' - Ovarian Hyper-stimulation Syndrome

'''P4''' - Progesterone - endogenous progestogen sex hormone.

'''PCOS''' - Polycystic Ovarian Syndrome. An endrocrine system disorder whereby the ovaries are enlarged with small collections of fluid.

'''FSH''' - Follicle Stimulating Hormone

'''LH''' - Luteinizing Hormone

'''Oliguria'''- Decreased urine output/small amounts of urine produced.

</div>

==References==

2015 Group Project 2

2015-10-22T22:39:47Z

Z3372824: /* Primary Prevention */

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==<span style="font-size:120%">'''Ovarian Hyper-stimulation Syndrome (OHSS)'''</span>==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

Ovarian Hyper stimulation Syndrome (OHSS) is an iatrogenic complication of '''Assisted Reproduction Technology''' (ART), in which women take medications to stimulate oocyte growth. It is generally identified by cystic enlargements of the ovaries and fluid accumulation in the peritoneal cavity due to the increased capillary permeability and ovarian neoangiogenesis <ref name="PMID22065820"><pubmed>22065820</pubmed></ref>. It is an occurrence which is dependent on the controlled stimulation of the ovaries in preparation for IVF i.e. administration of human Chorionic Gonadotropin (hCG).

OHSS was first described in 1943 as ''“syndrome d’hyperluteinisation massive
des ovaries”''. It was during this time that gonadotropins were prepared from animals such as sheep to bring on ovulation in women. The first recorded death as a result of OHSS occurred in 1951 and was due to renal failure as a result of oligouria, a complication of the syndrome <ref name="OHSS"> Marie M. Budev, DO, MPH; Alejandro C. Arroliga, MD; Tommaso Falcone, MD, [ http://utilis.net/Morning%20Topics/REI/Ovarian%20Hyperstimulation.pdf ], 'Ovarian Hyperstimulation Syndrome'</ref> <ref name="PMID12638783"><pubmed>12638783</pubmed></ref>.

<span style="color:#FA58D0">This wikipage aims to provide clear information on various areas surrounding OHSS such as diagnosis, prevention and complications and will look into the genetics behind the disorder and the various animals models used to research it.</span>

<html5media height="350" width="450">https://www.youtube.com/watch?v=aXmjJw234a4</html5media>

'''Overview of the Ovarian Hyperstimulation Syndrome''' <ref> Howcast (2013, August 27) Ovarian Hyperstimulation Syndrome | Infertility. Retrieved from https://www.youtube.com/watch?v=aXmjJw234a4</ref>

</div>

==Epidemiology==
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Ovarian Hyper-Stimulation Syndrome (OHSS) rarely occurs sporadically, and if it does, it is usually the result of an underlying genetic problem. The majority of OHSS is due to the ovaries being stimulated to mature and release an abundance of oocytes, in response to hormones Human Chorionic Gonadotropin (hCG) and Follicle Stimulating hormone (FSH), during IVF. Rarely, Clomifene Citrate therapy can cause OHSS.<ref name="WikiOHSS"> Wikipedia, [ https://en.wikipedia.org/wiki/Ovarian_hyperstimulation_syndrome ], 'Ovarian Hyperstimulation Syndrome'</ref>

OHSS only affects '''0.5-5%''' of women undergoing Ovarian Hyper-stimulation, but despite its small prevalence, it is a potentially fatal outcome of a non-vital procedure and remains a prevalent problem for fertility specialists <ref name="PMID12498425"><pubmed>12498425</pubmed></ref> <ref name="PMID12638783"><pubmed>12638783</pubmed></ref>. Age has been cited as a factor affecting those with OHSS, with younger women more at risk. Additionally, women with allergies were seen to have a higher incidence of OHSS. It is important to note that at this point in time, there is no positive correlation between gonadotropin dose and OHSS.

Of the 0.5-5% of women affected with OHSS mentioned above, 2% of those women will require hospitalisation. As of 2011, it has been reported that the incidence of OHSS was '''increasing''', resulting in approximately 3 deaths per 100,000 women undergoing ovarian stimulation per year <ref name="PMID21828116"><pubmed>21828116</pubmed></ref>. This is particularly worrying as in 2008, in the United States alone, there were around 150,000 IVF cycles undertaken.

{|
|-bgcolor="F8E0F1"
|
'''With the field of Assisted Reproductive Technologies expanding and more women partaking in IVF treatments, the threat of women developing OHSS is an ongoing and increasing one''' <ref name="PMID21828116" />.
|}
{| class="wikitable mw-collapsible mw-collapsed"
! Characteristics of women by complication group <ref name="PMID19591989"><pubmed>19591989</pubmed></ref>
|-
! scope="col" width="100px" height="60px" style="text-align:center| '''Characteristic'''
! scope="col" width="100px" height="60px" style="text-align:center| '''No Complications
(N = 212,041)'''
! scope="col" width="100px" height="60px" style="text-align:center| '''Moderate OHSS
(N = 1,523)'''
! scope="col" width="100px" height="60px" style="text-align:center| '''Severe OHSS
(N = 655)'''
|-
|style="text-align:center; background: #FF99FF;"| '''Maternal Age (Mean ± SD)'''
|style="text-align:center; background: #F6CEEC;"| 35.6 ± 4.6
|style="text-align:center; background: #F6CEEC;"| 33.0 ± 4.3
|style="text-align:center; background: #F6CEEC;"| 33.1 ± 4.4
|-
|style="text-align:center; background: #FF99FF;"| '''Maternal Age (%)'''
|-
|style="text-align:left; background: #F6CEEC;"| <30 years
|style="text-align:center; background: #F6CEEC;"| 10 %
|style="text-align:center; background: #F6CEEC;"| 21.1 %
|style="text-align:center; background: #F6CEEC;"| 20.6 %
|-
|style="text-align:left; background: #F6CEEC;"| 30-34 years
|style="text-align:center; background: #F6CEEC;"| 30.4 %
|style="text-align:center; background: #F6CEEC;"| 43.2 %
|style="text-align:center; background: #F6CEEC;"| 40.5 %
|-
|style="text-align:left; background: #F6CEEC;"| 35-39 years
|style="text-align:center; background: #F6CEEC;"| 37.8 %
|style="text-align:center; background: #F6CEEC;"| 27.2 %
|style="text-align:center; background: #F6CEEC;"| 32.5 %
|-
|style="text-align:left; background: #F6CEEC;"| >40 years
|style="text-align:center; background: #F6CEEC;"| 21.8 %
|style="text-align:center; background: #F6CEEC;"| 8.4 %
|style="text-align:center; background: #F6CEEC;"| 6.4 %
|-
|style="text-align:center; background: #FF99FF;"| '''Nulligravida (%)'''
|style="text-align:center; background: #F6CEEC;"| 45.8 %
|style="text-align:center; background: #F6CEEC;"| 51.5 %
|style="text-align:center; background: #F6CEEC;"| 51.8 %
|-
|style="text-align:center; background: #FF99FF;"| '''Infertility Diagnosis (%)'''
|-
|style="text-align:left; background: #F6CEEC;"| Male factor
|style="text-align:center; background: #F6CEEC;"| 37.7 %
|style="text-align:center; background: #F6CEEC;"| 41.0 %
|style="text-align:center; background: #F6CEEC;"| 33.4 %
|-
|style="text-align:left; background: #F6CEEC;"| Endometriosis
|style="text-align:center; background: #F6CEEC;"| 13.5 %
|style="text-align:center; background: #F6CEEC;"| 13.5 %
|style="text-align:center; background: #F6CEEC;"| 10.7 %
|-
|style="text-align:left; background: #F6CEEC;"| Ovulation Disorders
|style="text-align:center; background: #F6CEEC;"| 14.0 %
|style="text-align:center; background: #F6CEEC;"| 29.5 %
|style="text-align:center; background: #F6CEEC;"| 22.4 %
|-
|style="text-align:left; background: #F6CEEC;"| Diminished ovarian reserve
|style="text-align:center; background: #F6CEEC;"| 16.9 %
|style="text-align:center; background: #F6CEEC;"| 3.2 %
|style="text-align:center; background: #F6CEEC;"| 2.4 %
|-
|style="text-align:left; background: #F6CEEC;"| Tubal factors
|style="text-align:center; background: #F6CEEC;"| 20.4 %
|style="text-align:center; background: #F6CEEC;"| 22.6 %
|style="text-align:center; background: #F6CEEC;"| 22.3 %
|-
|style="text-align:left; background: #F6CEEC;"| Uterine factors
|style="text-align:center; background: #F6CEEC;"| 5.1 %
|style="text-align:center; background: #F6CEEC;"| 4.3 %
|style="text-align:center; background: #F6CEEC;"| 3.1 %
|-
|style="text-align:left; background: #F6CEEC;"| Other factors
|style="text-align:center; background: #F6CEEC;"| 13.9 %
|style="text-align:center; background: #F6CEEC;"| 13.1 %
|style="text-align:center; background: #F6CEEC;"| 10.4 %
|-
|style="text-align:left; background: #F6CEEC;"| Unexplained factor
|style="text-align:center; background: #F6CEEC;"| 12.7 %
|style="text-align:center; background: #F6CEEC;"| 11.8 %
|style="text-align:center; background: #F6CEEC;"| 18.6 %
|-
|}
</div>

==Causative Agents==
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[[File:Follicular Development.jpeg|right|thumbnail|500px|Infertility treatments aim to facilitate follicular development and induce ovulation to improve chances of fertilisation <ref name="PMID24717179"><pubmed>24717179</pubmed></ref>]]

Normally a woman produces one egg per month from the ovaries, which travel down the Fallopian tube to be fertilized or be released from the body. In cases where women have difficulty falling pregnant, they are given medication which help them to produce and release eggs (as shown in the diagram to the right), further increasing their chances of fertilization and pregnancy <ref><pubmed>19573285</pubmed></ref>. Ovarian Hyper stimulation Syndrome generally occurs during infertility treatments when the ovaries are overstimulated by the fertility medication which causes the ovaries to swell and leak fluids into the belly and abdomen. The prevalence of OHSS onset is linked with excessive number of follicle development in response to the administration of injectable Follicle Stimulating Hormones (FSH) followed by the '''Human Chorionic Gonadotrophins''' (hCG) which triggers the release of the oocytes <ref><pubmed>26190539</pubmed></ref>.

'''Follicle Stimulating Hormones''' (FSH) <ref name="PMID9020850"><pubmed>9020850</pubmed></ref> are glycoprotein hormones that are produced and secreted from the Anterior Pituitary gland into the bloodstream, which regulate the developmental, growth, maturation and the reproductive processes within the body. In females, the Follicle Stimulating Hormones initiates the stages of growth and development of immature ovarian follicles within the ovaries before the release of an egg from a follicle at ovulation. When FSH is administered to a patient who is suffering from infertility, the increase FSH levels affect the rate of development and production, in turn increasing the amount of follicles which are ready to be released during ovulation.

</div>

==Symptoms==
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OHSS is classified based on a criteria from mild, moderate and severe <ref name="WikiOHSS" />:

'''Mild Symptoms'''- abdominal bloating, minimal weight gain, nausea, diarrhoea and a feeling of fullness.

'''Moderate Symptoms'''- Substantial weight gain (on average 2 or more pounds a day), increased abdominal girth, darkend urine and excessive thirst in addition to the mild symptoms.

'''Severe Symptoms'''- In addition to the symptoms associated with Mild and Moderate OHSS, in severe OHSS, you see shortness of breath, calf and chest pains and pleural effusion.

<span style="font-size:100%">'''Classifications of Ovarian Hyper-stimulation Syndrome:'''</span> <ref name="PMID22065820"><pubmed>22065820</pubmed></ref>
{| class="wikitable" style="text-align:center
|-
! scope="col" width="70px"| '''Classification'''
! scope="col" width="650px"| '''Symptoms'''
|-
|style="text-align:center; background: #F6CEEC;"| '''Mild'''
|style="height: 60px; background: #F6CEEC;"| '''Grade 1''' - Abdominal distention and discomfort
'''Grade 2''' - Abdominal distention, discomfort with nausea, vomiting and/or diarrhea and ovarian enlargement from 5~12cm
|-
|style="text-align:center; background: #F8E0F1;"| '''Moderate'''
|style="height: 60px; background: #F8E0F1;"| '''Grade 3''' - All features of Mild OHSS with ultrasonographic evidence of ascites
|-
|style="text-align:center; background: #F6CEEC;"| '''Severe'''
|style="height: 60px; background: #F6CEEC;"| '''Grade 4''' - All features of Moderate OHSS with the addition of clinical evidence of ascites and breathing difficulties present
'''Grade 5''' - All of the above symptoms along with a change in the blood volume, increased blood viscosity due to coagulation and diminished renal function
|}

</div>

==Diagnosis==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

Whilst symptoms of OHSS can occur as soon as 24 hours post hCG administration, they are usually seen in women 7-10 days post administration. Initially women with OHSS will present with abdominal bloating, as a result of fluid in the peritoneal cavity and an increase in ovary size. When women present with severe OHSS they are often dehydrated, due to increased vascular permeability, and have hemoconcentration. The above results in a decrease in intravascular volume, leading to '''oligouria''' <ref name="PMID22416285" />.

===History===

Initially a thorough history of the patient is taken during which the clinician looks for evidence of ovarian stimulation, followed by ovulation. During this history taking, the clinician will inquire into any weight gain noticed, urine output, and the woman's ability to maintain oral hydration. A key diagnostic tool for clinicians regarding women who are taking gonadotropins is to identify if they are at an increased risk of developing OHSS. Some risk factors include woman aged less than 30, women who have polycystic ovaries, woman with a previous history of OHSS and women who have had greater than 20 oocytes retrieved <ref name="PMID22416285" />.

===Physical Exam===
[[File:Vaginal_Ultrasonography_in_Sagittal_Plane.jpg|right|thumbnail|600px|Vaginal Ultrasonography in Sagittal plane <ref name="Wikiversity Journal of Medicine"> Häggström, Mikael. "Medical gallery of Mikael Häggström 2014". Wikiversity Journal of Medicine 1 (2). DOI:10.15347/wjm/2014.008. ISSN 20018762</ref>]]
After a history of the patient is taken, the next step is to perform a physical exam on the patient. Women who present with abdominal bloating will produce a shifting dullness upon abdominal percussion. Additionally the clinician will test the woman's vital signs, measure her abdominal girth, weight and will look for evidence of ascites or increase in calf size (usually unilateral)<ref name="PMID22416285" />.

===Investigations===

If the clinician further suspects a women of having OHSS, various investigations can be done such as an ultrasound.The intraperitoneal fluid is best imaged via vaginal ultrasound due to the enlarged ovaries making it difficult to image the pelvis using transabdominal ultrasound. The clinician can also order laboratory testing to look for urine specific gravity and and complete blood count to look for hemoconcentration with a hematocrit. Additionally, liver function tests can be ordered to look for elevated function. The clinician will also look for evidence of elevated D-dimers and fibrinogen and decreased levels of anti-thrombin 3 <ref name="SAHealth"> Government of South Australia Health [ http://www.sahealth.sa.gov.au/wps/wcm/connect/9b61ed004ee5348da663afd150ce4f37/Ovarian-hyperstimulation-syndrome-WCHN-PPG-17072012.pdf?MOD=AJPERES&CACHEID=9b61ed004ee5348da663afd150ce4f37 ], 'South Australian Paediatric Clinical Guidelines OHSS'</ref>.

====Ultrasound====

Typical appearances of the ultrasound include <ref name="Ultrasound"> Radiopaedia [ http://radiopaedia.org/articles/ovarian-hyperstimulation-syndrome-1 ], 'Ovarian Hyperstimulation Syndrome'</ref>:

*Bilaterally and symmetrically enlarged ovaries (>12cm)
* "Spoke-Wheel appearance" - presence of multiple cysts of varying size
*May also see ascites (fluid)

===Severity===

Once a clinician has deduced a women is suffering from OHSS, the severity of their condition needs to be established as either mild, moderate or severe. This is done by referring to the criteria under the sub-heading [[Symptoms]].The subsequent course of treatment for the woman will be based upon this evaluation.

{|
|-bgcolor="F6CEEC"
|
'''Further investigations''' can be done including a Chest X-ray to check for pleural effusions and oedema and USS with Doppler's to check for ascites or possible ovary torsion. <ref name="PMID22416285"><pubmed>22416285</pubmed></ref>
|}

===Differential Diagnosis===

Conditions presenting with similar symptoms or ultrasound images include <ref name="Ultrasound" />:

*Polycystic Ovaries (PO)
:: The difference is that with PO is that the cycts are typically smaller than OHSS cysts and there is no evidence of ascited or pleural effusion
*Mucinous Ovarian Malignancy
:: A type of Ovarian Epithelial tumour
*Ectopic Pregnancy <ref name="Casereport"> Australian Medical Student Journal [ http://www.amsj.org/wpcontent/uploads/files/articles/amsj_v2_i1/AMSJ_v2_i1_pg58-60.pdf ], 'Ovarian hyperstimulation syndrome'</ref>
::A pregnancy in which the foetus develops outside of the uterus e.g. in the fallopian tube

</div>

==Pathophysiology==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

[[File:Pathogenesis_of_OHSS.png|600px|thumb|Pathogenesis of OHSS <ref name="PMID20416867"><pubmed>20416867</pubmed></ref>]]

The definition of Ovarian Stimulation is enlarged ovaries with many luteinized cysts, that can present with secondary complications. What distinguishes Ovarian Stimulation from OHSS is the presence of vascular hyper-permeability that results in fluids being redirected elsewhere in the body.

The key process to OHSS appears to be caused by '''Vascular Endothelial Growth Factor''' (VEGF), that is released along with other cytokines, estrogen and progesterone, due to the ovary undergoing luteinization as a result of stimulation by hCG. VEGF increases vascular permeability and as a result the capillaries become more "leaky" to the fluids in them. These fluids can then escape the capillaries and accumulate in the pleural and abdominal cavities as ascites. The woman then becomes hypovolemic and is at an increased risk of circulatory, renal and respiratory issues such as arterial thromboembolism due to the thickening of the blood. Note, the blood is thickened as fluid is leaving the capillaries, leaving behind red blood cells and other cellular components of the blood <ref name="WikiOHSS" />.

The increase in expression of VEGF and VEGF Receptor 2 (VEGFR2) is attributed to the greatly increased amount of their mRNA present in the body after stimulation with hCG <ref name="PMID21082502"><pubmed>21082502</pubmed></ref>. VEGF interacts with VEGF2 and VEGF Receptor 1 (VEGFR1) to create a strong angiogenic effect. Both VEGFR2 and VEGFR1 belong to a family of receptors called tyrosine kinases. VEGF2 is involved in the regulation of angiogenesis and vascular permeability whilst VEGF1 has a slightly contradictory role in that is is involved in the maintenance of the tight junctions between endothelial cells in blood vessels. A study by Gómez ''et. al.'' <ref name="PMID21082502" /> showed that women experiencing OHSS had substantially higher plasma levels of VEGF and lower levels of VEGFR1.

</div>

==Complications==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

Ovarian torsion or rupture, renal insufficiency and thrombophlebitis can all complicate OHSS. If a pregnancy occurs, symptoms may persist longer than the usual 1 to 2 weeks and become more severe, however, even with severe OHSS, they do not extend past the first trimester <ref name="WikiOHSS" />.

<span style="color:#FA58D0"> '''1-2% of women who undergo ovarian stimulation develop a severe form of OHSS''' </span>. Complications from severe OHSS include:

*Fluid collection in the abdomen
*Electrolyte disturbances (sodium and potassium)
*Kidney failure
*Ovary twisting
*Rupture of a cyst in an ovary
*Breathing problems
*Blood clots in large vessels (most commonly the legs)
*Pregnancy loss from miscarriage or termination
*Rarely, death

A study by Nouri ''et. al.'' <ref name="PMID24996451"><pubmed>24996451</pubmed></ref> found that women with '''Polycystic Ovarian Syndrome''' (PCOS) and those that were induced with hCG experienced longer recovery times from severe OHSS than women who were not pregnant. They looked at a cohort of women hospitalised for the first time with severe OHSS and subject them to the same treatments. Based on a defined criteria, they established the recovery time of these women and compared the times between those that were pregnant to those that were not pregnant. They also found that whether a woman had PCOS or ovulation induction did not affect her risk of developing OHSS if she was not pregnant. It is only a risk factor for pregnant women.

===Thromboembolic events===

A frequent and deadly complication of OHSS are thromboembolic events due to increased blood clotting. This increase in blood clotting has been attributed to a variety of complications such as hemoconcentration (which thickens the blood), hypovolemia and an increase in the permeability of blood vessels as a result of increased vasoactive substances in the body of ovarian origin. Thromboembolic events include venous thromboses often in the upper extremities and arterial thromboses such as those in the cerebrovascular region. These events can lead to amputations of extremities, brain damage, miscarriage and death. To avoid this, anti-coagulants are given to pateitns with OHSS and they are fitted with compression stockings (see [[Treatment]]) <ref name="PMID23378404"><pubmed>23378404</pubmed></ref>.

{|
|-bgcolor="F8E0F1"
|
The risk of a woman developing OHSS is higher if she is having a '''twin pregnancy''', as she is exposed to higher concentration of hCG. <ref name="PMID9756273"><pubmed>9756273</pubmed></ref>
|}

</div>

==Treatment==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

'''General treatment
'''
*''Acetaminophen'' with or without a narcotic agent- used to treat abdominal discomfort
*Women are encouraged to drink 2-3 litres of water a day to prevent hemoconcentration
*Women are advised to avoid sexual intercourse and vigorous exercise at the risk of torsion or rupture of the ovaries
*NSAID's with anti-platelet properties should NOT be used as they may effect renal function in a women with OHSS
*Patients with significantly painful ascites or breathing problems may undergo ''Paracentesis'' (drainage of the ascites)
*''Culdocentesis'' (extraction of fluid from recto-uterine pouch) can be done to decrease the likelihood of a woman with moderate OHSS progressing to severe OHSS.<ref name="PMID22416285" />

===Mild to Moderate OHSS===

Mild OHSS can often resolve on its own, however, moderate OHSS may include treatments such as<ref name="WikiOHSS" />:

*Anti-nausea medication and prescription painkillers
*Regular physical examinations and ultrasounds
*Daily weigh-ins and waist measurements
*Measuring the amount of urine produced each day
*Frequent blood tests for monitoring dehydration and electrolyte imbalance
*Maintaining a high balance of fluids
*Drainage of excess abdominal fluid by inserting a needle in the abdominal cavity
*Wearing support stockings which help prevent blood clots/thrombosis

===Severe OHSS===

Severe OHSS requires hospital care in order for constant monitoring and treatment such as <ref name="WikiOHSS" />:

*Intravenous fluids with a crystalloid solution (100-150mL/hr)
*Intravenous Albumin is administered is IV fluids are insufficient (15-20mL/hr of 25% albumin for 4 hrs)
*In addition to Acetaminophen, ''Opioid analgesics'' can be administered for pain relief
*''Antiemetics'' can be used to subside nauseas and/or vomiting
*Woman administered to hospital of OHSS are considered at high risk of thromboembolic complications and are given low molecular weight ''heparin'', an anti-coagulant
*''Cabergoline''- lessens OHSS symptoms
*''GnRH agonist''- suppresses ovarian activity
**If at risk of OHSS, alternates include using a GnRH agonist instead of hCG however its effects on pregnancy rates are questionable. Using a GnRH agonist to replace the use of hCG for final oocyte stimulation will see a 6% decrease in delivery rate.

*Daily monitoring of creatine, urea, creatine clearance C-reactive protein (to rule out infection) are all required in combination with weekly tests such as liver and renal function tests and chest x-rays (to check for pleural effusion) <ref name="PMID12638783" />.

If there are serious complications then additional treatments are required:

*Surgery for a ruptured ovarian cyst
*Intensive care for the liver or lung complications

====Paracentesis====

For women with severe/grade 3 OHSS, paracentesis, the removal of fluid from the body using an aspiration needle, can be undertaken. It is a diagnostic and a therapeutic method that can be done trans-abdominally and trans-vaginally. It is used to relieve symptoms, improve haemodynamics e.g. Urinary output, and shorten the women's hospital stay. Complications of paracentesis include bleeding, infection and organ injury, however are note common <ref name="Paracentesis"> S. Monica Soni, HMS 3, Gillian Lieberman, MD [ http://eradiology.bidmc.harvard.edu/LearningLab/genito/Soni.pdf ], 'Ovarian Hyperstimulation Syndrome'</ref>.

{|
|-bgcolor="F8E0F1"
|
The most important aspect of treatment for any women with OHSS is close and constant '''monitoring''' with her healthcare professional. Counselling may also be provided to women and their partners or families in order to provide them with the best possible knowledge base to manage and treat their OHSS. It is important to note that there is '''no one cure or treatment''' for OHSS. Treatment involves managing and eliminating the symptoms until such time as the syndrome resolves itself <ref name="WikiOHSS" />.
|}

</div>

==Prevention==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

There are three key avenues through which the incidence of OHSS may be prevented. These include identifying risk factors to predict OHSS development, modifying treatment regimes on the basis of the identified risk factors and intervention to prevent progression to OHSS once the patient has undergone '''Controlled Ovarian Stimulation''' (COS).

=== Risk factors===

'''Primary risk factors'''

Pre-existing factors likely to exacerbate the ovarian stimulation response. Primary risk factors include <ref name="PMID26074966"><pubmed>26074966</pubmed></ref>:

*Young age
*Low body weight
*History of elevated response to gonadotropins
*Polycystic Ovary Syndrome (PCOS)
*Isolated PCOS characteristic
*A previous history of OHSS.
*Hormonal markers (e.g. Anti-Mullerian Hormone markers)
*Ultrasonographic markers (e.g. Antral Follicle Count)

'''Secondary risk factors'''

Secondary risk factors involve the monitoring of ovarian response parameters once COS has been initiated. These parameters are monitored for <ref name="PMID19007627"><pubmed>19007627</pubmed></ref>:

*rapidly rising E2 levels
*E2 concentration larger than 2500 pg/mL
*large number of developing follicles (10-14mm) on the day hCG is administered
*large number of oocytes retrieved

These factors in combination, act as a predictive tool to assess the likelihood of severe OHSS development, with a 83% sensitivity and 84% specificity. <ref name="PMID19007627"/>

=== Primary Prevention===

Primary Prevention involves the modification of treatment regimens on the basis of OHSS risk classifications, in order to prevent OHSS occurrence.

'''Ovulation Induction'''

Unifollicular Ovulation Induction through Ovulation Induction (OI) is a primary means of avoiding OHSS in women with Polycystic Ovarian Syndrome, who are at an increased risk. In order to promote '''unifollicular development''', the ovaries are stimulated with a low starting dose of FSH (75 IU).<ref name="PMID20416867"><pubmed>20416867</pubmed></ref> Studies suggests that a minimum gonadotropin dose lowers OHSS risk and thus a step-up regimen is utilised to achieve an ovarian response, whereby the FSH dosage is increased every 7 days until follicular development of greater than 10mm is noted.<ref name="PMID26074966" /> Alternatively, a step-down regimen may be followed, whereby a high initial FSH dosage is lowered according to the ovarian response. Another method to increase FSH levels during OI, is through '''Aromatase Inhibitors''' which promote folliculogenesis by increasing pituitary secretion of FSH, and downregulate oestrogen production through a negative feedback loop. However, Aromatase Inhibitors have not been shown to reduce OHSS incidence in comparison to other methods of OI.<ref name="PMID26074966" /> During OI, a key objective is to prevent early cycle cancellation due to premature luteinisation from pituitary secretion of LH. In order to downregulate LH secretion, '''Gonadotropin-releasing hormone agonists''' (GnRHa) are administered in addition to gonadotropins. Alternatively, '''GnRH antagonists''' may be administered to downregulate endogenous LH secretion. Comparative studies have shown that the GnRH antagonist protocol has a greater effect in lowering the incidence of mild to severe OHSS. However due to the rare nature of OHSS, and insufficient sample sizes, the difference was not found to be significant. <ref name="PMID21082508"><pubmed>21082508</pubmed></ref>. Generally, the duration of exposure to gonadotropins and subsequent risk of OHSS may be minimised through '''mild stimulation protocols''' which administer FSH only in the mid to late follicular phase.<ref name="PMID20416867" />

'''Adjuvant Metformin Therapy'''

Adjuvant Metformin Therapy has been found to lower the risk of OHSS by 63%.<ref name="PMID25406011"><pubmed>25406011</pubmed></ref> It involves the administration of metformin at a daily dosage of 1000 to 2000mg, 2 months prior to Controlled Ovarian Stimulation <ref name="PMID26074966"/>. Metformin lowers the elevated insulin levels in PCOS which consequently reduce intraovarian androgen levels. This leads to a reduced sensitivity and expression of granulosa cell-follicle stimulating hormone receptors which result in a less exaggerated response to gonadotropins. Furthermore, it is suggested that Metformin prevents OHSS by controlling vascular permeability through the inhibition of various vasoactive molecules, including VEGF.

'''Avoiding hCG during Luteal Phase Support

Following Controlled Ovarian Stimulation, the steroid levels of E2 and P4 are reduced during the luteal phase due to the negative feedback on the pituitary. This leads to low endogenous LH levels, which consequently reduce endometrial receptivity as well as the luteal phase duration itself. As a result, implantation and pregnancy rates are reduced and early pregnancy loss rates are increased.<ref name="PMID20416867" /> Luteal Phase Support (LPS) serves to combat these adverse events with the use of hCG. However, hCG has been found to increase the risk of OHSS. Alternatively, the use of progesterone has been found to not only halve the risk of OHSS, but also induce similar improvements in pregnancy and miscarriage rates as hCG.<ref name="PMID26148507"><pubmed>26148507</pubmed></ref>

===Secondary Prevention===

Secondary Prevention aims to prevent progression to OHSS once COS has been initiated and the patient has been found to mount an exaggerated response. <ref name="PMID20416867" />

'''Coasting'''

Coasting is a first-line secondary preventative strategy. It consists of the withdrawal of gonadotrophins when a critical number of follicles and/or E2 concentration is reached. hCG is administered once the E2 concentration reduces to a safe level, before the process of oocyte retrieval commences. This preventative strategy is conducted for a period of less than 3 days in order to avoid compromising IVF outcomes.

'''Cryopreservation'''

Cryopreservation of embryos after oocyte retrieval is another avenue which may avert OHSS progression. The cryopreserved embryos are only reimplanted once the patient's hormone serum levels have normalised. Using oocyte vitrification, crystal formation within embryo tissue is avoided and so cryopreserved embryos have been found to produce better pregnancy rates with a 32% increase, than fresh embryo transfer. Recent studies suggest cryopreservation itself does not reduce OHSS rates, but must be followed by a GnRHa trigger to avert OHSS.

'''Cycle cancellation'''

Cycle cancellation is a guaranteed method to prevent early OHSS whereby hCG is withheld. This is a last resort strategy as it carries the risk of significant psychological distress and financial loss for the patient.

</div>

==Effect on the Newborn==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

</div>
Women who develop OHSS while undergoing Assisted Reproductive Technologies (ART) treatment are not only more likely to achieve a pregnancy, but have a live birth as the pregnancy outcome. This live birth is also more likely to be a multiple birth of two, three or more children. <ref name="PMID19591989"><pubmed>19591989</pubmed></ref> It has been postulated that a multifetal pregnancy leads to a more rapid increase in hCG levels, resulting in an increased risk of OHSS. However, the causal nature between multifetal pregnancy and OHSS development is disputed and further research is required to distinguish correlation from causation. <ref name="PMID19573292"><pubmed>19573292</pubmed></ref>

OHSS development is also associated with an increased risk of adverse outcomes including stillbirth, premature birth and low birthweight.<ref name="PMID19591989" /> Although the cause for the increased risk in adverse pregnancy outcomes is unknown, it is suggested that as the incidence of OHSS is reduced through various prevention strategies, the risk of such outcomes may be also be reduced.

==Genetics==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

Despite OHSS typically being of iatrogenic origin as a result of ovarian stimulation with gonadotropins, research has been conducted into the potential genetics behind OHSS as many sporadic and familial cases have been observed. '''Mutations''' in the receptor for hormones such as Follicle Simulating Hormone (FSH), Lutenizing Hormone (LH) and hCG have all been targets of OHSS genetics research. Interestingly, they too also arise from a common ancestral gene.

===Follicle Stimulating Hormome===

Dr. Botros Rizk, of the University of South Alabama College of Medicine <ref name="PMID19573286"><pubmed>19573286</pubmed></ref>, has written extensively regarding the genetics behind OHSS. In particular, he talks about '''FSH receptors''' (FSHR) and their role in the syndrome. He hypothesises that mutations in these receptors could be activating or inactivating, leading to an increased risk of developing OHSS or sterility respectively. Currently, 744 single nucleotide polymorphisms (a type of mutation) have been found in the gene encoding the FSHR, 8 of which are located in its exons (coding regions of the gene). How the ovary responds is resultant on the FSHR genotype. For example, Ser680Asn, a polymorphism in the FSHR gene has been shown to aid in predicting the severity of a woman's OHSS. Ordinarily FSH stimulates the growth of ovarian follicles, however, when mutated, it is stimulated by the hCG resulting in excessive follicle development.

Spontaneous OHSS, OHSS that arises and cannot be attributed to any form of ovarian stimulation or Assisted Reproductive Technology, has been linked to activating mutations in the FSHR <ref name="PMID23499866"><pubmed>23499866</pubmed></ref>. This familial disorder is an autosomal dominant one. In most cases the FSHR can be stimulated by the presence of Thyroid Stimulating Hormone (TSH) or hCG, in the absence of FSH (the ligand for FSHR).

===Lutenizing Hormome===

The '''Lutenizing Hormone Receptor''' (LHR) gene in humans is comprised of 11 exons. Animal studies have shown that many primates exhibit a similar gene which is comprised of only 10 exons, however a gene lacking the 10th exon has been identified and termed the type 2 LHR. Expression of the type 2 LHR has been seen in humans. The type 2 LHR, compared to the wild-type LHR appears to be repaired with regard to its function. Defects in the type 2 LHR include a decrease in efficiency of transport to the plasma membrane and irregularities in signal transduction. Inactivating mutations in the LHR have been seen to cause infertility in women as well as amenorrhoea. Activating LHR gene mutations are asymptomatic and are not associated with OHSS in women.

===Bone Morphogenic Protein===

An imporant growth factor, derived from oocytes called '''BMP-15''' (Bone Morphogenic Protein 15) is vital for female fertility. It belongs to the family of growth factors, Transforming Growth Factor β (TGF-β) and is heavily involved in folliculogenesis. It has been found that mutations in the BMP-15 gene caused infertility in female sheep. Conversely, it has also been indicated in enhanced fertility when BMP-15 is present is high amounts in follicular fluid <ref name="PMID19573286" />.

A case study done by Hanevik ''et. al.'' in 2013 <ref name="PMID21565556"><pubmed>21565556</pubmed></ref> found that a Single Nuclear Polymorphism (SNP) in the BMP-15 gene is responsible for a high response to ovarian hyper-stimulation. The aim of the study was to test the effect the SNP had on BMP-15 with regard to high and low responders buy taking blood from 53 high responders, 38 low responders and 100 non-responders (controls) and analysing 5 noted SNP's. Results from their study showed a correlation between a high response to ovarian hyper-stimulation and the BMP-15 9G allele. The article does state however, that further research is required into the molecular effects of SNP's on the function of BMP-15.

===Vascular Endothelial Growth Factor===

'''Vascular endothelial growth factor''' (VEGF) has been indicated as one of the key agents causing vascular permeability and subsequent ascites in OHSS. The gene, which is located on chromosome 12, is made up of 8 exons (coding regions), of which exons 6 and 7 do not always appear due to the exons being spliced out.The splicing of this gene allows for various isoforms of the gene to exist of which VEGF 121 and 165 appear to play a role in angiogenesis. There are two VEGF Receptors, VEGFR-1 and VEGFR-2 that belong to the tyrosine kinase family of receptors (for more information on VEGF see [[Pathophysiology]]). Because of its distinct role in OHSS, it has been targeted as an area for research for potential treatments. The idea is that if the genetic expression of VEGF and its receptors can be controlled, OHSS can be avoided or treated.<ref name="PMID19573286" />

A different study by Hanevik ''et. al.'' , <ref name="PMID22587628"><pubmed>22587628</pubmed></ref> done in 2012 involved analysing blood samples from 53 women with OHSS and 100 women without it (controls) and analysing 6 SNP's in the VEGFR2 gene to find any genetic variations. They found a correlation between women with the VEGF +405cc genotype and the development of OHSS indicating women that undergo controlled ovarian hyper-stimulation and posses his genotype, are at an increased risk of developing OHSS.

</div>

== Current Research on Animal Models==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">
{|
|-bgcolor="F8E0F1"
|
<span style="font-size:120%">'''Inhibition of Cyclooxygenase-2 (COX-2) by Meloxican decreasing the incidence of OHSS in Rat Model'''</span> <ref name="PMID18166186"><pubmed>18166186</pubmed></ref>

Reasearch was carried out to investigate the effects of selective inhibition of the enzyme COX-2 on the Ovarian Hyperstimulation Syndrome (OHSS) using Female Wistar rates as the subjects. The research aimed to find results by measuring the number of antral and luteinized follicles, ovarian weight, vascualr endothelial growth factors and COX-2 immunohistochemistry. The rats being tested were all 22 days old and were divided into four equal groups;

'''Group 1 (Control group)''' was subject to a 0.1 ml of Intraperitoneal Saline from days 22 ~ 26

'''Group 2 (Mildly-stimulated group)''' subject to 10IU of pregnant mare serum gonadotrophin (PMSG) on day 24 and then 10IU of Human Chorionic Gonadotrophin (hCG) on day 26

'''Group 3 (OHSS positive group)''' was subject to 10IU of PMSG from days 22 ~ 26 and then administered 30IU of hCG on day 26 to induce OHSS

'''Group 4 (OHSS positive variant group)''' received 15mg/ml of Meloxicam 2 hours prior to administration of 10IU PMSG from days 22 ~ 26

Results showed there was no difference in ovarian weight in samples from Group 1 and Group 2, however Group 3 showed signs of significant ovarian weight increase which in group 4 was suppressed by the introduction of Meloxicam. No differences were observed in the number of antral follicles amongst the four test groups. Results from Group 2 and Group 3 showed that the granulosa cells of preovulatory follicles and the stromal cells were highly VEGF immunoreactive, however the Meloxicam treated Group 4 showed less immunoreactivity than Group 2 and Group 3 which indicated the correlation between Meloxicam and the diminished VEGF expression. Group 3 presented an increased COS-2 immunoreactivity which was highly diminished than in Group 4.

The research concluded that in a rat model, the enzyme Meloxicam has a beneficial effect on OHSS by reducing the increase of ovarian weight and the expression of VEGF associated with OHSS, the effects of which may be mediated by the inhibitory capacity of COX-2 on Meloxicam
|}

{|
|-bgcolor="FF99FF"
|
<span style="font-size:120%">'''Inhibition of Ovarian VEGF secretion by activation of Dopamine Receptor 2'''</span> <ref name="PMID25217874"><pubmed>25217874</pubmed></ref>

This research was carried out to investigate a possibility in whether a Dopamine Receptor 2 agonist '''(D2-ag)''' can assist in the prevention of Ovarian Hyperstimulation Syndrome, using rat models, by decreasing the ovarian vascular endothelial growth factor '''(VEGF)''' production. Using Immature Wistar rats (22 days old) as their animal model, the rats were initially stimulated with Gonadotrophins to mimic the onset and effects of OHSS and then subjected to treatment with a D2-agonist and/or a D2-antagonist (D2-ant). The vascular permeability was measured at the endpoint after day 26 by measuring the peritoneal extravasion of a previously injected dye and ovaries from all subjects were collected to assess the effects of D2-ag and D2-ant on the production of Ovarian VEGF. The expression of VEGF mRNA was measured by quantitative real time PCR and the levels of VEGF proteins were measured by Western Blots.

Results showed that the D2-ag caused a large reduction in the vascular permeability which was in turn associated with the great decreased in VEGF protein production in the OHSS rat ovaries, whereas the introduction of D2-ant showed opposite results with a increase in the vascular permeability leading to the increase of VEGF protein production in the ovaries. Ovarian VEGF mRNA levels were found to be unaffected by the introduction of these drugs in OHSS rat subjects. Conclusions were drawn on the fact that Dopamine Receptor 2 agonists prevent the increase of vascular permeability in subjects with OHSS by decreasing the ovarian production of VEGF and also that due to the dose-dependent inhibitory effect of the D2-ag on ovarian VEGF, current OHSS therapies used in humans can benefit by increasing the intraovarian concentration of D2-ag.
|}
</div>

==Glossary==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

'''Aromatase Inhibitor''' - A drug that inhibits enzyme aromatase, which in turn suppresses estrogen synthesis.

'''Ascites''' - An accumulation of fluid in the peritoneal cavity with resultant abdominal swelling.

'''Cabergoline''' - A dopamine receptor agonist used to treat hormone imbalance.

'''Controlled Ovarian Stimulation''' - female infertility treatment using medications to stimulate the ovaries to develop follicles.

'''E2''' - Estradiol - Potent estrogen sex hormone.

'''Gonadotropin''' - Any hormone that has a stimulating effect on the gonads.

'''GnRH agonist''' - Gonadotropin Releasing Hormone - A class of compounds that mimic the effect of the natural Gonadotropin Releasing Hormone.

'''GnRH antagonist''' - Gonadotropin Releasing Hormone - A class of compounds that are similar in terms of the structure of natural Gonadotropin Releasing Hormone but has a antagonistic effect.

'''hCG'''- Human Chorionic Gonadotropin

'''Hemoconcentration''' - An increase in the concentration of circulating red blood cells in response to a decrease in blood plasma volume.

'''Hypovolemic''' - A decrease in circulating blood volume.

'''Iatrogenic''' - Illness caused as a result of a medical examination or treatment.

'''Intravenous fluids''' - Is the infusion of liquid substances directly into a vein.

'''IVF''' - In-vitro Fertilization

'''NSAID''' - Non-steroidal Anti-Inflammatory Drug e.g. Ibuprofen

'''OHSS''' - Ovarian Hyper-stimulation Syndrome

'''P4''' - Progesterone - endogenous progestogen sex hormone.

'''PCOS''' - Polycystic Ovarian Syndrome. An endrocrine system disorder whereby the ovaries are enlarged with small collections of fluid.

'''FSH''' - Follicle Stimulating Hormone

'''LH''' - Luteinizing Hormone

'''Oliguria'''- Decreased urine output/small amounts of urine produced.

</div>

==References==

2015 Group Project 2

2015-10-22T22:37:14Z

Z3372824: /* Glossary */

{{ANAT2341Project2015header}}

==<span style="font-size:120%">'''Ovarian Hyper-stimulation Syndrome (OHSS)'''</span>==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

Ovarian Hyper stimulation Syndrome (OHSS) is an iatrogenic complication of '''Assisted Reproduction Technology''' (ART), in which women take medications to stimulate oocyte growth. It is generally identified by cystic enlargements of the ovaries and fluid accumulation in the peritoneal cavity due to the increased capillary permeability and ovarian neoangiogenesis <ref name="PMID22065820"><pubmed>22065820</pubmed></ref>. It is an occurrence which is dependent on the controlled stimulation of the ovaries in preparation for IVF i.e. administration of human Chorionic Gonadotropin (hCG).

OHSS was first described in 1943 as ''“syndrome d’hyperluteinisation massive
des ovaries”''. It was during this time that gonadotropins were prepared from animals such as sheep to bring on ovulation in women. The first recorded death as a result of OHSS occurred in 1951 and was due to renal failure as a result of oligouria, a complication of the syndrome <ref name="OHSS"> Marie M. Budev, DO, MPH; Alejandro C. Arroliga, MD; Tommaso Falcone, MD, [ http://utilis.net/Morning%20Topics/REI/Ovarian%20Hyperstimulation.pdf ], 'Ovarian Hyperstimulation Syndrome'</ref> <ref name="PMID12638783"><pubmed>12638783</pubmed></ref>.

<span style="color:#FA58D0">This wikipage aims to provide clear information on various areas surrounding OHSS such as diagnosis, prevention and complications and will look into the genetics behind the disorder and the various animals models used to research it.</span>

<html5media height="350" width="450">https://www.youtube.com/watch?v=aXmjJw234a4</html5media>

'''Overview of the Ovarian Hyperstimulation Syndrome''' <ref> Howcast (2013, August 27) Ovarian Hyperstimulation Syndrome | Infertility. Retrieved from https://www.youtube.com/watch?v=aXmjJw234a4</ref>

</div>

==Epidemiology==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

Ovarian Hyper-Stimulation Syndrome (OHSS) rarely occurs sporadically, and if it does, it is usually the result of an underlying genetic problem. The majority of OHSS is due to the ovaries being stimulated to mature and release an abundance of oocytes, in response to hormones Human Chorionic Gonadotropin (hCG) and Follicle Stimulating hormone (FSH), during IVF. Rarely, Clomifene Citrate therapy can cause OHSS.<ref name="WikiOHSS"> Wikipedia, [ https://en.wikipedia.org/wiki/Ovarian_hyperstimulation_syndrome ], 'Ovarian Hyperstimulation Syndrome'</ref>

OHSS only affects '''0.5-5%''' of women undergoing Ovarian Hyper-stimulation, but despite its small prevalence, it is a potentially fatal outcome of a non-vital procedure and remains a prevalent problem for fertility specialists <ref name="PMID12498425"><pubmed>12498425</pubmed></ref> <ref name="PMID12638783"><pubmed>12638783</pubmed></ref>. Age has been cited as a factor affecting those with OHSS, with younger women more at risk. Additionally, women with allergies were seen to have a higher incidence of OHSS. It is important to note that at this point in time, there is no positive correlation between gonadotropin dose and OHSS.

Of the 0.5-5% of women affected with OHSS mentioned above, 2% of those women will require hospitalisation. As of 2011, it has been reported that the incidence of OHSS was '''increasing''', resulting in approximately 3 deaths per 100,000 women undergoing ovarian stimulation per year <ref name="PMID21828116"><pubmed>21828116</pubmed></ref>. This is particularly worrying as in 2008, in the United States alone, there were around 150,000 IVF cycles undertaken.

{|
|-bgcolor="F8E0F1"
|
'''With the field of Assisted Reproductive Technologies expanding and more women partaking in IVF treatments, the threat of women developing OHSS is an ongoing and increasing one''' <ref name="PMID21828116" />.
|}
{| class="wikitable mw-collapsible mw-collapsed"
! Characteristics of women by complication group <ref name="PMID19591989"><pubmed>19591989</pubmed></ref>
|-
! scope="col" width="100px" height="60px" style="text-align:center| '''Characteristic'''
! scope="col" width="100px" height="60px" style="text-align:center| '''No Complications
(N = 212,041)'''
! scope="col" width="100px" height="60px" style="text-align:center| '''Moderate OHSS
(N = 1,523)'''
! scope="col" width="100px" height="60px" style="text-align:center| '''Severe OHSS
(N = 655)'''
|-
|style="text-align:center; background: #FF99FF;"| '''Maternal Age (Mean ± SD)'''
|style="text-align:center; background: #F6CEEC;"| 35.6 ± 4.6
|style="text-align:center; background: #F6CEEC;"| 33.0 ± 4.3
|style="text-align:center; background: #F6CEEC;"| 33.1 ± 4.4
|-
|style="text-align:center; background: #FF99FF;"| '''Maternal Age (%)'''
|-
|style="text-align:left; background: #F6CEEC;"| <30 years
|style="text-align:center; background: #F6CEEC;"| 10 %
|style="text-align:center; background: #F6CEEC;"| 21.1 %
|style="text-align:center; background: #F6CEEC;"| 20.6 %
|-
|style="text-align:left; background: #F6CEEC;"| 30-34 years
|style="text-align:center; background: #F6CEEC;"| 30.4 %
|style="text-align:center; background: #F6CEEC;"| 43.2 %
|style="text-align:center; background: #F6CEEC;"| 40.5 %
|-
|style="text-align:left; background: #F6CEEC;"| 35-39 years
|style="text-align:center; background: #F6CEEC;"| 37.8 %
|style="text-align:center; background: #F6CEEC;"| 27.2 %
|style="text-align:center; background: #F6CEEC;"| 32.5 %
|-
|style="text-align:left; background: #F6CEEC;"| >40 years
|style="text-align:center; background: #F6CEEC;"| 21.8 %
|style="text-align:center; background: #F6CEEC;"| 8.4 %
|style="text-align:center; background: #F6CEEC;"| 6.4 %
|-
|style="text-align:center; background: #FF99FF;"| '''Nulligravida (%)'''
|style="text-align:center; background: #F6CEEC;"| 45.8 %
|style="text-align:center; background: #F6CEEC;"| 51.5 %
|style="text-align:center; background: #F6CEEC;"| 51.8 %
|-
|style="text-align:center; background: #FF99FF;"| '''Infertility Diagnosis (%)'''
|-
|style="text-align:left; background: #F6CEEC;"| Male factor
|style="text-align:center; background: #F6CEEC;"| 37.7 %
|style="text-align:center; background: #F6CEEC;"| 41.0 %
|style="text-align:center; background: #F6CEEC;"| 33.4 %
|-
|style="text-align:left; background: #F6CEEC;"| Endometriosis
|style="text-align:center; background: #F6CEEC;"| 13.5 %
|style="text-align:center; background: #F6CEEC;"| 13.5 %
|style="text-align:center; background: #F6CEEC;"| 10.7 %
|-
|style="text-align:left; background: #F6CEEC;"| Ovulation Disorders
|style="text-align:center; background: #F6CEEC;"| 14.0 %
|style="text-align:center; background: #F6CEEC;"| 29.5 %
|style="text-align:center; background: #F6CEEC;"| 22.4 %
|-
|style="text-align:left; background: #F6CEEC;"| Diminished ovarian reserve
|style="text-align:center; background: #F6CEEC;"| 16.9 %
|style="text-align:center; background: #F6CEEC;"| 3.2 %
|style="text-align:center; background: #F6CEEC;"| 2.4 %
|-
|style="text-align:left; background: #F6CEEC;"| Tubal factors
|style="text-align:center; background: #F6CEEC;"| 20.4 %
|style="text-align:center; background: #F6CEEC;"| 22.6 %
|style="text-align:center; background: #F6CEEC;"| 22.3 %
|-
|style="text-align:left; background: #F6CEEC;"| Uterine factors
|style="text-align:center; background: #F6CEEC;"| 5.1 %
|style="text-align:center; background: #F6CEEC;"| 4.3 %
|style="text-align:center; background: #F6CEEC;"| 3.1 %
|-
|style="text-align:left; background: #F6CEEC;"| Other factors
|style="text-align:center; background: #F6CEEC;"| 13.9 %
|style="text-align:center; background: #F6CEEC;"| 13.1 %
|style="text-align:center; background: #F6CEEC;"| 10.4 %
|-
|style="text-align:left; background: #F6CEEC;"| Unexplained factor
|style="text-align:center; background: #F6CEEC;"| 12.7 %
|style="text-align:center; background: #F6CEEC;"| 11.8 %
|style="text-align:center; background: #F6CEEC;"| 18.6 %
|-
|}
</div>

==Causative Agents==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

[[File:Follicular Development.jpeg|right|thumbnail|500px|Infertility treatments aim to facilitate follicular development and induce ovulation to improve chances of fertilisation <ref name="PMID24717179"><pubmed>24717179</pubmed></ref>]]

Normally a woman produces one egg per month from the ovaries, which travel down the Fallopian tube to be fertilized or be released from the body. In cases where women have difficulty falling pregnant, they are given medication which help them to produce and release eggs (as shown in the diagram to the right), further increasing their chances of fertilization and pregnancy <ref><pubmed>19573285</pubmed></ref>. Ovarian Hyper stimulation Syndrome generally occurs during infertility treatments when the ovaries are overstimulated by the fertility medication which causes the ovaries to swell and leak fluids into the belly and abdomen. The prevalence of OHSS onset is linked with excessive number of follicle development in response to the administration of injectable Follicle Stimulating Hormones (FSH) followed by the '''Human Chorionic Gonadotrophins''' (hCG) which triggers the release of the oocytes <ref><pubmed>26190539</pubmed></ref>.

'''Follicle Stimulating Hormones''' (FSH) <ref name="PMID9020850"><pubmed>9020850</pubmed></ref> are glycoprotein hormones that are produced and secreted from the Anterior Pituitary gland into the bloodstream, which regulate the developmental, growth, maturation and the reproductive processes within the body. In females, the Follicle Stimulating Hormones initiates the stages of growth and development of immature ovarian follicles within the ovaries before the release of an egg from a follicle at ovulation. When FSH is administered to a patient who is suffering from infertility, the increase FSH levels affect the rate of development and production, in turn increasing the amount of follicles which are ready to be released during ovulation.

</div>

==Symptoms==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

OHSS is classified based on a criteria from mild, moderate and severe <ref name="WikiOHSS" />:

'''Mild Symptoms'''- abdominal bloating, minimal weight gain, nausea, diarrhoea and a feeling of fullness.

'''Moderate Symptoms'''- Substantial weight gain (on average 2 or more pounds a day), increased abdominal girth, darkend urine and excessive thirst in addition to the mild symptoms.

'''Severe Symptoms'''- In addition to the symptoms associated with Mild and Moderate OHSS, in severe OHSS, you see shortness of breath, calf and chest pains and pleural effusion.

<span style="font-size:100%">'''Classifications of Ovarian Hyper-stimulation Syndrome:'''</span> <ref name="PMID22065820"><pubmed>22065820</pubmed></ref>
{| class="wikitable" style="text-align:center
|-
! scope="col" width="70px"| '''Classification'''
! scope="col" width="650px"| '''Symptoms'''
|-
|style="text-align:center; background: #F6CEEC;"| '''Mild'''
|style="height: 60px; background: #F6CEEC;"| '''Grade 1''' - Abdominal distention and discomfort
'''Grade 2''' - Abdominal distention, discomfort with nausea, vomiting and/or diarrhea and ovarian enlargement from 5~12cm
|-
|style="text-align:center; background: #F8E0F1;"| '''Moderate'''
|style="height: 60px; background: #F8E0F1;"| '''Grade 3''' - All features of Mild OHSS with ultrasonographic evidence of ascites
|-
|style="text-align:center; background: #F6CEEC;"| '''Severe'''
|style="height: 60px; background: #F6CEEC;"| '''Grade 4''' - All features of Moderate OHSS with the addition of clinical evidence of ascites and breathing difficulties present
'''Grade 5''' - All of the above symptoms along with a change in the blood volume, increased blood viscosity due to coagulation and diminished renal function
|}

</div>

==Diagnosis==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

Whilst symptoms of OHSS can occur as soon as 24 hours post hCG administration, they are usually seen in women 7-10 days post administration. Initially women with OHSS will present with abdominal bloating, as a result of fluid in the peritoneal cavity and an increase in ovary size. When women present with severe OHSS they are often dehydrated, due to increased vascular permeability, and have hemoconcentration. The above results in a decrease in intravascular volume, leading to '''oligouria''' <ref name="PMID22416285" />.

===History===

Initially a thorough history of the patient is taken during which the clinician looks for evidence of ovarian stimulation, followed by ovulation. During this history taking, the clinician will inquire into any weight gain noticed, urine output, and the woman's ability to maintain oral hydration. A key diagnostic tool for clinicians regarding women who are taking gonadotropins is to identify if they are at an increased risk of developing OHSS. Some risk factors include woman aged less than 30, women who have polycystic ovaries, woman with a previous history of OHSS and women who have had greater than 20 oocytes retrieved <ref name="PMID22416285" />.

===Physical Exam===
[[File:Vaginal_Ultrasonography_in_Sagittal_Plane.jpg|right|thumbnail|600px|Vaginal Ultrasonography in Sagittal plane <ref name="Wikiversity Journal of Medicine"> Häggström, Mikael. "Medical gallery of Mikael Häggström 2014". Wikiversity Journal of Medicine 1 (2). DOI:10.15347/wjm/2014.008. ISSN 20018762</ref>]]
After a history of the patient is taken, the next step is to perform a physical exam on the patient. Women who present with abdominal bloating will produce a shifting dullness upon abdominal percussion. Additionally the clinician will test the woman's vital signs, measure her abdominal girth, weight and will look for evidence of ascites or increase in calf size (usually unilateral)<ref name="PMID22416285" />.

===Investigations===

If the clinician further suspects a women of having OHSS, various investigations can be done such as an ultrasound.The intraperitoneal fluid is best imaged via vaginal ultrasound due to the enlarged ovaries making it difficult to image the pelvis using transabdominal ultrasound. The clinician can also order laboratory testing to look for urine specific gravity and and complete blood count to look for hemoconcentration with a hematocrit. Additionally, liver function tests can be ordered to look for elevated function. The clinician will also look for evidence of elevated D-dimers and fibrinogen and decreased levels of anti-thrombin 3 <ref name="SAHealth"> Government of South Australia Health [ http://www.sahealth.sa.gov.au/wps/wcm/connect/9b61ed004ee5348da663afd150ce4f37/Ovarian-hyperstimulation-syndrome-WCHN-PPG-17072012.pdf?MOD=AJPERES&CACHEID=9b61ed004ee5348da663afd150ce4f37 ], 'South Australian Paediatric Clinical Guidelines OHSS'</ref>.

====Ultrasound====

Typical appearances of the ultrasound include <ref name="Ultrasound"> Radiopaedia [ http://radiopaedia.org/articles/ovarian-hyperstimulation-syndrome-1 ], 'Ovarian Hyperstimulation Syndrome'</ref>:

*Bilaterally and symmetrically enlarged ovaries (>12cm)
* "Spoke-Wheel appearance" - presence of multiple cysts of varying size
*May also see ascites (fluid)

===Severity===

Once a clinician has deduced a women is suffering from OHSS, the severity of their condition needs to be established as either mild, moderate or severe. This is done by referring to the criteria under the sub-heading [[Symptoms]].The subsequent course of treatment for the woman will be based upon this evaluation.

{|
|-bgcolor="F6CEEC"
|
'''Further investigations''' can be done including a Chest X-ray to check for pleural effusions and oedema and USS with Doppler's to check for ascites or possible ovary torsion. <ref name="PMID22416285"><pubmed>22416285</pubmed></ref>
|}

===Differential Diagnosis===

Conditions presenting with similar symptoms or ultrasound images include <ref name="Ultrasound" />:

*Polycystic Ovaries (PO)
:: The difference is that with PO is that the cycts are typically smaller than OHSS cysts and there is no evidence of ascited or pleural effusion
*Mucinous Ovarian Malignancy
:: A type of Ovarian Epithelial tumour
*Ectopic Pregnancy <ref name="Casereport"> Australian Medical Student Journal [ http://www.amsj.org/wpcontent/uploads/files/articles/amsj_v2_i1/AMSJ_v2_i1_pg58-60.pdf ], 'Ovarian hyperstimulation syndrome'</ref>
::A pregnancy in which the foetus develops outside of the uterus e.g. in the fallopian tube

</div>

==Pathophysiology==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

[[File:Pathogenesis_of_OHSS.png|600px|thumb|Pathogenesis of OHSS <ref name="PMID20416867"><pubmed>20416867</pubmed></ref>]]

The definition of Ovarian Stimulation is enlarged ovaries with many luteinized cysts, that can present with secondary complications. What distinguishes Ovarian Stimulation from OHSS is the presence of vascular hyper-permeability that results in fluids being redirected elsewhere in the body.

The key process to OHSS appears to be caused by '''Vascular Endothelial Growth Factor''' (VEGF), that is released along with other cytokines, estrogen and progesterone, due to the ovary undergoing luteinization as a result of stimulation by hCG. VEGF increases vascular permeability and as a result the capillaries become more "leaky" to the fluids in them. These fluids can then escape the capillaries and accumulate in the pleural and abdominal cavities as ascites. The woman then becomes hypovolemic and is at an increased risk of circulatory, renal and respiratory issues such as arterial thromboembolism due to the thickening of the blood. Note, the blood is thickened as fluid is leaving the capillaries, leaving behind red blood cells and other cellular components of the blood <ref name="WikiOHSS" />.

The increase in expression of VEGF and VEGF Receptor 2 (VEGFR2) is attributed to the greatly increased amount of their mRNA present in the body after stimulation with hCG <ref name="PMID21082502"><pubmed>21082502</pubmed></ref>. VEGF interacts with VEGF2 and VEGF Receptor 1 (VEGFR1) to create a strong angiogenic effect. Both VEGFR2 and VEGFR1 belong to a family of receptors called tyrosine kinases. VEGF2 is involved in the regulation of angiogenesis and vascular permeability whilst VEGF1 has a slightly contradictory role in that is is involved in the maintenance of the tight junctions between endothelial cells in blood vessels. A study by Gómez ''et. al.'' <ref name="PMID21082502" /> showed that women experiencing OHSS had substantially higher plasma levels of VEGF and lower levels of VEGFR1.

</div>

==Complications==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

Ovarian torsion or rupture, renal insufficiency and thrombophlebitis can all complicate OHSS. If a pregnancy occurs, symptoms may persist longer than the usual 1 to 2 weeks and become more severe, however, even with severe OHSS, they do not extend past the first trimester <ref name="WikiOHSS" />.

<span style="color:#FA58D0"> '''1-2% of women who undergo ovarian stimulation develop a severe form of OHSS''' </span>. Complications from severe OHSS include:

*Fluid collection in the abdomen
*Electrolyte disturbances (sodium and potassium)
*Kidney failure
*Ovary twisting
*Rupture of a cyst in an ovary
*Breathing problems
*Blood clots in large vessels (most commonly the legs)
*Pregnancy loss from miscarriage or termination
*Rarely, death

A study by Nouri ''et. al.'' <ref name="PMID24996451"><pubmed>24996451</pubmed></ref> found that women with '''Polycystic Ovarian Syndrome''' (PCOS) and those that were induced with hCG experienced longer recovery times from severe OHSS than women who were not pregnant. They looked at a cohort of women hospitalised for the first time with severe OHSS and subject them to the same treatments. Based on a defined criteria, they established the recovery time of these women and compared the times between those that were pregnant to those that were not pregnant. They also found that whether a woman had PCOS or ovulation induction did not affect her risk of developing OHSS if she was not pregnant. It is only a risk factor for pregnant women.

===Thromboembolic events===

A frequent and deadly complication of OHSS are thromboembolic events due to increased blood clotting. This increase in blood clotting has been attributed to a variety of complications such as hemoconcentration (which thickens the blood), hypovolemia and an increase in the permeability of blood vessels as a result of increased vasoactive substances in the body of ovarian origin. Thromboembolic events include venous thromboses often in the upper extremities and arterial thromboses such as those in the cerebrovascular region. These events can lead to amputations of extremities, brain damage, miscarriage and death. To avoid this, anti-coagulants are given to pateitns with OHSS and they are fitted with compression stockings (see [[Treatment]]) <ref name="PMID23378404"><pubmed>23378404</pubmed></ref>.

{|
|-bgcolor="F8E0F1"
|
The risk of a woman developing OHSS is higher if she is having a '''twin pregnancy''', as she is exposed to higher concentration of hCG. <ref name="PMID9756273"><pubmed>9756273</pubmed></ref>
|}

</div>

==Treatment==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

'''General treatment
'''
*''Acetaminophen'' with or without a narcotic agent- used to treat abdominal discomfort
*Women are encouraged to drink 2-3 litres of water a day to prevent hemoconcentration
*Women are advised to avoid sexual intercourse and vigorous exercise at the risk of torsion or rupture of the ovaries
*NSAID's with anti-platelet properties should NOT be used as they may effect renal function in a women with OHSS
*Patients with significantly painful ascites or breathing problems may undergo ''Paracentesis'' (drainage of the ascites)
*''Culdocentesis'' (extraction of fluid from recto-uterine pouch) can be done to decrease the likelihood of a woman with moderate OHSS progressing to severe OHSS.<ref name="PMID22416285" />

===Mild to Moderate OHSS===

Mild OHSS can often resolve on its own, however, moderate OHSS may include treatments such as<ref name="WikiOHSS" />:

*Anti-nausea medication and prescription painkillers
*Regular physical examinations and ultrasounds
*Daily weigh-ins and waist measurements
*Measuring the amount of urine produced each day
*Frequent blood tests for monitoring dehydration and electrolyte imbalance
*Maintaining a high balance of fluids
*Drainage of excess abdominal fluid by inserting a needle in the abdominal cavity
*Wearing support stockings which help prevent blood clots/thrombosis

===Severe OHSS===

Severe OHSS requires hospital care in order for constant monitoring and treatment such as <ref name="WikiOHSS" />:

*Intravenous fluids with a crystalloid solution (100-150mL/hr)
*Intravenous Albumin is administered is IV fluids are insufficient (15-20mL/hr of 25% albumin for 4 hrs)
*In addition to Acetaminophen, ''Opioid analgesics'' can be administered for pain relief
*''Antiemetics'' can be used to subside nauseas and/or vomiting
*Woman administered to hospital of OHSS are considered at high risk of thromboembolic complications and are given low molecular weight ''heparin'', an anti-coagulant
*''Cabergoline''- lessens OHSS symptoms
*''GnRH agonist''- suppresses ovarian activity
**If at risk of OHSS, alternates include using a GnRH agonist instead of hCG however its effects on pregnancy rates are questionable. Using a GnRH agonist to replace the use of hCG for final oocyte stimulation will see a 6% decrease in delivery rate.

*Daily monitoring of creatine, urea, creatine clearance C-reactive protein (to rule out infection) are all required in combination with weekly tests such as liver and renal function tests and chest x-rays (to check for pleural effusion) <ref name="PMID12638783" />.

If there are serious complications then additional treatments are required:

*Surgery for a ruptured ovarian cyst
*Intensive care for the liver or lung complications

====Paracentesis====

For women with severe/grade 3 OHSS, paracentesis, the removal of fluid from the body using an aspiration needle, can be undertaken. It is a diagnostic and a therapeutic method that can be done trans-abdominally and trans-vaginally. It is used to relieve symptoms, improve haemodynamics e.g. Urinary output, and shorten the women's hospital stay. Complications of paracentesis include bleeding, infection and organ injury, however are note common <ref name="Paracentesis"> S. Monica Soni, HMS 3, Gillian Lieberman, MD [ http://eradiology.bidmc.harvard.edu/LearningLab/genito/Soni.pdf ], 'Ovarian Hyperstimulation Syndrome'</ref>.

{|
|-bgcolor="F8E0F1"
|
The most important aspect of treatment for any women with OHSS is close and constant '''monitoring''' with her healthcare professional. Counselling may also be provided to women and their partners or families in order to provide them with the best possible knowledge base to manage and treat their OHSS. It is important to note that there is '''no one cure or treatment''' for OHSS. Treatment involves managing and eliminating the symptoms until such time as the syndrome resolves itself <ref name="WikiOHSS" />.
|}

</div>

==Prevention==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

There are three key avenues through which the incidence of OHSS may be prevented. These include identifying risk factors to predict OHSS development, modifying treatment regimes on the basis of the identified risk factors and intervention to prevent progression to OHSS once the patient has undergone '''Controlled Ovarian Stimulation''' (COS).

=== Risk factors===

'''Primary risk factors'''

Pre-existing factors likely to exacerbate the ovarian stimulation response. Primary risk factors include <ref name="PMID26074966"><pubmed>26074966</pubmed></ref>:

*Young age
*Low body weight
*History of elevated response to gonadotropins
*Polycystic Ovary Syndrome (PCOS)
*Isolated PCOS characteristic
*A previous history of OHSS.
*Hormonal markers (e.g. Anti-Mullerian Hormone markers)
*Ultrasonographic markers (e.g. Antral Follicle Count)

'''Secondary risk factors'''

Secondary risk factors involve the monitoring of ovarian response parameters once COS has been initiated. These parameters are monitored for <ref name="PMID19007627"><pubmed>19007627</pubmed></ref>:

*rapidly rising E2 levels
*E2 concentration larger than 2500 pg/mL
*large number of developing follicles (10-14mm) on the day hCG is administered
*large number of oocytes retrieved

These factors in combination, act as a predictive tool to assess the likelihood of severe OHSS development, with a 83% sensitivity and 84% specificity. <ref name="PMID19007627"/>

=== Primary Prevention===

Primary Prevention involves the modification of treatment regimens on the basis of OHSS risk classifications, in order to prevent OHSS occurrence.

'''Ovulation Induction'''

Unifollicular Ovulation Induction through Ovulation Induction (OI) is a primary means of avoiding OHSS in women with Polycystic Ovarian Syndrome, who are at an increased risk. In order to promote unifollicular development, the ovaries are stimulated with a low starting dose of FSH (75 IU).<ref name="PMID20416867"><pubmed>20416867</pubmed></ref> Studies suggests that a minimum gonadotropin dose lowers OHSS risk and thus a step-up regimen is utilised to achieve an ovarian response, whereby the FSH dosage is increased every 7 days until follicular development of greater than 10mm is noted.<ref name="PMID26074966" /> Alternatively, a step-down regimen may be followed, whereby a high initial FSH dosage is lowered according to the ovarian response. Another method to increase FSH levels during OI, is through Aromatase Inhibitors which promote folliculogenesis by increasing pituitary secretion of FSH, and downregulate oestrogen production through a negative feedback loop. However, Aromatase Inhibitors have not been shown to reduce OHSS incidence in comparison to other methods of OI.<ref name="PMID26074966" /> During OI, a key objective is to prevent early cycle cancellation due to premature luteinisation from pituitary secretion of LH. In order to downregulate LH secretion, Gonadotropin-releasing hormone agonists (GnRHa) are administered in addition to gonadotropins. Alternatively, GnRH antagonists may be administered to downregulate endogenous LH secretion. Comparative studies have shown that the GnRH antagonist protocol has a greater effect in lowering the incidence of mild to severe OHSS. However due to the rare nature of OHSS, and insufficient sample sizes, the difference was not found to be significant. <ref name="PMID21082508"><pubmed>21082508</pubmed></ref>. Generally, the duration of exposure to gonadotropins and subsequent risk of OHSS may be minimised through mild stimulation protocols which administer FSH only in the mid to late follicular phase.<ref name="PMID20416867" />

'''Adjuvant Metformin Therapy'''

Adjuvant Metformin Therapy has been found to lower the risk of OHSS by 63%.<ref name="PMID25406011"><pubmed>25406011</pubmed></ref> It involves the administration of metformin at a daily dosage of 1000 to 2000mg, 2 months prior to Controlled Ovarian Stimulation <ref name="PMID26074966"/>. Metformin lowers the elevated insulin levels in PCOS which consequently reduce intraovarian androgen levels. This leads to a reduced sensitivity and expression of granulosa cell-follicle stimulating hormone receptors which result in a less exaggerated response to gonadotropins. Furthermore, it is suggested that Metformin prevents OHSS by controlling vascular permeability through the inhibition of various vasoactive molecules, including VEGF.

'''Avoiding hCG during Luteal Phase Support

Following Controlled Ovarian Stimulation, the steroid levels of E2 and P4 are reduced during the luteal phase due to the negative feedback on the pituitary. This leads to low endogenous LH levels, which consequently reduce endometrial receptivity as well as the luteal phase duration itself. As a result, implantation and pregnancy rates are reduced and early pregnancy loss rates are increased.<ref name="PMID20416867" /> Luteal Phase Support (LPS) serves to combat these adverse events with the use of hCG. However, hCG has been found to increase the risk of OHSS. Alternatively, the use of progesterone has been found to not only halve the risk of OHSS, but also induce similar improvements in pregnancy and miscarriage rates as hCG.<ref name="PMID26148507"><pubmed>26148507</pubmed></ref>

===Secondary Prevention===

Secondary Prevention aims to prevent progression to OHSS once COS has been initiated and the patient has been found to mount an exaggerated response. <ref name="PMID20416867" />

'''Coasting'''

Coasting is a first-line secondary preventative strategy. It consists of the withdrawal of gonadotrophins when a critical number of follicles and/or E2 concentration is reached. hCG is administered once the E2 concentration reduces to a safe level, before the process of oocyte retrieval commences. This preventative strategy is conducted for a period of less than 3 days in order to avoid compromising IVF outcomes.

'''Cryopreservation'''

Cryopreservation of embryos after oocyte retrieval is another avenue which may avert OHSS progression. The cryopreserved embryos are only reimplanted once the patient's hormone serum levels have normalised. Using oocyte vitrification, crystal formation within embryo tissue is avoided and so cryopreserved embryos have been found to produce better pregnancy rates with a 32% increase, than fresh embryo transfer. Recent studies suggest cryopreservation itself does not reduce OHSS rates, but must be followed by a GnRHa trigger to avert OHSS.

'''Cycle cancellation'''

Cycle cancellation is a guaranteed method to prevent early OHSS whereby hCG is withheld. This is a last resort strategy as it carries the risk of significant psychological distress and financial loss for the patient.

</div>

==Effect on the Newborn==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

</div>
Women who develop OHSS while undergoing Assisted Reproductive Technologies (ART) treatment are not only more likely to achieve a pregnancy, but have a live birth as the pregnancy outcome. This live birth is also more likely to be a multiple birth of two, three or more children. <ref name="PMID19591989"><pubmed>19591989</pubmed></ref> It has been postulated that a multifetal pregnancy leads to a more rapid increase in hCG levels, resulting in an increased risk of OHSS. However, the causal nature between multifetal pregnancy and OHSS development is disputed and further research is required to distinguish correlation from causation. <ref name="PMID19573292"><pubmed>19573292</pubmed></ref>

OHSS development is also associated with an increased risk of adverse outcomes including stillbirth, premature birth and low birthweight.<ref name="PMID19591989" /> Although the cause for the increased risk in adverse pregnancy outcomes is unknown, it is suggested that as the incidence of OHSS is reduced through various prevention strategies, the risk of such outcomes may be also be reduced.

==Genetics==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

Despite OHSS typically being of iatrogenic origin as a result of ovarian stimulation with gonadotropins, research has been conducted into the potential genetics behind OHSS as many sporadic and familial cases have been observed. '''Mutations''' in the receptor for hormones such as Follicle Simulating Hormone (FSH), Lutenizing Hormone (LH) and hCG have all been targets of OHSS genetics research. Interestingly, they too also arise from a common ancestral gene.

===Follicle Stimulating Hormome===

Dr. Botros Rizk, of the University of South Alabama College of Medicine <ref name="PMID19573286"><pubmed>19573286</pubmed></ref>, has written extensively regarding the genetics behind OHSS. In particular, he talks about '''FSH receptors''' (FSHR) and their role in the syndrome. He hypothesises that mutations in these receptors could be activating or inactivating, leading to an increased risk of developing OHSS or sterility respectively. Currently, 744 single nucleotide polymorphisms (a type of mutation) have been found in the gene encoding the FSHR, 8 of which are located in its exons (coding regions of the gene). How the ovary responds is resultant on the FSHR genotype. For example, Ser680Asn, a polymorphism in the FSHR gene has been shown to aid in predicting the severity of a woman's OHSS. Ordinarily FSH stimulates the growth of ovarian follicles, however, when mutated, it is stimulated by the hCG resulting in excessive follicle development.

Spontaneous OHSS, OHSS that arises and cannot be attributed to any form of ovarian stimulation or Assisted Reproductive Technology, has been linked to activating mutations in the FSHR <ref name="PMID23499866"><pubmed>23499866</pubmed></ref>. This familial disorder is an autosomal dominant one. In most cases the FSHR can be stimulated by the presence of Thyroid Stimulating Hormone (TSH) or hCG, in the absence of FSH (the ligand for FSHR).

===Lutenizing Hormome===

The '''Lutenizing Hormone Receptor''' (LHR) gene in humans is comprised of 11 exons. Animal studies have shown that many primates exhibit a similar gene which is comprised of only 10 exons, however a gene lacking the 10th exon has been identified and termed the type 2 LHR. Expression of the type 2 LHR has been seen in humans. The type 2 LHR, compared to the wild-type LHR appears to be repaired with regard to its function. Defects in the type 2 LHR include a decrease in efficiency of transport to the plasma membrane and irregularities in signal transduction. Inactivating mutations in the LHR have been seen to cause infertility in women as well as amenorrhoea. Activating LHR gene mutations are asymptomatic and are not associated with OHSS in women.

===Bone Morphogenic Protein===

An imporant growth factor, derived from oocytes called '''BMP-15''' (Bone Morphogenic Protein 15) is vital for female fertility. It belongs to the family of growth factors, Transforming Growth Factor β (TGF-β) and is heavily involved in folliculogenesis. It has been found that mutations in the BMP-15 gene caused infertility in female sheep. Conversely, it has also been indicated in enhanced fertility when BMP-15 is present is high amounts in follicular fluid <ref name="PMID19573286" />.

A case study done by Hanevik ''et. al.'' in 2013 <ref name="PMID21565556"><pubmed>21565556</pubmed></ref> found that a Single Nuclear Polymorphism (SNP) in the BMP-15 gene is responsible for a high response to ovarian hyper-stimulation. The aim of the study was to test the effect the SNP had on BMP-15 with regard to high and low responders buy taking blood from 53 high responders, 38 low responders and 100 non-responders (controls) and analysing 5 noted SNP's. Results from their study showed a correlation between a high response to ovarian hyper-stimulation and the BMP-15 9G allele. The article does state however, that further research is required into the molecular effects of SNP's on the function of BMP-15.

===Vascular Endothelial Growth Factor===

'''Vascular endothelial growth factor''' (VEGF) has been indicated as one of the key agents causing vascular permeability and subsequent ascites in OHSS. The gene, which is located on chromosome 12, is made up of 8 exons (coding regions), of which exons 6 and 7 do not always appear due to the exons being spliced out.The splicing of this gene allows for various isoforms of the gene to exist of which VEGF 121 and 165 appear to play a role in angiogenesis. There are two VEGF Receptors, VEGFR-1 and VEGFR-2 that belong to the tyrosine kinase family of receptors (for more information on VEGF see [[Pathophysiology]]). Because of its distinct role in OHSS, it has been targeted as an area for research for potential treatments. The idea is that if the genetic expression of VEGF and its receptors can be controlled, OHSS can be avoided or treated.<ref name="PMID19573286" />

A different study by Hanevik ''et. al.'' , <ref name="PMID22587628"><pubmed>22587628</pubmed></ref> done in 2012 involved analysing blood samples from 53 women with OHSS and 100 women without it (controls) and analysing 6 SNP's in the VEGFR2 gene to find any genetic variations. They found a correlation between women with the VEGF +405cc genotype and the development of OHSS indicating women that undergo controlled ovarian hyper-stimulation and posses his genotype, are at an increased risk of developing OHSS.

</div>

== Current Research on Animal Models==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">
{|
|-bgcolor="F8E0F1"
|
<span style="font-size:120%">'''Inhibition of Cyclooxygenase-2 (COX-2) by Meloxican decreasing the incidence of OHSS in Rat Model'''</span> <ref name="PMID18166186"><pubmed>18166186</pubmed></ref>

Reasearch was carried out to investigate the effects of selective inhibition of the enzyme COX-2 on the Ovarian Hyperstimulation Syndrome (OHSS) using Female Wistar rates as the subjects. The research aimed to find results by measuring the number of antral and luteinized follicles, ovarian weight, vascualr endothelial growth factors and COX-2 immunohistochemistry. The rats being tested were all 22 days old and were divided into four equal groups;

'''Group 1 (Control group)''' was subject to a 0.1 ml of Intraperitoneal Saline from days 22 ~ 26

'''Group 2 (Mildly-stimulated group)''' subject to 10IU of pregnant mare serum gonadotrophin (PMSG) on day 24 and then 10IU of Human Chorionic Gonadotrophin (hCG) on day 26

'''Group 3 (OHSS positive group)''' was subject to 10IU of PMSG from days 22 ~ 26 and then administered 30IU of hCG on day 26 to induce OHSS

'''Group 4 (OHSS positive variant group)''' received 15mg/ml of Meloxicam 2 hours prior to administration of 10IU PMSG from days 22 ~ 26

Results showed there was no difference in ovarian weight in samples from Group 1 and Group 2, however Group 3 showed signs of significant ovarian weight increase which in group 4 was suppressed by the introduction of Meloxicam. No differences were observed in the number of antral follicles amongst the four test groups. Results from Group 2 and Group 3 showed that the granulosa cells of preovulatory follicles and the stromal cells were highly VEGF immunoreactive, however the Meloxicam treated Group 4 showed less immunoreactivity than Group 2 and Group 3 which indicated the correlation between Meloxicam and the diminished VEGF expression. Group 3 presented an increased COS-2 immunoreactivity which was highly diminished than in Group 4.

The research concluded that in a rat model, the enzyme Meloxicam has a beneficial effect on OHSS by reducing the increase of ovarian weight and the expression of VEGF associated with OHSS, the effects of which may be mediated by the inhibitory capacity of COX-2 on Meloxicam
|}

{|
|-bgcolor="FF99FF"
|
<span style="font-size:120%">'''Inhibition of Ovarian VEGF secretion by activation of Dopamine Receptor 2'''</span> <ref name="PMID25217874"><pubmed>25217874</pubmed></ref>

This research was carried out to investigate a possibility in whether a Dopamine Receptor 2 agonist '''(D2-ag)''' can assist in the prevention of Ovarian Hyperstimulation Syndrome, using rat models, by decreasing the ovarian vascular endothelial growth factor '''(VEGF)''' production. Using Immature Wistar rats (22 days old) as their animal model, the rats were initially stimulated with Gonadotrophins to mimic the onset and effects of OHSS and then subjected to treatment with a D2-agonist and/or a D2-antagonist (D2-ant). The vascular permeability was measured at the endpoint after day 26 by measuring the peritoneal extravasion of a previously injected dye and ovaries from all subjects were collected to assess the effects of D2-ag and D2-ant on the production of Ovarian VEGF. The expression of VEGF mRNA was measured by quantitative real time PCR and the levels of VEGF proteins were measured by Western Blots.

Results showed that the D2-ag caused a large reduction in the vascular permeability which was in turn associated with the great decreased in VEGF protein production in the OHSS rat ovaries, whereas the introduction of D2-ant showed opposite results with a increase in the vascular permeability leading to the increase of VEGF protein production in the ovaries. Ovarian VEGF mRNA levels were found to be unaffected by the introduction of these drugs in OHSS rat subjects. Conclusions were drawn on the fact that Dopamine Receptor 2 agonists prevent the increase of vascular permeability in subjects with OHSS by decreasing the ovarian production of VEGF and also that due to the dose-dependent inhibitory effect of the D2-ag on ovarian VEGF, current OHSS therapies used in humans can benefit by increasing the intraovarian concentration of D2-ag.
|}
</div>

==Glossary==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

'''Aromatase Inhibitor''' - A drug that inhibits enzyme aromatase, which in turn suppresses estrogen synthesis.

'''Ascites''' - An accumulation of fluid in the peritoneal cavity with resultant abdominal swelling.

'''Cabergoline''' - A dopamine receptor agonist used to treat hormone imbalance.

'''Controlled Ovarian Stimulation''' - female infertility treatment using medications to stimulate the ovaries to develop follicles.

'''E2''' - Estradiol - Potent estrogen sex hormone.

'''Gonadotropin''' - Any hormone that has a stimulating effect on the gonads.

'''GnRH agonist''' - Gonadotropin Releasing Hormone - A class of compounds that mimic the effect of the natural Gonadotropin Releasing Hormone.

'''GnRH antagonist''' - Gonadotropin Releasing Hormone - A class of compounds that are similar in terms of the structure of natural Gonadotropin Releasing Hormone but has a antagonistic effect.

'''hCG'''- Human Chorionic Gonadotropin

'''Hemoconcentration''' - An increase in the concentration of circulating red blood cells in response to a decrease in blood plasma volume.

'''Hypovolemic''' - A decrease in circulating blood volume.

'''Iatrogenic''' - Illness caused as a result of a medical examination or treatment.

'''Intravenous fluids''' - Is the infusion of liquid substances directly into a vein.

'''IVF''' - In-vitro Fertilization

'''NSAID''' - Non-steroidal Anti-Inflammatory Drug e.g. Ibuprofen

'''OHSS''' - Ovarian Hyper-stimulation Syndrome

'''P4''' - Progesterone - endogenous progestogen sex hormone.

'''PCOS''' - Polycystic Ovarian Syndrome. An endrocrine system disorder whereby the ovaries are enlarged with small collections of fluid.

'''FSH''' - Follicle Stimulating Hormone

'''LH''' - Luteinizing Hormone

'''Oliguria'''- Decreased urine output/small amounts of urine produced.

</div>

==References==

2015 Group Project 2

2015-10-22T22:29:49Z

Z3372824: /* Primary Prevention */

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==<span style="font-size:120%">'''Ovarian Hyper-stimulation Syndrome (OHSS)'''</span>==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

Ovarian Hyper stimulation Syndrome (OHSS) is an iatrogenic complication of '''Assisted Reproduction Technology''' (ART), in which women take medications to stimulate oocyte growth. It is generally identified by cystic enlargements of the ovaries and fluid accumulation in the peritoneal cavity due to the increased capillary permeability and ovarian neoangiogenesis <ref name="PMID22065820"><pubmed>22065820</pubmed></ref>. It is an occurrence which is dependent on the controlled stimulation of the ovaries in preparation for IVF i.e. administration of human Chorionic Gonadotropin (hCG).

OHSS was first described in 1943 as ''“syndrome d’hyperluteinisation massive
des ovaries”''. It was during this time that gonadotropins were prepared from animals such as sheep to bring on ovulation in women. The first recorded death as a result of OHSS occurred in 1951 and was due to renal failure as a result of oligouria, a complication of the syndrome <ref name="OHSS"> Marie M. Budev, DO, MPH; Alejandro C. Arroliga, MD; Tommaso Falcone, MD, [ http://utilis.net/Morning%20Topics/REI/Ovarian%20Hyperstimulation.pdf ], 'Ovarian Hyperstimulation Syndrome'</ref> <ref name="PMID12638783"><pubmed>12638783</pubmed></ref>.

<span style="color:#FA58D0">This wikipage aims to provide clear information on various areas surrounding OHSS such as diagnosis, prevention and complications and will look into the genetics behind the disorder and the various animals models used to research it.</span>

<html5media height="350" width="450">https://www.youtube.com/watch?v=aXmjJw234a4</html5media>

'''Overview of the Ovarian Hyperstimulation Syndrome''' <ref> Howcast (2013, August 27) Ovarian Hyperstimulation Syndrome | Infertility. Retrieved from https://www.youtube.com/watch?v=aXmjJw234a4</ref>

</div>

==Epidemiology==
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Ovarian Hyper-Stimulation Syndrome (OHSS) rarely occurs sporadically, and if it does, it is usually the result of an underlying genetic problem. The majority of OHSS is due to the ovaries being stimulated to mature and release an abundance of oocytes, in response to hormones Human Chorionic Gonadotropin (hCG) and Follicle Stimulating hormone (FSH), during IVF. Rarely, Clomifene Citrate therapy can cause OHSS.<ref name="WikiOHSS"> Wikipedia, [ https://en.wikipedia.org/wiki/Ovarian_hyperstimulation_syndrome ], 'Ovarian Hyperstimulation Syndrome'</ref>

OHSS only affects '''0.5-5%''' of women undergoing Ovarian Hyper-stimulation, but despite its small prevalence, it is a potentially fatal outcome of a non-vital procedure and remains a prevalent problem for fertility specialists <ref name="PMID12498425"><pubmed>12498425</pubmed></ref> <ref name="PMID12638783"><pubmed>12638783</pubmed></ref>. Age has been cited as a factor affecting those with OHSS, with younger women more at risk. Additionally, women with allergies were seen to have a higher incidence of OHSS. It is important to note that at this point in time, there is no positive correlation between gonadotropin dose and OHSS.

Of the 0.5-5% of women affected with OHSS mentioned above, 2% of those women will require hospitalisation. As of 2011, it has been reported that the incidence of OHSS was '''increasing''', resulting in approximately 3 deaths per 100,000 women undergoing ovarian stimulation per year <ref name="PMID21828116"><pubmed>21828116</pubmed></ref>. This is particularly worrying as in 2008, in the United States alone, there were around 150,000 IVF cycles undertaken.

{|
|-bgcolor="F8E0F1"
|
'''With the field of Assisted Reproductive Technologies expanding and more women partaking in IVF treatments, the threat of women developing OHSS is an ongoing and increasing one''' <ref name="PMID21828116" />.
|}
{| class="wikitable mw-collapsible mw-collapsed"
! Characteristics of women by complication group <ref name="PMID19591989"><pubmed>19591989</pubmed></ref>
|-
! scope="col" width="100px" height="60px" style="text-align:center| '''Characteristic'''
! scope="col" width="100px" height="60px" style="text-align:center| '''No Complications
(N = 212,041)'''
! scope="col" width="100px" height="60px" style="text-align:center| '''Moderate OHSS
(N = 1,523)'''
! scope="col" width="100px" height="60px" style="text-align:center| '''Severe OHSS
(N = 655)'''
|-
|style="text-align:center; background: #FF99FF;"| '''Maternal Age (Mean ± SD)'''
|style="text-align:center; background: #F6CEEC;"| 35.6 ± 4.6
|style="text-align:center; background: #F6CEEC;"| 33.0 ± 4.3
|style="text-align:center; background: #F6CEEC;"| 33.1 ± 4.4
|-
|style="text-align:center; background: #FF99FF;"| '''Maternal Age (%)'''
|-
|style="text-align:left; background: #F6CEEC;"| <30 years
|style="text-align:center; background: #F6CEEC;"| 10 %
|style="text-align:center; background: #F6CEEC;"| 21.1 %
|style="text-align:center; background: #F6CEEC;"| 20.6 %
|-
|style="text-align:left; background: #F6CEEC;"| 30-34 years
|style="text-align:center; background: #F6CEEC;"| 30.4 %
|style="text-align:center; background: #F6CEEC;"| 43.2 %
|style="text-align:center; background: #F6CEEC;"| 40.5 %
|-
|style="text-align:left; background: #F6CEEC;"| 35-39 years
|style="text-align:center; background: #F6CEEC;"| 37.8 %
|style="text-align:center; background: #F6CEEC;"| 27.2 %
|style="text-align:center; background: #F6CEEC;"| 32.5 %
|-
|style="text-align:left; background: #F6CEEC;"| >40 years
|style="text-align:center; background: #F6CEEC;"| 21.8 %
|style="text-align:center; background: #F6CEEC;"| 8.4 %
|style="text-align:center; background: #F6CEEC;"| 6.4 %
|-
|style="text-align:center; background: #FF99FF;"| '''Nulligravida (%)'''
|style="text-align:center; background: #F6CEEC;"| 45.8 %
|style="text-align:center; background: #F6CEEC;"| 51.5 %
|style="text-align:center; background: #F6CEEC;"| 51.8 %
|-
|style="text-align:center; background: #FF99FF;"| '''Infertility Diagnosis (%)'''
|-
|style="text-align:left; background: #F6CEEC;"| Male factor
|style="text-align:center; background: #F6CEEC;"| 37.7 %
|style="text-align:center; background: #F6CEEC;"| 41.0 %
|style="text-align:center; background: #F6CEEC;"| 33.4 %
|-
|style="text-align:left; background: #F6CEEC;"| Endometriosis
|style="text-align:center; background: #F6CEEC;"| 13.5 %
|style="text-align:center; background: #F6CEEC;"| 13.5 %
|style="text-align:center; background: #F6CEEC;"| 10.7 %
|-
|style="text-align:left; background: #F6CEEC;"| Ovulation Disorders
|style="text-align:center; background: #F6CEEC;"| 14.0 %
|style="text-align:center; background: #F6CEEC;"| 29.5 %
|style="text-align:center; background: #F6CEEC;"| 22.4 %
|-
|style="text-align:left; background: #F6CEEC;"| Diminished ovarian reserve
|style="text-align:center; background: #F6CEEC;"| 16.9 %
|style="text-align:center; background: #F6CEEC;"| 3.2 %
|style="text-align:center; background: #F6CEEC;"| 2.4 %
|-
|style="text-align:left; background: #F6CEEC;"| Tubal factors
|style="text-align:center; background: #F6CEEC;"| 20.4 %
|style="text-align:center; background: #F6CEEC;"| 22.6 %
|style="text-align:center; background: #F6CEEC;"| 22.3 %
|-
|style="text-align:left; background: #F6CEEC;"| Uterine factors
|style="text-align:center; background: #F6CEEC;"| 5.1 %
|style="text-align:center; background: #F6CEEC;"| 4.3 %
|style="text-align:center; background: #F6CEEC;"| 3.1 %
|-
|style="text-align:left; background: #F6CEEC;"| Other factors
|style="text-align:center; background: #F6CEEC;"| 13.9 %
|style="text-align:center; background: #F6CEEC;"| 13.1 %
|style="text-align:center; background: #F6CEEC;"| 10.4 %
|-
|style="text-align:left; background: #F6CEEC;"| Unexplained factor
|style="text-align:center; background: #F6CEEC;"| 12.7 %
|style="text-align:center; background: #F6CEEC;"| 11.8 %
|style="text-align:center; background: #F6CEEC;"| 18.6 %
|-
|}
</div>

==Causative Agents==
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[[File:Follicular Development.jpeg|right|thumbnail|500px|Infertility treatments aim to facilitate follicular development and induce ovulation to improve chances of fertilisation <ref name="PMID24717179"><pubmed>24717179</pubmed></ref>]]

Normally a woman produces one egg per month from the ovaries, which travel down the Fallopian tube to be fertilized or be released from the body. In cases where women have difficulty falling pregnant, they are given medication which help them to produce and release eggs (as shown in the diagram to the right), further increasing their chances of fertilization and pregnancy <ref><pubmed>19573285</pubmed></ref>. Ovarian Hyper stimulation Syndrome generally occurs during infertility treatments when the ovaries are overstimulated by the fertility medication which causes the ovaries to swell and leak fluids into the belly and abdomen. The prevalence of OHSS onset is linked with excessive number of follicle development in response to the administration of injectable Follicle Stimulating Hormones (FSH) followed by the '''Human Chorionic Gonadotrophins''' (hCG) which triggers the release of the oocytes <ref><pubmed>26190539</pubmed></ref>.

'''Follicle Stimulating Hormones''' (FSH) <ref name="PMID9020850"><pubmed>9020850</pubmed></ref> are glycoprotein hormones that are produced and secreted from the Anterior Pituitary gland into the bloodstream, which regulate the developmental, growth, maturation and the reproductive processes within the body. In females, the Follicle Stimulating Hormones initiates the stages of growth and development of immature ovarian follicles within the ovaries before the release of an egg from a follicle at ovulation. When FSH is administered to a patient who is suffering from infertility, the increase FSH levels affect the rate of development and production, in turn increasing the amount of follicles which are ready to be released during ovulation.

</div>

==Symptoms==
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OHSS is classified based on a criteria from mild, moderate and severe <ref name="WikiOHSS" />:

'''Mild Symptoms'''- abdominal bloating, minimal weight gain, nausea, diarrhoea and a feeling of fullness.

'''Moderate Symptoms'''- Substantial weight gain (on average 2 or more pounds a day), increased abdominal girth, darkend urine and excessive thirst in addition to the mild symptoms.

'''Severe Symptoms'''- In addition to the symptoms associated with Mild and Moderate OHSS, in severe OHSS, you see shortness of breath, calf and chest pains and pleural effusion.

<span style="font-size:100%">'''Classifications of Ovarian Hyper-stimulation Syndrome:'''</span> <ref name="PMID22065820"><pubmed>22065820</pubmed></ref>
{| class="wikitable" style="text-align:center
|-
! scope="col" width="70px"| '''Classification'''
! scope="col" width="650px"| '''Symptoms'''
|-
|style="text-align:center; background: #F6CEEC;"| '''Mild'''
|style="height: 60px; background: #F6CEEC;"| '''Grade 1''' - Abdominal distention and discomfort
'''Grade 2''' - Abdominal distention, discomfort with nausea, vomiting and/or diarrhea and ovarian enlargement from 5~12cm
|-
|style="text-align:center; background: #F8E0F1;"| '''Moderate'''
|style="height: 60px; background: #F8E0F1;"| '''Grade 3''' - All features of Mild OHSS with ultrasonographic evidence of ascites
|-
|style="text-align:center; background: #F6CEEC;"| '''Severe'''
|style="height: 60px; background: #F6CEEC;"| '''Grade 4''' - All features of Moderate OHSS with the addition of clinical evidence of ascites and breathing difficulties present
'''Grade 5''' - All of the above symptoms along with a change in the blood volume, increased blood viscosity due to coagulation and diminished renal function
|}

</div>

==Diagnosis==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

Whilst symptoms of OHSS can occur as soon as 24 hours post hCG administration, they are usually seen in women 7-10 days post administration. Initially women with OHSS will present with abdominal bloating, as a result of fluid in the peritoneal cavity and an increase in ovary size. When women present with severe OHSS they are often dehydrated, due to increased vascular permeability, and have hemoconcentration. The above results in a decrease in intravascular volume, leading to '''oligouria''' <ref name="PMID22416285" />.

===History===

Initially a thorough history of the patient is taken during which the clinician looks for evidence of ovarian stimulation, followed by ovulation. During this history taking, the clinician will inquire into any weight gain noticed, urine output, and the woman's ability to maintain oral hydration. A key diagnostic tool for clinicians regarding women who are taking gonadotropins is to identify if they are at an increased risk of developing OHSS. Some risk factors include woman aged less than 30, women who have polycystic ovaries, woman with a previous history of OHSS and women who have had greater than 20 oocytes retrieved <ref name="PMID22416285" />.

===Physical Exam===
[[File:Vaginal_Ultrasonography_in_Sagittal_Plane.jpg|right|thumbnail|600px|Vaginal Ultrasonography in Sagittal plane <ref name="Wikiversity Journal of Medicine"> Häggström, Mikael. "Medical gallery of Mikael Häggström 2014". Wikiversity Journal of Medicine 1 (2). DOI:10.15347/wjm/2014.008. ISSN 20018762</ref>]]
After a history of the patient is taken, the next step is to perform a physical exam on the patient. Women who present with abdominal bloating will produce a shifting dullness upon abdominal percussion. Additionally the clinician will test the woman's vital signs, measure her abdominal girth, weight and will look for evidence of ascites or increase in calf size (usually unilateral)<ref name="PMID22416285" />.

===Investigations===

If the clinician further suspects a women of having OHSS, various investigations can be done such as an ultrasound.The intraperitoneal fluid is best imaged via vaginal ultrasound due to the enlarged ovaries making it difficult to image the pelvis using transabdominal ultrasound. The clinician can also order laboratory testing to look for urine specific gravity and and complete blood count to look for hemoconcentration with a hematocrit. Additionally, liver function tests can be ordered to look for elevated function. The clinician will also look for evidence of elevated D-dimers and fibrinogen and decreased levels of anti-thrombin 3 <ref name="SAHealth"> Government of South Australia Health [ http://www.sahealth.sa.gov.au/wps/wcm/connect/9b61ed004ee5348da663afd150ce4f37/Ovarian-hyperstimulation-syndrome-WCHN-PPG-17072012.pdf?MOD=AJPERES&CACHEID=9b61ed004ee5348da663afd150ce4f37 ], 'South Australian Paediatric Clinical Guidelines OHSS'</ref>.

====Ultrasound====

Typical appearances of the ultrasound include <ref name="Ultrasound"> Radiopaedia [ http://radiopaedia.org/articles/ovarian-hyperstimulation-syndrome-1 ], 'Ovarian Hyperstimulation Syndrome'</ref>:

*Bilaterally and symmetrically enlarged ovaries (>12cm)
* "Spoke-Wheel appearance" - presence of multiple cysts of varying size
*May also see ascites (fluid)

===Severity===

Once a clinician has deduced a women is suffering from OHSS, the severity of their condition needs to be established as either mild, moderate or severe. This is done by referring to the criteria under the sub-heading [[Symptoms]].The subsequent course of treatment for the woman will be based upon this evaluation.

{|
|-bgcolor="F6CEEC"
|
'''Further investigations''' can be done including a Chest X-ray to check for pleural effusions and oedema and USS with Doppler's to check for ascites or possible ovary torsion. <ref name="PMID22416285"><pubmed>22416285</pubmed></ref>
|}

===Differential Diagnosis===

Conditions presenting with similar symptoms or ultrasound images include <ref name="Ultrasound" />:

*Polycystic Ovaries (PO)
:: The difference is that with PO is that the cycts are typically smaller than OHSS cysts and there is no evidence of ascited or pleural effusion
*Mucinous Ovarian Malignancy
:: A type of Ovarian Epithelial tumour
*Ectopic Pregnancy <ref name="Casereport"> Australian Medical Student Journal [ http://www.amsj.org/wpcontent/uploads/files/articles/amsj_v2_i1/AMSJ_v2_i1_pg58-60.pdf ], 'Ovarian hyperstimulation syndrome'</ref>
::A pregnancy in which the foetus develops outside of the uterus e.g. in the fallopian tube

</div>

==Pathophysiology==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

[[File:Pathogenesis_of_OHSS.png|600px|thumb|Pathogenesis of OHSS <ref name="PMID20416867"><pubmed>20416867</pubmed></ref>]]

The definition of Ovarian Stimulation is enlarged ovaries with many luteinized cysts, that can present with secondary complications. What distinguishes Ovarian Stimulation from OHSS is the presence of vascular hyper-permeability that results in fluids being redirected elsewhere in the body.

The key process to OHSS appears to be caused by '''Vascular Endothelial Growth Factor''' (VEGF), that is released along with other cytokines, estrogen and progesterone, due to the ovary undergoing luteinization as a result of stimulation by hCG. VEGF increases vascular permeability and as a result the capillaries become more "leaky" to the fluids in them. These fluids can then escape the capillaries and accumulate in the pleural and abdominal cavities as ascites. The woman then becomes hypovolemic and is at an increased risk of circulatory, renal and respiratory issues such as arterial thromboembolism due to the thickening of the blood. Note, the blood is thickened as fluid is leaving the capillaries, leaving behind red blood cells and other cellular components of the blood <ref name="WikiOHSS" />.

The increase in expression of VEGF and VEGF Receptor 2 (VEGFR2) is attributed to the greatly increased amount of their mRNA present in the body after stimulation with hCG <ref name="PMID21082502"><pubmed>21082502</pubmed></ref>. VEGF interacts with VEGF2 and VEGF Receptor 1 (VEGFR1) to create a strong angiogenic effect. Both VEGFR2 and VEGFR1 belong to a family of receptors called tyrosine kinases. VEGF2 is involved in the regulation of angiogenesis and vascular permeability whilst VEGF1 has a slightly contradictory role in that is is involved in the maintenance of the tight junctions between endothelial cells in blood vessels. A study by Gómez ''et. al.'' <ref name="PMID21082502" /> showed that women experiencing OHSS had substantially higher plasma levels of VEGF and lower levels of VEGFR1.

</div>

==Complications==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

Ovarian torsion or rupture, renal insufficiency and thrombophlebitis can all complicate OHSS. If a pregnancy occurs, symptoms may persist longer than the usual 1 to 2 weeks and become more severe, however, even with severe OHSS, they do not extend past the first trimester <ref name="WikiOHSS" />.

<span style="color:#FA58D0"> '''1-2% of women who undergo ovarian stimulation develop a severe form of OHSS''' </span>. Complications from severe OHSS include:

*Fluid collection in the abdomen
*Electrolyte disturbances (sodium and potassium)
*Kidney failure
*Ovary twisting
*Rupture of a cyst in an ovary
*Breathing problems
*Blood clots in large vessels (most commonly the legs)
*Pregnancy loss from miscarriage or termination
*Rarely, death

A study by Nouri ''et. al.'' <ref name="PMID24996451"><pubmed>24996451</pubmed></ref> found that women with '''Polycystic Ovarian Syndrome''' (PCOS) and those that were induced with hCG experienced longer recovery times from severe OHSS than women who were not pregnant. They looked at a cohort of women hospitalised for the first time with severe OHSS and subject them to the same treatments. Based on a defined criteria, they established the recovery time of these women and compared the times between those that were pregnant to those that were not pregnant. They also found that whether a woman had PCOS or ovulation induction did not affect her risk of developing OHSS if she was not pregnant. It is only a risk factor for pregnant women.

===Thromboembolic events===

A frequent and deadly complication of OHSS are thromboembolic events due to increased blood clotting. This increase in blood clotting has been attributed to a variety of complications such as hemoconcentration (which thickens the blood), hypovolemia and an increase in the permeability of blood vessels as a result of increased vasoactive substances in the body of ovarian origin. Thromboembolic events include venous thromboses often in the upper extremities and arterial thromboses such as those in the cerebrovascular region. These events can lead to amputations of extremities, brain damage, miscarriage and death. To avoid this, anti-coagulants are given to pateitns with OHSS and they are fitted with compression stockings (see [[Treatment]]) <ref name="PMID23378404"><pubmed>23378404</pubmed></ref>.

{|
|-bgcolor="F8E0F1"
|
The risk of a woman developing OHSS is higher if she is having a '''twin pregnancy''', as she is exposed to higher concentration of hCG. <ref name="PMID9756273"><pubmed>9756273</pubmed></ref>
|}

</div>

==Treatment==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

'''General treatment
'''
*''Acetaminophen'' with or without a narcotic agent- used to treat abdominal discomfort
*Women are encouraged to drink 2-3 litres of water a day to prevent hemoconcentration
*Women are advised to avoid sexual intercourse and vigorous exercise at the risk of torsion or rupture of the ovaries
*NSAID's with anti-platelet properties should NOT be used as they may effect renal function in a women with OHSS
*Patients with significantly painful ascites or breathing problems may undergo ''Paracentesis'' (drainage of the ascites)
*''Culdocentesis'' (extraction of fluid from recto-uterine pouch) can be done to decrease the likelihood of a woman with moderate OHSS progressing to severe OHSS.<ref name="PMID22416285" />

===Mild to Moderate OHSS===

Mild OHSS can often resolve on its own, however, moderate OHSS may include treatments such as<ref name="WikiOHSS" />:

*Anti-nausea medication and prescription painkillers
*Regular physical examinations and ultrasounds
*Daily weigh-ins and waist measurements
*Measuring the amount of urine produced each day
*Frequent blood tests for monitoring dehydration and electrolyte imbalance
*Maintaining a high balance of fluids
*Drainage of excess abdominal fluid by inserting a needle in the abdominal cavity
*Wearing support stockings which help prevent blood clots/thrombosis

===Severe OHSS===

Severe OHSS requires hospital care in order for constant monitoring and treatment such as <ref name="WikiOHSS" />:

*Intravenous fluids with a crystalloid solution (100-150mL/hr)
*Intravenous Albumin is administered is IV fluids are insufficient (15-20mL/hr of 25% albumin for 4 hrs)
*In addition to Acetaminophen, ''Opioid analgesics'' can be administered for pain relief
*''Antiemetics'' can be used to subside nauseas and/or vomiting
*Woman administered to hospital of OHSS are considered at high risk of thromboembolic complications and are given low molecular weight ''heparin'', an anti-coagulant
*''Cabergoline''- lessens OHSS symptoms
*''GnRH agonist''- suppresses ovarian activity
**If at risk of OHSS, alternates include using a GnRH agonist instead of hCG however its effects on pregnancy rates are questionable. Using a GnRH agonist to replace the use of hCG for final oocyte stimulation will see a 6% decrease in delivery rate.

*Daily monitoring of creatine, urea, creatine clearance C-reactive protein (to rule out infection) are all required in combination with weekly tests such as liver and renal function tests and chest x-rays (to check for pleural effusion) <ref name="PMID12638783" />.

If there are serious complications then additional treatments are required:

*Surgery for a ruptured ovarian cyst
*Intensive care for the liver or lung complications

====Paracentesis====

For women with severe/grade 3 OHSS, paracentesis, the removal of fluid from the body using an aspiration needle, can be undertaken. It is a diagnostic and a therapeutic method that can be done trans-abdominally and trans-vaginally. It is used to relieve symptoms, improve haemodynamics e.g. Urinary output, and shorten the women's hospital stay. Complications of paracentesis include bleeding, infection and organ injury, however are note common <ref name="Paracentesis"> S. Monica Soni, HMS 3, Gillian Lieberman, MD [ http://eradiology.bidmc.harvard.edu/LearningLab/genito/Soni.pdf ], 'Ovarian Hyperstimulation Syndrome'</ref>.

{|
|-bgcolor="F8E0F1"
|
The most important aspect of treatment for any women with OHSS is close and constant '''monitoring''' with her healthcare professional. Counselling may also be provided to women and their partners or families in order to provide them with the best possible knowledge base to manage and treat their OHSS. It is important to note that there is '''no one cure or treatment''' for OHSS. Treatment involves managing and eliminating the symptoms until such time as the syndrome resolves itself <ref name="WikiOHSS" />.
|}

</div>

==Prevention==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

There are three key avenues through which the incidence of OHSS may be prevented. These include identifying risk factors to predict OHSS development, modifying treatment regimes on the basis of the identified risk factors and intervention to prevent progression to OHSS once the patient has undergone '''Controlled Ovarian Stimulation''' (COS).

=== Risk factors===

'''Primary risk factors'''

Pre-existing factors likely to exacerbate the ovarian stimulation response. Primary risk factors include <ref name="PMID26074966"><pubmed>26074966</pubmed></ref>:

*Young age
*Low body weight
*History of elevated response to gonadotropins
*Polycystic Ovary Syndrome (PCOS)
*Isolated PCOS characteristic
*A previous history of OHSS.
*Hormonal markers (e.g. Anti-Mullerian Hormone markers)
*Ultrasonographic markers (e.g. Antral Follicle Count)

'''Secondary risk factors'''

Secondary risk factors involve the monitoring of ovarian response parameters once COS has been initiated. These parameters are monitored for <ref name="PMID19007627"><pubmed>19007627</pubmed></ref>:

*rapidly rising E2 levels
*E2 concentration larger than 2500 pg/mL
*large number of developing follicles (10-14mm) on the day hCG is administered
*large number of oocytes retrieved

These factors in combination, act as a predictive tool to assess the likelihood of severe OHSS development, with a 83% sensitivity and 84% specificity. <ref name="PMID19007627"/>

=== Primary Prevention===

Primary Prevention involves the modification of treatment regimens on the basis of OHSS risk classifications, in order to prevent OHSS occurrence.

'''Ovulation Induction'''

Unifollicular Ovulation Induction through Ovulation Induction (OI) is a primary means of avoiding OHSS in women with Polycystic Ovarian Syndrome, who are at an increased risk. In order to promote unifollicular development, the ovaries are stimulated with a low starting dose of FSH (75 IU).<ref name="PMID20416867"><pubmed>20416867</pubmed></ref> Studies suggests that a minimum gonadotropin dose lowers OHSS risk and thus a step-up regimen is utilised to achieve an ovarian response, whereby the FSH dosage is increased every 7 days until follicular development of greater than 10mm is noted.<ref name="PMID26074966" /> Alternatively, a step-down regimen may be followed, whereby a high initial FSH dosage is lowered according to the ovarian response. Another method to increase FSH levels during OI, is through Aromatase Inhibitors which promote folliculogenesis by increasing pituitary secretion of FSH, and downregulate oestrogen production through a negative feedback loop. However, Aromatase Inhibitors have not been shown to reduce OHSS incidence in comparison to other methods of OI.<ref name="PMID26074966" /> During OI, a key objective is to prevent early cycle cancellation due to premature luteinisation from pituitary secretion of LH. In order to downregulate LH secretion, Gonadotropin-releasing hormone agonists (GnRHa) are administered in addition to gonadotropins. Alternatively, GnRH antagonists may be administered to downregulate endogenous LH secretion. Comparative studies have shown that the GnRH antagonist protocol has a greater effect in lowering the incidence of mild to severe OHSS. However due to the rare nature of OHSS, and insufficient sample sizes, the difference was not found to be significant. <ref name="PMID21082508"><pubmed>21082508</pubmed></ref>. Generally, the duration of exposure to gonadotropins and subsequent risk of OHSS may be minimised through mild stimulation protocols which administer FSH only in the mid to late follicular phase.<ref name="PMID20416867" />

'''Adjuvant Metformin Therapy'''

Adjuvant Metformin Therapy has been found to lower the risk of OHSS by 63%.<ref name="PMID25406011"><pubmed>25406011</pubmed></ref> It involves the administration of metformin at a daily dosage of 1000 to 2000mg, 2 months prior to Controlled Ovarian Stimulation <ref name="PMID26074966"/>. Metformin lowers the elevated insulin levels in PCOS which consequently reduce intraovarian androgen levels. This leads to a reduced sensitivity and expression of granulosa cell-follicle stimulating hormone receptors which result in a less exaggerated response to gonadotropins. Furthermore, it is suggested that Metformin prevents OHSS by controlling vascular permeability through the inhibition of various vasoactive molecules, including VEGF.

'''Avoiding hCG during Luteal Phase Support

Following Controlled Ovarian Stimulation, the steroid levels of E2 and P4 are reduced during the luteal phase due to the negative feedback on the pituitary. This leads to low endogenous LH levels, which consequently reduce endometrial receptivity as well as the luteal phase duration itself. As a result, implantation and pregnancy rates are reduced and early pregnancy loss rates are increased.<ref name="PMID20416867" /> Luteal Phase Support (LPS) serves to combat these adverse events with the use of hCG. However, hCG has been found to increase the risk of OHSS. Alternatively, the use of progesterone has been found to not only halve the risk of OHSS, but also induce similar improvements in pregnancy and miscarriage rates as hCG.<ref name="PMID26148507"><pubmed>26148507</pubmed></ref>

===Secondary Prevention===

Secondary Prevention aims to prevent progression to OHSS once COS has been initiated and the patient has been found to mount an exaggerated response. <ref name="PMID20416867" />

'''Coasting'''

Coasting is a first-line secondary preventative strategy. It consists of the withdrawal of gonadotrophins when a critical number of follicles and/or E2 concentration is reached. hCG is administered once the E2 concentration reduces to a safe level, before the process of oocyte retrieval commences. This preventative strategy is conducted for a period of less than 3 days in order to avoid compromising IVF outcomes.

'''Cryopreservation'''

Cryopreservation of embryos after oocyte retrieval is another avenue which may avert OHSS progression. The cryopreserved embryos are only reimplanted once the patient's hormone serum levels have normalised. Using oocyte vitrification, crystal formation within embryo tissue is avoided and so cryopreserved embryos have been found to produce better pregnancy rates with a 32% increase, than fresh embryo transfer. Recent studies suggest cryopreservation itself does not reduce OHSS rates, but must be followed by a GnRHa trigger to avert OHSS.

'''Cycle cancellation'''

Cycle cancellation is a guaranteed method to prevent early OHSS whereby hCG is withheld. This is a last resort strategy as it carries the risk of significant psychological distress and financial loss for the patient.

</div>

==Effect on the Newborn==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

</div>
Women who develop OHSS while undergoing Assisted Reproductive Technologies (ART) treatment are not only more likely to achieve a pregnancy, but have a live birth as the pregnancy outcome. This live birth is also more likely to be a multiple birth of two, three or more children. <ref name="PMID19591989"><pubmed>19591989</pubmed></ref> It has been postulated that a multifetal pregnancy leads to a more rapid increase in hCG levels, resulting in an increased risk of OHSS. However, the causal nature between multifetal pregnancy and OHSS development is disputed and further research is required to distinguish correlation from causation. <ref name="PMID19573292"><pubmed>19573292</pubmed></ref>

OHSS development is also associated with an increased risk of adverse outcomes including stillbirth, premature birth and low birthweight.<ref name="PMID19591989" /> Although the cause for the increased risk in adverse pregnancy outcomes is unknown, it is suggested that as the incidence of OHSS is reduced through various prevention strategies, the risk of such outcomes may be also be reduced.

==Genetics==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

Despite OHSS typically being of iatrogenic origin as a result of ovarian stimulation with gonadotropins, research has been conducted into the potential genetics behind OHSS as many sporadic and familial cases have been observed. '''Mutations''' in the receptor for hormones such as Follicle Simulating Hormone (FSH), Lutenizing Hormone (LH) and hCG have all been targets of OHSS genetics research. Interestingly, they too also arise from a common ancestral gene.

===Follicle Stimulating Hormome===

Dr. Botros Rizk, of the University of South Alabama College of Medicine <ref name="PMID19573286"><pubmed>19573286</pubmed></ref>, has written extensively regarding the genetics behind OHSS. In particular, he talks about '''FSH receptors''' (FSHR) and their role in the syndrome. He hypothesises that mutations in these receptors could be activating or inactivating, leading to an increased risk of developing OHSS or sterility respectively. Currently, 744 single nucleotide polymorphisms (a type of mutation) have been found in the gene encoding the FSHR, 8 of which are located in its exons (coding regions of the gene). How the ovary responds is resultant on the FSHR genotype. For example, Ser680Asn, a polymorphism in the FSHR gene has been shown to aid in predicting the severity of a woman's OHSS. Ordinarily FSH stimulates the growth of ovarian follicles, however, when mutated, it is stimulated by the hCG resulting in excessive follicle development.

Spontaneous OHSS, OHSS that arises and cannot be attributed to any form of ovarian stimulation or Assisted Reproductive Technology, has been linked to activating mutations in the FSHR <ref name="PMID23499866"><pubmed>23499866</pubmed></ref>. This familial disorder is an autosomal dominant one. In most cases the FSHR can be stimulated by the presence of Thyroid Stimulating Hormone (TSH) or hCG, in the absence of FSH (the ligand for FSHR).

===Lutenizing Hormome===

The '''Lutenizing Hormone Receptor''' (LHR) gene in humans is comprised of 11 exons. Animal studies have shown that many primates exhibit a similar gene which is comprised of only 10 exons, however a gene lacking the 10th exon has been identified and termed the type 2 LHR. Expression of the type 2 LHR has been seen in humans. The type 2 LHR, compared to the wild-type LHR appears to be repaired with regard to its function. Defects in the type 2 LHR include a decrease in efficiency of transport to the plasma membrane and irregularities in signal transduction. Inactivating mutations in the LHR have been seen to cause infertility in women as well as amenorrhoea. Activating LHR gene mutations are asymptomatic and are not associated with OHSS in women.

===Bone Morphogenic Protein===

An imporant growth factor, derived from oocytes called '''BMP-15''' (Bone Morphogenic Protein 15) is vital for female fertility. It belongs to the family of growth factors, Transforming Growth Factor β (TGF-β) and is heavily involved in folliculogenesis. It has been found that mutations in the BMP-15 gene caused infertility in female sheep. Conversely, it has also been indicated in enhanced fertility when BMP-15 is present is high amounts in follicular fluid <ref name="PMID19573286" />.

A case study done by Hanevik ''et. al.'' in 2013 <ref name="PMID21565556"><pubmed>21565556</pubmed></ref> found that a Single Nuclear Polymorphism (SNP) in the BMP-15 gene is responsible for a high response to ovarian hyper-stimulation. The aim of the study was to test the effect the SNP had on BMP-15 with regard to high and low responders buy taking blood from 53 high responders, 38 low responders and 100 non-responders (controls) and analysing 5 noted SNP's. Results from their study showed a correlation between a high response to ovarian hyper-stimulation and the BMP-15 9G allele. The article does state however, that further research is required into the molecular effects of SNP's on the function of BMP-15.

===Vascular Endothelial Growth Factor===

'''Vascular endothelial growth factor''' (VEGF) has been indicated as one of the key agents causing vascular permeability and subsequent ascites in OHSS. The gene, which is located on chromosome 12, is made up of 8 exons (coding regions), of which exons 6 and 7 do not always appear due to the exons being spliced out.The splicing of this gene allows for various isoforms of the gene to exist of which VEGF 121 and 165 appear to play a role in angiogenesis. There are two VEGF Receptors, VEGFR-1 and VEGFR-2 that belong to the tyrosine kinase family of receptors (for more information on VEGF see [[Pathophysiology]]). Because of its distinct role in OHSS, it has been targeted as an area for research for potential treatments. The idea is that if the genetic expression of VEGF and its receptors can be controlled, OHSS can be avoided or treated.<ref name="PMID19573286" />

A different study by Hanevik ''et. al.'' , <ref name="PMID22587628"><pubmed>22587628</pubmed></ref> done in 2012 involved analysing blood samples from 53 women with OHSS and 100 women without it (controls) and analysing 6 SNP's in the VEGFR2 gene to find any genetic variations. They found a correlation between women with the VEGF +405cc genotype and the development of OHSS indicating women that undergo controlled ovarian hyper-stimulation and posses his genotype, are at an increased risk of developing OHSS.

</div>

== Current Research on Animal Models==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">
{|
|-bgcolor="F8E0F1"
|
<span style="font-size:120%">'''Inhibition of Cyclooxygenase-2 (COX-2) by Meloxican decreasing the incidence of OHSS in Rat Model'''</span> <ref name="PMID18166186"><pubmed>18166186</pubmed></ref>

Reasearch was carried out to investigate the effects of selective inhibition of the enzyme COX-2 on the Ovarian Hyperstimulation Syndrome (OHSS) using Female Wistar rates as the subjects. The research aimed to find results by measuring the number of antral and luteinized follicles, ovarian weight, vascualr endothelial growth factors and COX-2 immunohistochemistry. The rats being tested were all 22 days old and were divided into four equal groups;

'''Group 1 (Control group)''' was subject to a 0.1 ml of Intraperitoneal Saline from days 22 ~ 26

'''Group 2 (Mildly-stimulated group)''' subject to 10IU of pregnant mare serum gonadotrophin (PMSG) on day 24 and then 10IU of Human Chorionic Gonadotrophin (hCG) on day 26

'''Group 3 (OHSS positive group)''' was subject to 10IU of PMSG from days 22 ~ 26 and then administered 30IU of hCG on day 26 to induce OHSS

'''Group 4 (OHSS positive variant group)''' received 15mg/ml of Meloxicam 2 hours prior to administration of 10IU PMSG from days 22 ~ 26

Results showed there was no difference in ovarian weight in samples from Group 1 and Group 2, however Group 3 showed signs of significant ovarian weight increase which in group 4 was suppressed by the introduction of Meloxicam. No differences were observed in the number of antral follicles amongst the four test groups. Results from Group 2 and Group 3 showed that the granulosa cells of preovulatory follicles and the stromal cells were highly VEGF immunoreactive, however the Meloxicam treated Group 4 showed less immunoreactivity than Group 2 and Group 3 which indicated the correlation between Meloxicam and the diminished VEGF expression. Group 3 presented an increased COS-2 immunoreactivity which was highly diminished than in Group 4.

The research concluded that in a rat model, the enzyme Meloxicam has a beneficial effect on OHSS by reducing the increase of ovarian weight and the expression of VEGF associated with OHSS, the effects of which may be mediated by the inhibitory capacity of COX-2 on Meloxicam
|}

{|
|-bgcolor="FF99FF"
|
<span style="font-size:120%">'''Inhibition of Ovarian VEGF secretion by activation of Dopamine Receptor 2'''</span> <ref name="PMID25217874"><pubmed>25217874</pubmed></ref>

This research was carried out to investigate a possibility in whether a Dopamine Receptor 2 agonist '''(D2-ag)''' can assist in the prevention of Ovarian Hyperstimulation Syndrome, using rat models, by decreasing the ovarian vascular endothelial growth factor '''(VEGF)''' production. Using Immature Wistar rats (22 days old) as their animal model, the rats were initially stimulated with Gonadotrophins to mimic the onset and effects of OHSS and then subjected to treatment with a D2-agonist and/or a D2-antagonist (D2-ant). The vascular permeability was measured at the endpoint after day 26 by measuring the peritoneal extravasion of a previously injected dye and ovaries from all subjects were collected to assess the effects of D2-ag and D2-ant on the production of Ovarian VEGF. The expression of VEGF mRNA was measured by quantitative real time PCR and the levels of VEGF proteins were measured by Western Blots.

Results showed that the D2-ag caused a large reduction in the vascular permeability which was in turn associated with the great decreased in VEGF protein production in the OHSS rat ovaries, whereas the introduction of D2-ant showed opposite results with a increase in the vascular permeability leading to the increase of VEGF protein production in the ovaries. Ovarian VEGF mRNA levels were found to be unaffected by the introduction of these drugs in OHSS rat subjects. Conclusions were drawn on the fact that Dopamine Receptor 2 agonists prevent the increase of vascular permeability in subjects with OHSS by decreasing the ovarian production of VEGF and also that due to the dose-dependent inhibitory effect of the D2-ag on ovarian VEGF, current OHSS therapies used in humans can benefit by increasing the intraovarian concentration of D2-ag.
|}
</div>

==Glossary==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

'''Ascites''' - An accumulation of fluid in the peritoneal cavity with resultant abdominal swelling.

'''Cabergoline''' - A dopamine receptor agonist used to treat hormone imbalance.

'''Controlled Ovarian Stimulation''' - female infertility treatment using medications to stimulate the ovaries to develop follicles.

'''E2''' - Estradiol - Potent estrogen sex hormone.

'''Gonadotropin''' - Any hormone that has a stimulating effect on the gonads.

'''GnRH antagonist''' - Gonadotropin Releasing Hormone - A class of compounds that are similar in terms of the structure of natural Gonadotropin Releasing Hormone but has a antagonistic effect.

'''hCG'''- Human Chorionic Gonadotropin

'''Hemoconcentration''' - An increase in the concentration of circulating red blood cells in response to a decrease in blood plasma volume.

'''Hypovolemic''' - A decrease in circulating blood volume.

'''Iatrogenic'''- Illness caused as a result of a medical examination or treatment.

'''Intravenous fluids''' - Is the infusion of liquid substances directly into a vein.

'''IVF'''- In-vitro Fertilization

'''NSAID'''- Non-steroidal Anti-Inflammatory Drug e.g. Ibuprofen

'''OHSS'''- Ovarian Hyper-stimulation Syndrome

'''PCOS'''- Polycystic Ovarian Syndrome. An endrocrine system disorder whereby the ovaries are enlarged with small collections of fluid.

'''FSH''' - Follicle Stimulating Hormone

'''LH''' - Luteinizing Hormone

'''Oliguria'''- Decreased urine output/small amounts of urine produced.

</div>

==References==

2015 Group Project 2

2015-10-22T22:28:24Z

Z3372824: /* Glossary */

{{ANAT2341Project2015header}}

==<span style="font-size:120%">'''Ovarian Hyper-stimulation Syndrome (OHSS)'''</span>==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

Ovarian Hyper stimulation Syndrome (OHSS) is an iatrogenic complication of '''Assisted Reproduction Technology''' (ART), in which women take medications to stimulate oocyte growth. It is generally identified by cystic enlargements of the ovaries and fluid accumulation in the peritoneal cavity due to the increased capillary permeability and ovarian neoangiogenesis <ref name="PMID22065820"><pubmed>22065820</pubmed></ref>. It is an occurrence which is dependent on the controlled stimulation of the ovaries in preparation for IVF i.e. administration of human Chorionic Gonadotropin (hCG).

OHSS was first described in 1943 as ''“syndrome d’hyperluteinisation massive
des ovaries”''. It was during this time that gonadotropins were prepared from animals such as sheep to bring on ovulation in women. The first recorded death as a result of OHSS occurred in 1951 and was due to renal failure as a result of oligouria, a complication of the syndrome <ref name="OHSS"> Marie M. Budev, DO, MPH; Alejandro C. Arroliga, MD; Tommaso Falcone, MD, [ http://utilis.net/Morning%20Topics/REI/Ovarian%20Hyperstimulation.pdf ], 'Ovarian Hyperstimulation Syndrome'</ref> <ref name="PMID12638783"><pubmed>12638783</pubmed></ref>.

<span style="color:#FA58D0">This wikipage aims to provide clear information on various areas surrounding OHSS such as diagnosis, prevention and complications and will look into the genetics behind the disorder and the various animals models used to research it.</span>

<html5media height="350" width="450">https://www.youtube.com/watch?v=aXmjJw234a4</html5media>

'''Overview of the Ovarian Hyperstimulation Syndrome''' <ref> Howcast (2013, August 27) Ovarian Hyperstimulation Syndrome | Infertility. Retrieved from https://www.youtube.com/watch?v=aXmjJw234a4</ref>

</div>

==Epidemiology==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

Ovarian Hyper-Stimulation Syndrome (OHSS) rarely occurs sporadically, and if it does, it is usually the result of an underlying genetic problem. The majority of OHSS is due to the ovaries being stimulated to mature and release an abundance of oocytes, in response to hormones Human Chorionic Gonadotropin (hCG) and Follicle Stimulating hormone (FSH), during IVF. Rarely, Clomifene Citrate therapy can cause OHSS.<ref name="WikiOHSS"> Wikipedia, [ https://en.wikipedia.org/wiki/Ovarian_hyperstimulation_syndrome ], 'Ovarian Hyperstimulation Syndrome'</ref>

OHSS only affects '''0.5-5%''' of women undergoing Ovarian Hyper-stimulation, but despite its small prevalence, it is a potentially fatal outcome of a non-vital procedure and remains a prevalent problem for fertility specialists <ref name="PMID12498425"><pubmed>12498425</pubmed></ref> <ref name="PMID12638783"><pubmed>12638783</pubmed></ref>. Age has been cited as a factor affecting those with OHSS, with younger women more at risk. Additionally, women with allergies were seen to have a higher incidence of OHSS. It is important to note that at this point in time, there is no positive correlation between gonadotropin dose and OHSS.

Of the 0.5-5% of women affected with OHSS mentioned above, 2% of those women will require hospitalisation. As of 2011, it has been reported that the incidence of OHSS was '''increasing''', resulting in approximately 3 deaths per 100,000 women undergoing ovarian stimulation per year <ref name="PMID21828116"><pubmed>21828116</pubmed></ref>. This is particularly worrying as in 2008, in the United States alone, there were around 150,000 IVF cycles undertaken.

{|
|-bgcolor="F8E0F1"
|
'''With the field of Assisted Reproductive Technologies expanding and more women partaking in IVF treatments, the threat of women developing OHSS is an ongoing and increasing one''' <ref name="PMID21828116" />.
|}
{| class="wikitable mw-collapsible mw-collapsed"
! Characteristics of women by complication group <ref name="PMID19591989"><pubmed>19591989</pubmed></ref>
|-
! scope="col" width="100px" height="60px" style="text-align:center| '''Characteristic'''
! scope="col" width="100px" height="60px" style="text-align:center| '''No Complications
(N = 212,041)'''
! scope="col" width="100px" height="60px" style="text-align:center| '''Moderate OHSS
(N = 1,523)'''
! scope="col" width="100px" height="60px" style="text-align:center| '''Severe OHSS
(N = 655)'''
|-
|style="text-align:center; background: #FF99FF;"| '''Maternal Age (Mean ± SD)'''
|style="text-align:center; background: #F6CEEC;"| 35.6 ± 4.6
|style="text-align:center; background: #F6CEEC;"| 33.0 ± 4.3
|style="text-align:center; background: #F6CEEC;"| 33.1 ± 4.4
|-
|style="text-align:center; background: #FF99FF;"| '''Maternal Age (%)'''
|-
|style="text-align:left; background: #F6CEEC;"| <30 years
|style="text-align:center; background: #F6CEEC;"| 10 %
|style="text-align:center; background: #F6CEEC;"| 21.1 %
|style="text-align:center; background: #F6CEEC;"| 20.6 %
|-
|style="text-align:left; background: #F6CEEC;"| 30-34 years
|style="text-align:center; background: #F6CEEC;"| 30.4 %
|style="text-align:center; background: #F6CEEC;"| 43.2 %
|style="text-align:center; background: #F6CEEC;"| 40.5 %
|-
|style="text-align:left; background: #F6CEEC;"| 35-39 years
|style="text-align:center; background: #F6CEEC;"| 37.8 %
|style="text-align:center; background: #F6CEEC;"| 27.2 %
|style="text-align:center; background: #F6CEEC;"| 32.5 %
|-
|style="text-align:left; background: #F6CEEC;"| >40 years
|style="text-align:center; background: #F6CEEC;"| 21.8 %
|style="text-align:center; background: #F6CEEC;"| 8.4 %
|style="text-align:center; background: #F6CEEC;"| 6.4 %
|-
|style="text-align:center; background: #FF99FF;"| '''Nulligravida (%)'''
|style="text-align:center; background: #F6CEEC;"| 45.8 %
|style="text-align:center; background: #F6CEEC;"| 51.5 %
|style="text-align:center; background: #F6CEEC;"| 51.8 %
|-
|style="text-align:center; background: #FF99FF;"| '''Infertility Diagnosis (%)'''
|-
|style="text-align:left; background: #F6CEEC;"| Male factor
|style="text-align:center; background: #F6CEEC;"| 37.7 %
|style="text-align:center; background: #F6CEEC;"| 41.0 %
|style="text-align:center; background: #F6CEEC;"| 33.4 %
|-
|style="text-align:left; background: #F6CEEC;"| Endometriosis
|style="text-align:center; background: #F6CEEC;"| 13.5 %
|style="text-align:center; background: #F6CEEC;"| 13.5 %
|style="text-align:center; background: #F6CEEC;"| 10.7 %
|-
|style="text-align:left; background: #F6CEEC;"| Ovulation Disorders
|style="text-align:center; background: #F6CEEC;"| 14.0 %
|style="text-align:center; background: #F6CEEC;"| 29.5 %
|style="text-align:center; background: #F6CEEC;"| 22.4 %
|-
|style="text-align:left; background: #F6CEEC;"| Diminished ovarian reserve
|style="text-align:center; background: #F6CEEC;"| 16.9 %
|style="text-align:center; background: #F6CEEC;"| 3.2 %
|style="text-align:center; background: #F6CEEC;"| 2.4 %
|-
|style="text-align:left; background: #F6CEEC;"| Tubal factors
|style="text-align:center; background: #F6CEEC;"| 20.4 %
|style="text-align:center; background: #F6CEEC;"| 22.6 %
|style="text-align:center; background: #F6CEEC;"| 22.3 %
|-
|style="text-align:left; background: #F6CEEC;"| Uterine factors
|style="text-align:center; background: #F6CEEC;"| 5.1 %
|style="text-align:center; background: #F6CEEC;"| 4.3 %
|style="text-align:center; background: #F6CEEC;"| 3.1 %
|-
|style="text-align:left; background: #F6CEEC;"| Other factors
|style="text-align:center; background: #F6CEEC;"| 13.9 %
|style="text-align:center; background: #F6CEEC;"| 13.1 %
|style="text-align:center; background: #F6CEEC;"| 10.4 %
|-
|style="text-align:left; background: #F6CEEC;"| Unexplained factor
|style="text-align:center; background: #F6CEEC;"| 12.7 %
|style="text-align:center; background: #F6CEEC;"| 11.8 %
|style="text-align:center; background: #F6CEEC;"| 18.6 %
|-
|}
</div>

==Causative Agents==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

[[File:Follicular Development.jpeg|right|thumbnail|500px|Infertility treatments aim to facilitate follicular development and induce ovulation to improve chances of fertilisation <ref name="PMID24717179"><pubmed>24717179</pubmed></ref>]]

Normally a woman produces one egg per month from the ovaries, which travel down the Fallopian tube to be fertilized or be released from the body. In cases where women have difficulty falling pregnant, they are given medication which help them to produce and release eggs (as shown in the diagram to the right), further increasing their chances of fertilization and pregnancy <ref><pubmed>19573285</pubmed></ref>. Ovarian Hyper stimulation Syndrome generally occurs during infertility treatments when the ovaries are overstimulated by the fertility medication which causes the ovaries to swell and leak fluids into the belly and abdomen. The prevalence of OHSS onset is linked with excessive number of follicle development in response to the administration of injectable Follicle Stimulating Hormones (FSH) followed by the '''Human Chorionic Gonadotrophins''' (hCG) which triggers the release of the oocytes <ref><pubmed>26190539</pubmed></ref>.

'''Follicle Stimulating Hormones''' (FSH) <ref name="PMID9020850"><pubmed>9020850</pubmed></ref> are glycoprotein hormones that are produced and secreted from the Anterior Pituitary gland into the bloodstream, which regulate the developmental, growth, maturation and the reproductive processes within the body. In females, the Follicle Stimulating Hormones initiates the stages of growth and development of immature ovarian follicles within the ovaries before the release of an egg from a follicle at ovulation. When FSH is administered to a patient who is suffering from infertility, the increase FSH levels affect the rate of development and production, in turn increasing the amount of follicles which are ready to be released during ovulation.

</div>

==Symptoms==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

OHSS is classified based on a criteria from mild, moderate and severe <ref name="WikiOHSS" />:

'''Mild Symptoms'''- abdominal bloating, minimal weight gain, nausea, diarrhoea and a feeling of fullness.

'''Moderate Symptoms'''- Substantial weight gain (on average 2 or more pounds a day), increased abdominal girth, darkend urine and excessive thirst in addition to the mild symptoms.

'''Severe Symptoms'''- In addition to the symptoms associated with Mild and Moderate OHSS, in severe OHSS, you see shortness of breath, calf and chest pains and pleural effusion.

<span style="font-size:100%">'''Classifications of Ovarian Hyper-stimulation Syndrome:'''</span> <ref name="PMID22065820"><pubmed>22065820</pubmed></ref>
{| class="wikitable" style="text-align:center
|-
! scope="col" width="70px"| '''Classification'''
! scope="col" width="650px"| '''Symptoms'''
|-
|style="text-align:center; background: #F6CEEC;"| '''Mild'''
|style="height: 60px; background: #F6CEEC;"| '''Grade 1''' - Abdominal distention and discomfort
'''Grade 2''' - Abdominal distention, discomfort with nausea, vomiting and/or diarrhea and ovarian enlargement from 5~12cm
|-
|style="text-align:center; background: #F8E0F1;"| '''Moderate'''
|style="height: 60px; background: #F8E0F1;"| '''Grade 3''' - All features of Mild OHSS with ultrasonographic evidence of ascites
|-
|style="text-align:center; background: #F6CEEC;"| '''Severe'''
|style="height: 60px; background: #F6CEEC;"| '''Grade 4''' - All features of Moderate OHSS with the addition of clinical evidence of ascites and breathing difficulties present
'''Grade 5''' - All of the above symptoms along with a change in the blood volume, increased blood viscosity due to coagulation and diminished renal function
|}

</div>

==Diagnosis==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

Whilst symptoms of OHSS can occur as soon as 24 hours post hCG administration, they are usually seen in women 7-10 days post administration. Initially women with OHSS will present with abdominal bloating, as a result of fluid in the peritoneal cavity and an increase in ovary size. When women present with severe OHSS they are often dehydrated, due to increased vascular permeability, and have hemoconcentration. The above results in a decrease in intravascular volume, leading to '''oligouria''' <ref name="PMID22416285" />.

===History===

Initially a thorough history of the patient is taken during which the clinician looks for evidence of ovarian stimulation, followed by ovulation. During this history taking, the clinician will inquire into any weight gain noticed, urine output, and the woman's ability to maintain oral hydration. A key diagnostic tool for clinicians regarding women who are taking gonadotropins is to identify if they are at an increased risk of developing OHSS. Some risk factors include woman aged less than 30, women who have polycystic ovaries, woman with a previous history of OHSS and women who have had greater than 20 oocytes retrieved <ref name="PMID22416285" />.

===Physical Exam===
[[File:Vaginal_Ultrasonography_in_Sagittal_Plane.jpg|right|thumbnail|600px|Vaginal Ultrasonography in Sagittal plane <ref name="Wikiversity Journal of Medicine"> Häggström, Mikael. "Medical gallery of Mikael Häggström 2014". Wikiversity Journal of Medicine 1 (2). DOI:10.15347/wjm/2014.008. ISSN 20018762</ref>]]
After a history of the patient is taken, the next step is to perform a physical exam on the patient. Women who present with abdominal bloating will produce a shifting dullness upon abdominal percussion. Additionally the clinician will test the woman's vital signs, measure her abdominal girth, weight and will look for evidence of ascites or increase in calf size (usually unilateral)<ref name="PMID22416285" />.

===Investigations===

If the clinician further suspects a women of having OHSS, various investigations can be done such as an ultrasound.The intraperitoneal fluid is best imaged via vaginal ultrasound due to the enlarged ovaries making it difficult to image the pelvis using transabdominal ultrasound. The clinician can also order laboratory testing to look for urine specific gravity and and complete blood count to look for hemoconcentration with a hematocrit. Additionally, liver function tests can be ordered to look for elevated function. The clinician will also look for evidence of elevated D-dimers and fibrinogen and decreased levels of anti-thrombin 3 <ref name="SAHealth"> Government of South Australia Health [ http://www.sahealth.sa.gov.au/wps/wcm/connect/9b61ed004ee5348da663afd150ce4f37/Ovarian-hyperstimulation-syndrome-WCHN-PPG-17072012.pdf?MOD=AJPERES&CACHEID=9b61ed004ee5348da663afd150ce4f37 ], 'South Australian Paediatric Clinical Guidelines OHSS'</ref>.

====Ultrasound====

Typical appearances of the ultrasound include <ref name="Ultrasound"> Radiopaedia [ http://radiopaedia.org/articles/ovarian-hyperstimulation-syndrome-1 ], 'Ovarian Hyperstimulation Syndrome'</ref>:

*Bilaterally and symmetrically enlarged ovaries (>12cm)
* "Spoke-Wheel appearance" - presence of multiple cysts of varying size
*May also see ascites (fluid)

===Severity===

Once a clinician has deduced a women is suffering from OHSS, the severity of their condition needs to be established as either mild, moderate or severe. This is done by referring to the criteria under the sub-heading [[Symptoms]].The subsequent course of treatment for the woman will be based upon this evaluation.

{|
|-bgcolor="F6CEEC"
|
'''Further investigations''' can be done including a Chest X-ray to check for pleural effusions and oedema and USS with Doppler's to check for ascites or possible ovary torsion. <ref name="PMID22416285"><pubmed>22416285</pubmed></ref>
|}

===Differential Diagnosis===

Conditions presenting with similar symptoms or ultrasound images include <ref name="Ultrasound" />:

*Polycystic Ovaries (PO)
:: The difference is that with PO is that the cycts are typically smaller than OHSS cysts and there is no evidence of ascited or pleural effusion
*Mucinous Ovarian Malignancy
:: A type of Ovarian Epithelial tumour
*Ectopic Pregnancy <ref name="Casereport"> Australian Medical Student Journal [ http://www.amsj.org/wpcontent/uploads/files/articles/amsj_v2_i1/AMSJ_v2_i1_pg58-60.pdf ], 'Ovarian hyperstimulation syndrome'</ref>
::A pregnancy in which the foetus develops outside of the uterus e.g. in the fallopian tube

</div>

==Pathophysiology==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

[[File:Pathogenesis_of_OHSS.png|600px|thumb|Pathogenesis of OHSS <ref name="PMID20416867"><pubmed>20416867</pubmed></ref>]]

The definition of Ovarian Stimulation is enlarged ovaries with many luteinized cysts, that can present with secondary complications. What distinguishes Ovarian Stimulation from OHSS is the presence of vascular hyper-permeability that results in fluids being redirected elsewhere in the body.

The key process to OHSS appears to be caused by '''Vascular Endothelial Growth Factor''' (VEGF), that is released along with other cytokines, estrogen and progesterone, due to the ovary undergoing luteinization as a result of stimulation by hCG. VEGF increases vascular permeability and as a result the capillaries become more "leaky" to the fluids in them. These fluids can then escape the capillaries and accumulate in the pleural and abdominal cavities as ascites. The woman then becomes hypovolemic and is at an increased risk of circulatory, renal and respiratory issues such as arterial thromboembolism due to the thickening of the blood. Note, the blood is thickened as fluid is leaving the capillaries, leaving behind red blood cells and other cellular components of the blood <ref name="WikiOHSS" />.

The increase in expression of VEGF and VEGF Receptor 2 (VEGFR2) is attributed to the greatly increased amount of their mRNA present in the body after stimulation with hCG <ref name="PMID21082502"><pubmed>21082502</pubmed></ref>. VEGF interacts with VEGF2 and VEGF Receptor 1 (VEGFR1) to create a strong angiogenic effect. Both VEGFR2 and VEGFR1 belong to a family of receptors called tyrosine kinases. VEGF2 is involved in the regulation of angiogenesis and vascular permeability whilst VEGF1 has a slightly contradictory role in that is is involved in the maintenance of the tight junctions between endothelial cells in blood vessels. A study by Gómez ''et. al.'' <ref name="PMID21082502" /> showed that women experiencing OHSS had substantially higher plasma levels of VEGF and lower levels of VEGFR1.

</div>

==Complications==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

Ovarian torsion or rupture, renal insufficiency and thrombophlebitis can all complicate OHSS. If a pregnancy occurs, symptoms may persist longer than the usual 1 to 2 weeks and become more severe, however, even with severe OHSS, they do not extend past the first trimester <ref name="WikiOHSS" />.

<span style="color:#FA58D0"> '''1-2% of women who undergo ovarian stimulation develop a severe form of OHSS''' </span>. Complications from severe OHSS include:

*Fluid collection in the abdomen
*Electrolyte disturbances (sodium and potassium)
*Kidney failure
*Ovary twisting
*Rupture of a cyst in an ovary
*Breathing problems
*Blood clots in large vessels (most commonly the legs)
*Pregnancy loss from miscarriage or termination
*Rarely, death

A study by Nouri ''et. al.'' <ref name="PMID24996451"><pubmed>24996451</pubmed></ref> found that women with '''Polycystic Ovarian Syndrome''' (PCOS) and those that were induced with hCG experienced longer recovery times from severe OHSS than women who were not pregnant. They looked at a cohort of women hospitalised for the first time with severe OHSS and subject them to the same treatments. Based on a defined criteria, they established the recovery time of these women and compared the times between those that were pregnant to those that were not pregnant. They also found that whether a woman had PCOS or ovulation induction did not affect her risk of developing OHSS if she was not pregnant. It is only a risk factor for pregnant women.

===Thromboembolic events===

A frequent and deadly complication of OHSS are thromboembolic events due to increased blood clotting. This increase in blood clotting has been attributed to a variety of complications such as hemoconcentration (which thickens the blood), hypovolemia and an increase in the permeability of blood vessels as a result of increased vasoactive substances in the body of ovarian origin. Thromboembolic events include venous thromboses often in the upper extremities and arterial thromboses such as those in the cerebrovascular region. These events can lead to amputations of extremities, brain damage, miscarriage and death. To avoid this, anti-coagulants are given to pateitns with OHSS and they are fitted with compression stockings (see [[Treatment]]) <ref name="PMID23378404"><pubmed>23378404</pubmed></ref>.

{|
|-bgcolor="F8E0F1"
|
The risk of a woman developing OHSS is higher if she is having a '''twin pregnancy''', as she is exposed to higher concentration of hCG. <ref name="PMID9756273"><pubmed>9756273</pubmed></ref>
|}

</div>

==Treatment==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

'''General treatment
'''
*''Acetaminophen'' with or without a narcotic agent- used to treat abdominal discomfort
*Women are encouraged to drink 2-3 litres of water a day to prevent hemoconcentration
*Women are advised to avoid sexual intercourse and vigorous exercise at the risk of torsion or rupture of the ovaries
*NSAID's with anti-platelet properties should NOT be used as they may effect renal function in a women with OHSS
*Patients with significantly painful ascites or breathing problems may undergo ''Paracentesis'' (drainage of the ascites)
*''Culdocentesis'' (extraction of fluid from recto-uterine pouch) can be done to decrease the likelihood of a woman with moderate OHSS progressing to severe OHSS.<ref name="PMID22416285" />

===Mild to Moderate OHSS===

Mild OHSS can often resolve on its own, however, moderate OHSS may include treatments such as<ref name="WikiOHSS" />:

*Anti-nausea medication and prescription painkillers
*Regular physical examinations and ultrasounds
*Daily weigh-ins and waist measurements
*Measuring the amount of urine produced each day
*Frequent blood tests for monitoring dehydration and electrolyte imbalance
*Maintaining a high balance of fluids
*Drainage of excess abdominal fluid by inserting a needle in the abdominal cavity
*Wearing support stockings which help prevent blood clots/thrombosis

===Severe OHSS===

Severe OHSS requires hospital care in order for constant monitoring and treatment such as <ref name="WikiOHSS" />:

*Intravenous fluids with a crystalloid solution (100-150mL/hr)
*Intravenous Albumin is administered is IV fluids are insufficient (15-20mL/hr of 25% albumin for 4 hrs)
*In addition to Acetaminophen, ''Opioid analgesics'' can be administered for pain relief
*''Antiemetics'' can be used to subside nauseas and/or vomiting
*Woman administered to hospital of OHSS are considered at high risk of thromboembolic complications and are given low molecular weight ''heparin'', an anti-coagulant
*''Cabergoline''- lessens OHSS symptoms
*''GnRH agonist''- suppresses ovarian activity
**If at risk of OHSS, alternates include using a GnRH agonist instead of hCG however its effects on pregnancy rates are questionable. Using a GnRH agonist to replace the use of hCG for final oocyte stimulation will see a 6% decrease in delivery rate.

*Daily monitoring of creatine, urea, creatine clearance C-reactive protein (to rule out infection) are all required in combination with weekly tests such as liver and renal function tests and chest x-rays (to check for pleural effusion) <ref name="PMID12638783" />.

If there are serious complications then additional treatments are required:

*Surgery for a ruptured ovarian cyst
*Intensive care for the liver or lung complications

====Paracentesis====

For women with severe/grade 3 OHSS, paracentesis, the removal of fluid from the body using an aspiration needle, can be undertaken. It is a diagnostic and a therapeutic method that can be done trans-abdominally and trans-vaginally. It is used to relieve symptoms, improve haemodynamics e.g. Urinary output, and shorten the women's hospital stay. Complications of paracentesis include bleeding, infection and organ injury, however are note common <ref name="Paracentesis"> S. Monica Soni, HMS 3, Gillian Lieberman, MD [ http://eradiology.bidmc.harvard.edu/LearningLab/genito/Soni.pdf ], 'Ovarian Hyperstimulation Syndrome'</ref>.

{|
|-bgcolor="F8E0F1"
|
The most important aspect of treatment for any women with OHSS is close and constant '''monitoring''' with her healthcare professional. Counselling may also be provided to women and their partners or families in order to provide them with the best possible knowledge base to manage and treat their OHSS. It is important to note that there is '''no one cure or treatment''' for OHSS. Treatment involves managing and eliminating the symptoms until such time as the syndrome resolves itself <ref name="WikiOHSS" />.
|}

</div>

==Prevention==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

There are three key avenues through which the incidence of OHSS may be prevented. These include identifying risk factors to predict OHSS development, modifying treatment regimes on the basis of the identified risk factors and intervention to prevent progression to OHSS once the patient has undergone '''Controlled Ovarian Stimulation''' (COS).

=== Risk factors===

'''Primary risk factors'''

Pre-existing factors likely to exacerbate the ovarian stimulation response. Primary risk factors include <ref name="PMID26074966"><pubmed>26074966</pubmed></ref>:

*Young age
*Low body weight
*History of elevated response to gonadotropins
*Polycystic Ovary Syndrome (PCOS)
*Isolated PCOS characteristic
*A previous history of OHSS.
*Hormonal markers (e.g. Anti-Mullerian Hormone markers)
*Ultrasonographic markers (e.g. Antral Follicle Count)

'''Secondary risk factors'''

Secondary risk factors involve the monitoring of ovarian response parameters once COS has been initiated. These parameters are monitored for <ref name="PMID19007627"><pubmed>19007627</pubmed></ref>:

*rapidly rising E2 levels
*E2 concentration larger than 2500 pg/mL
*large number of developing follicles (10-14mm) on the day hCG is administered
*large number of oocytes retrieved

These factors in combination, act as a predictive tool to assess the likelihood of severe OHSS development, with a 83% sensitivity and 84% specificity. <ref name="PMID19007627"/>

=== Primary Prevention===

Primary Prevention involves the modification of treatment regimens on the basis of OHSS risk classifications, in order to prevent OHSS occurrence.

'''Ovulation Induction'''

Unifollicular Ovulation Induction through Ovulation Induction (OI) is a primary means of avoiding OHSS in women with Polycystic Ovarian Syndrome, who are at an increased risk. In order to promote unifollicular development, the ovaries are stimulated with a low starting dose of FSH (75 IU).<ref name="PMID20416867"><pubmed>20416867</pubmed></ref> Studies suggests that a minimum gonadotropin dose lowers OHSS risk and thus a step-up regimen is utilised to achieve an ovarian response, whereby the FSH dosage is increased every 7 days until follicular development of greater than 10mm is noted.<ref name="PMID26074966" /> Alternatively, a step-down regimen may be followed, whereby a high initial FSH dosage is lowered according to the ovarian response. Another method to increase FSH levels during OI, is through Aromatase Inhibitors which promote folliculogenesis by increasing pituitary secretion of FSH, and downregulate oestrogen production through a negative feedback loop. However, Aromatase Inhibitors have not been shown to reduce OHSS incidence in comparison to other methods of OI.<ref name="PMID26074966" /> During OI, a key objective is to prevent early cycle cancellation due to premature luteinisation from pituitary secretion of LH. In order to downregulate LH secretion, Gonadotropin-releasing hormone agonists (GnRHa) are administered in addition to gonadotropins. Alternatively, GnRH antagonists may be administered to downregulate endogenous LH secretion. Comparative studies have shown that the GnRH antagonist protocol has a greater effect in lowering the incidence of mild to severe OHSS. However due to the rare nature of OHSS, and insufficient sample sizes, the difference was not found to be significant. <ref name="PMID21082508"><pubmed>21082508</pubmed></ref>. Generally, the duration of exposure to gonadotropins and subsequent risk of OHSS may be minimised through mild stimulation protocols which administer FSH only in the mid to late follicular phase.<ref name="PMID20416867" />

'''Adjuvant Metformin Therapy'''

Adjuvant Metformin Therapy has been found to lower the risk of OHSS by 63%.<ref name="PMID25406011"><pubmed>25406011</pubmed></ref> It involves the administration of metformin at a daily dosage of 1000 to 2000mg, 2 months prior to Controlled Ovarian Stimulation <ref name="PMID26074966"/>. Metformin lowers the elevated insulin levels in PCOS which consequently reduce intraovarian androgen levels. This leads to a reduced sensitivity and expression of granulosa cell-follicle stimulating hormone receptors which result in a less exaggerated response to gonadotropins. Furthermore, it is suggested that Metformin prevents OHSS by controlling vascular permeability through the inhibition of various vasoactive molecules, including VEGF.

'''Avoiding hCG during Luteal Phase Support

Following Controlled Ovarian Stimulation, the steroid levels of E2 and P4 are reduced during the luteal phase due to the negative feedback on the pituitary. This leads to low endogenous LH levels, which consequently reduce endometrial receptivity as well as the luteal phase duration itself. As a result, implantation and pregnancy rates are reduced and early pregnancy loss rates are increased.<ref name="PMID20416867" /> Luteal Phase Support (LPS) serves to combat these adverse events with the use of hCG. However, hCG has been found to increase the risk of OHSS. Alternatively, the use of progesterone has been found to not only halve the risk of OHSS, but also induce similar improvements in pregnancy and miscarriage rates as hCG.<ref name="PMID26148507"><pubmed>26148507</pubmed></ref>

===Secondary Prevention===

Secondary Prevention aims to prevent progression to OHSS once COS has been initiated and the patient has been found to mount an exaggerated response. <ref name="PMID20416867" />

'''Coasting'''

Coasting is a first-line secondary preventative strategy. It consists of the withdrawal of gonadotrophins when a critical number of follicles and/or E2 concentration is reached. hCG is administered once the E2 concentration reduces to a safe level, before the process of oocyte retrieval commences. This preventative strategy is conducted for a period of less than 3 days in order to avoid compromising IVF outcomes.

'''Cryopreservation'''

Cryopreservation of embryos after oocyte retrieval is another avenue which may avert OHSS progression. The cryopreserved embryos are only reimplanted once the patient's hormone serum levels have normalised. Using oocyte vitrification, crystal formation within embryo tissue is avoided and so cryopreserved embryos have been found to produce better pregnancy rates with a 32% increase, than fresh embryo transfer. Recent studies suggest cryopreservation itself does not reduce OHSS rates, but must be followed by a GnRHa trigger to avert OHSS.

'''Cycle cancellation'''

Cycle cancellation is a guaranteed method to prevent early OHSS whereby hCG is withheld. This is a last resort strategy as it carries the risk of significant psychological distress and financial loss for the patient.

</div>

==Effect on the Newborn==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

</div>
Women who develop OHSS while undergoing Assisted Reproductive Technologies (ART) treatment are not only more likely to achieve a pregnancy, but have a live birth as the pregnancy outcome. This live birth is also more likely to be a multiple birth of two, three or more children. <ref name="PMID19591989"><pubmed>19591989</pubmed></ref> It has been postulated that a multifetal pregnancy leads to a more rapid increase in hCG levels, resulting in an increased risk of OHSS. However, the causal nature between multifetal pregnancy and OHSS development is disputed and further research is required to distinguish correlation from causation. <ref name="PMID19573292"><pubmed>19573292</pubmed></ref>

OHSS development is also associated with an increased risk of adverse outcomes including stillbirth, premature birth and low birthweight.<ref name="PMID19591989" /> Although the cause for the increased risk in adverse pregnancy outcomes is unknown, it is suggested that as the incidence of OHSS is reduced through various prevention strategies, the risk of such outcomes may be also be reduced.

==Genetics==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

Despite OHSS typically being of iatrogenic origin as a result of ovarian stimulation with gonadotropins, research has been conducted into the potential genetics behind OHSS as many sporadic and familial cases have been observed. '''Mutations''' in the receptor for hormones such as Follicle Simulating Hormone (FSH), Lutenizing Hormone (LH) and hCG have all been targets of OHSS genetics research. Interestingly, they too also arise from a common ancestral gene.

===Follicle Stimulating Hormome===

Dr. Botros Rizk, of the University of South Alabama College of Medicine <ref name="PMID19573286"><pubmed>19573286</pubmed></ref>, has written extensively regarding the genetics behind OHSS. In particular, he talks about '''FSH receptors''' (FSHR) and their role in the syndrome. He hypothesises that mutations in these receptors could be activating or inactivating, leading to an increased risk of developing OHSS or sterility respectively. Currently, 744 single nucleotide polymorphisms (a type of mutation) have been found in the gene encoding the FSHR, 8 of which are located in its exons (coding regions of the gene). How the ovary responds is resultant on the FSHR genotype. For example, Ser680Asn, a polymorphism in the FSHR gene has been shown to aid in predicting the severity of a woman's OHSS. Ordinarily FSH stimulates the growth of ovarian follicles, however, when mutated, it is stimulated by the hCG resulting in excessive follicle development.

Spontaneous OHSS, OHSS that arises and cannot be attributed to any form of ovarian stimulation or Assisted Reproductive Technology, has been linked to activating mutations in the FSHR <ref name="PMID23499866"><pubmed>23499866</pubmed></ref>. This familial disorder is an autosomal dominant one. In most cases the FSHR can be stimulated by the presence of Thyroid Stimulating Hormone (TSH) or hCG, in the absence of FSH (the ligand for FSHR).

===Lutenizing Hormome===

The '''Lutenizing Hormone Receptor''' (LHR) gene in humans is comprised of 11 exons. Animal studies have shown that many primates exhibit a similar gene which is comprised of only 10 exons, however a gene lacking the 10th exon has been identified and termed the type 2 LHR. Expression of the type 2 LHR has been seen in humans. The type 2 LHR, compared to the wild-type LHR appears to be repaired with regard to its function. Defects in the type 2 LHR include a decrease in efficiency of transport to the plasma membrane and irregularities in signal transduction. Inactivating mutations in the LHR have been seen to cause infertility in women as well as amenorrhoea. Activating LHR gene mutations are asymptomatic and are not associated with OHSS in women.

===Bone Morphogenic Protein===

An imporant growth factor, derived from oocytes called '''BMP-15''' (Bone Morphogenic Protein 15) is vital for female fertility. It belongs to the family of growth factors, Transforming Growth Factor β (TGF-β) and is heavily involved in folliculogenesis. It has been found that mutations in the BMP-15 gene caused infertility in female sheep. Conversely, it has also been indicated in enhanced fertility when BMP-15 is present is high amounts in follicular fluid <ref name="PMID19573286" />.

A case study done by Hanevik ''et. al.'' in 2013 <ref name="PMID21565556"><pubmed>21565556</pubmed></ref> found that a Single Nuclear Polymorphism (SNP) in the BMP-15 gene is responsible for a high response to ovarian hyper-stimulation. The aim of the study was to test the effect the SNP had on BMP-15 with regard to high and low responders buy taking blood from 53 high responders, 38 low responders and 100 non-responders (controls) and analysing 5 noted SNP's. Results from their study showed a correlation between a high response to ovarian hyper-stimulation and the BMP-15 9G allele. The article does state however, that further research is required into the molecular effects of SNP's on the function of BMP-15.

===Vascular Endothelial Growth Factor===

'''Vascular endothelial growth factor''' (VEGF) has been indicated as one of the key agents causing vascular permeability and subsequent ascites in OHSS. The gene, which is located on chromosome 12, is made up of 8 exons (coding regions), of which exons 6 and 7 do not always appear due to the exons being spliced out.The splicing of this gene allows for various isoforms of the gene to exist of which VEGF 121 and 165 appear to play a role in angiogenesis. There are two VEGF Receptors, VEGFR-1 and VEGFR-2 that belong to the tyrosine kinase family of receptors (for more information on VEGF see [[Pathophysiology]]). Because of its distinct role in OHSS, it has been targeted as an area for research for potential treatments. The idea is that if the genetic expression of VEGF and its receptors can be controlled, OHSS can be avoided or treated.<ref name="PMID19573286" />

A different study by Hanevik ''et. al.'' , <ref name="PMID22587628"><pubmed>22587628</pubmed></ref> done in 2012 involved analysing blood samples from 53 women with OHSS and 100 women without it (controls) and analysing 6 SNP's in the VEGFR2 gene to find any genetic variations. They found a correlation between women with the VEGF +405cc genotype and the development of OHSS indicating women that undergo controlled ovarian hyper-stimulation and posses his genotype, are at an increased risk of developing OHSS.

</div>

== Current Research on Animal Models==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">
{|
|-bgcolor="F8E0F1"
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<span style="font-size:120%">'''Inhibition of Cyclooxygenase-2 (COX-2) by Meloxican decreasing the incidence of OHSS in Rat Model'''</span> <ref name="PMID18166186"><pubmed>18166186</pubmed></ref>

Reasearch was carried out to investigate the effects of selective inhibition of the enzyme COX-2 on the Ovarian Hyperstimulation Syndrome (OHSS) using Female Wistar rates as the subjects. The research aimed to find results by measuring the number of antral and luteinized follicles, ovarian weight, vascualr endothelial growth factors and COX-2 immunohistochemistry. The rats being tested were all 22 days old and were divided into four equal groups;

'''Group 1 (Control group)''' was subject to a 0.1 ml of Intraperitoneal Saline from days 22 ~ 26

'''Group 2 (Mildly-stimulated group)''' subject to 10IU of pregnant mare serum gonadotrophin (PMSG) on day 24 and then 10IU of Human Chorionic Gonadotrophin (hCG) on day 26

'''Group 3 (OHSS positive group)''' was subject to 10IU of PMSG from days 22 ~ 26 and then administered 30IU of hCG on day 26 to induce OHSS

'''Group 4 (OHSS positive variant group)''' received 15mg/ml of Meloxicam 2 hours prior to administration of 10IU PMSG from days 22 ~ 26

Results showed there was no difference in ovarian weight in samples from Group 1 and Group 2, however Group 3 showed signs of significant ovarian weight increase which in group 4 was suppressed by the introduction of Meloxicam. No differences were observed in the number of antral follicles amongst the four test groups. Results from Group 2 and Group 3 showed that the granulosa cells of preovulatory follicles and the stromal cells were highly VEGF immunoreactive, however the Meloxicam treated Group 4 showed less immunoreactivity than Group 2 and Group 3 which indicated the correlation between Meloxicam and the diminished VEGF expression. Group 3 presented an increased COS-2 immunoreactivity which was highly diminished than in Group 4.

The research concluded that in a rat model, the enzyme Meloxicam has a beneficial effect on OHSS by reducing the increase of ovarian weight and the expression of VEGF associated with OHSS, the effects of which may be mediated by the inhibitory capacity of COX-2 on Meloxicam
|}

{|
|-bgcolor="FF99FF"
|
<span style="font-size:120%">'''Inhibition of Ovarian VEGF secretion by activation of Dopamine Receptor 2'''</span> <ref name="PMID25217874"><pubmed>25217874</pubmed></ref>

This research was carried out to investigate a possibility in whether a Dopamine Receptor 2 agonist '''(D2-ag)''' can assist in the prevention of Ovarian Hyperstimulation Syndrome, using rat models, by decreasing the ovarian vascular endothelial growth factor '''(VEGF)''' production. Using Immature Wistar rats (22 days old) as their animal model, the rats were initially stimulated with Gonadotrophins to mimic the onset and effects of OHSS and then subjected to treatment with a D2-agonist and/or a D2-antagonist (D2-ant). The vascular permeability was measured at the endpoint after day 26 by measuring the peritoneal extravasion of a previously injected dye and ovaries from all subjects were collected to assess the effects of D2-ag and D2-ant on the production of Ovarian VEGF. The expression of VEGF mRNA was measured by quantitative real time PCR and the levels of VEGF proteins were measured by Western Blots.

Results showed that the D2-ag caused a large reduction in the vascular permeability which was in turn associated with the great decreased in VEGF protein production in the OHSS rat ovaries, whereas the introduction of D2-ant showed opposite results with a increase in the vascular permeability leading to the increase of VEGF protein production in the ovaries. Ovarian VEGF mRNA levels were found to be unaffected by the introduction of these drugs in OHSS rat subjects. Conclusions were drawn on the fact that Dopamine Receptor 2 agonists prevent the increase of vascular permeability in subjects with OHSS by decreasing the ovarian production of VEGF and also that due to the dose-dependent inhibitory effect of the D2-ag on ovarian VEGF, current OHSS therapies used in humans can benefit by increasing the intraovarian concentration of D2-ag.
|}
</div>

==Glossary==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

'''Ascites''' - An accumulation of fluid in the peritoneal cavity with resultant abdominal swelling.

'''Cabergoline''' - A dopamine receptor agonist used to treat hormone imbalance.

'''Controlled Ovarian Stimulation''' - female infertility treatment using medications to stimulate the ovaries to develop follicles.

'''E2''' - Estradiol - Potent estrogen sex hormone.

'''Gonadotropin''' - Any hormone that has a stimulating effect on the gonads.

'''GnRH antagonist''' - Gonadotropin Releasing Hormone - A class of compounds that are similar in terms of the structure of natural Gonadotropin Releasing Hormone but has a antagonistic effect.

'''hCG'''- Human Chorionic Gonadotropin

'''Hemoconcentration''' - An increase in the concentration of circulating red blood cells in response to a decrease in blood plasma volume.

'''Hypovolemic''' - A decrease in circulating blood volume.

'''Iatrogenic'''- Illness caused as a result of a medical examination or treatment.

'''Intravenous fluids''' - Is the infusion of liquid substances directly into a vein.

'''IVF'''- In-vitro Fertilization

'''NSAID'''- Non-steroidal Anti-Inflammatory Drug e.g. Ibuprofen

'''OHSS'''- Ovarian Hyper-stimulation Syndrome

'''PCOS'''- Polycystic Ovarian Syndrome. An endrocrine system disorder whereby the ovaries are enlarged with small collections of fluid.

'''FSH''' - Follicle Stimulating Hormone

'''LH''' - Luteinizing Hormone

'''Oliguria'''- Decreased urine output/small amounts of urine produced.

</div>

==References==

2015 Group Project 2

2015-10-22T22:23:16Z

Z3372824: /* Glossary */

{{ANAT2341Project2015header}}

==<span style="font-size:120%">'''Ovarian Hyper-stimulation Syndrome (OHSS)'''</span>==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

Ovarian Hyper stimulation Syndrome (OHSS) is an iatrogenic complication of '''Assisted Reproduction Technology''' (ART), in which women take medications to stimulate oocyte growth. It is generally identified by cystic enlargements of the ovaries and fluid accumulation in the peritoneal cavity due to the increased capillary permeability and ovarian neoangiogenesis <ref name="PMID22065820"><pubmed>22065820</pubmed></ref>. It is an occurrence which is dependent on the controlled stimulation of the ovaries in preparation for IVF i.e. administration of human Chorionic Gonadotropin (hCG).

OHSS was first described in 1943 as ''“syndrome d’hyperluteinisation massive
des ovaries”''. It was during this time that gonadotropins were prepared from animals such as sheep to bring on ovulation in women. The first recorded death as a result of OHSS occurred in 1951 and was due to renal failure as a result of oligouria, a complication of the syndrome <ref name="OHSS"> Marie M. Budev, DO, MPH; Alejandro C. Arroliga, MD; Tommaso Falcone, MD, [ http://utilis.net/Morning%20Topics/REI/Ovarian%20Hyperstimulation.pdf ], 'Ovarian Hyperstimulation Syndrome'</ref> <ref name="PMID12638783"><pubmed>12638783</pubmed></ref>.

<span style="color:#FA58D0">This wikipage aims to provide clear information on various areas surrounding OHSS such as diagnosis, prevention and complications and will look into the genetics behind the disorder and the various animals models used to research it.</span>

<html5media height="350" width="450">https://www.youtube.com/watch?v=aXmjJw234a4</html5media>

'''Overview of the Ovarian Hyperstimulation Syndrome''' <ref> Howcast (2013, August 27) Ovarian Hyperstimulation Syndrome | Infertility. Retrieved from https://www.youtube.com/watch?v=aXmjJw234a4</ref>

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==Epidemiology==
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Ovarian Hyper-Stimulation Syndrome (OHSS) rarely occurs sporadically, and if it does, it is usually the result of an underlying genetic problem. The majority of OHSS is due to the ovaries being stimulated to mature and release an abundance of oocytes, in response to hormones Human Chorionic Gonadotropin (hCG) and Follicle Stimulating hormone (FSH), during IVF. Rarely, Clomifene Citrate therapy can cause OHSS.<ref name="WikiOHSS"> Wikipedia, [ https://en.wikipedia.org/wiki/Ovarian_hyperstimulation_syndrome ], 'Ovarian Hyperstimulation Syndrome'</ref>

OHSS only affects '''0.5-5%''' of women undergoing Ovarian Hyper-stimulation, but despite its small prevalence, it is a potentially fatal outcome of a non-vital procedure and remains a prevalent problem for fertility specialists <ref name="PMID12498425"><pubmed>12498425</pubmed></ref> <ref name="PMID12638783"><pubmed>12638783</pubmed></ref>. Age has been cited as a factor affecting those with OHSS, with younger women more at risk. Additionally, women with allergies were seen to have a higher incidence of OHSS. It is important to note that at this point in time, there is no positive correlation between gonadotropin dose and OHSS.

Of the 0.5-5% of women affected with OHSS mentioned above, 2% of those women will require hospitalisation. As of 2011, it has been reported that the incidence of OHSS was '''increasing''', resulting in approximately 3 deaths per 100,000 women undergoing ovarian stimulation per year <ref name="PMID21828116"><pubmed>21828116</pubmed></ref>. This is particularly worrying as in 2008, in the United States alone, there were around 150,000 IVF cycles undertaken.

{|
|-bgcolor="F8E0F1"
|
'''With the field of Assisted Reproductive Technologies expanding and more women partaking in IVF treatments, the threat of women developing OHSS is an ongoing and increasing one''' <ref name="PMID21828116" />.
|}
{| class="wikitable mw-collapsible mw-collapsed"
! Characteristics of women by complication group <ref name="PMID19591989"><pubmed>19591989</pubmed></ref>
|-
! scope="col" width="100px" height="60px" style="text-align:center| '''Characteristic'''
! scope="col" width="100px" height="60px" style="text-align:center| '''No Complications
(N = 212,041)'''
! scope="col" width="100px" height="60px" style="text-align:center| '''Moderate OHSS
(N = 1,523)'''
! scope="col" width="100px" height="60px" style="text-align:center| '''Severe OHSS
(N = 655)'''
|-
|style="text-align:center; background: #FF99FF;"| '''Maternal Age (Mean ± SD)'''
|style="text-align:center; background: #F6CEEC;"| 35.6 ± 4.6
|style="text-align:center; background: #F6CEEC;"| 33.0 ± 4.3
|style="text-align:center; background: #F6CEEC;"| 33.1 ± 4.4
|-
|style="text-align:center; background: #FF99FF;"| '''Maternal Age (%)'''
|-
|style="text-align:left; background: #F6CEEC;"| <30 years
|style="text-align:center; background: #F6CEEC;"| 10 %
|style="text-align:center; background: #F6CEEC;"| 21.1 %
|style="text-align:center; background: #F6CEEC;"| 20.6 %
|-
|style="text-align:left; background: #F6CEEC;"| 30-34 years
|style="text-align:center; background: #F6CEEC;"| 30.4 %
|style="text-align:center; background: #F6CEEC;"| 43.2 %
|style="text-align:center; background: #F6CEEC;"| 40.5 %
|-
|style="text-align:left; background: #F6CEEC;"| 35-39 years
|style="text-align:center; background: #F6CEEC;"| 37.8 %
|style="text-align:center; background: #F6CEEC;"| 27.2 %
|style="text-align:center; background: #F6CEEC;"| 32.5 %
|-
|style="text-align:left; background: #F6CEEC;"| >40 years
|style="text-align:center; background: #F6CEEC;"| 21.8 %
|style="text-align:center; background: #F6CEEC;"| 8.4 %
|style="text-align:center; background: #F6CEEC;"| 6.4 %
|-
|style="text-align:center; background: #FF99FF;"| '''Nulligravida (%)'''
|style="text-align:center; background: #F6CEEC;"| 45.8 %
|style="text-align:center; background: #F6CEEC;"| 51.5 %
|style="text-align:center; background: #F6CEEC;"| 51.8 %
|-
|style="text-align:center; background: #FF99FF;"| '''Infertility Diagnosis (%)'''
|-
|style="text-align:left; background: #F6CEEC;"| Male factor
|style="text-align:center; background: #F6CEEC;"| 37.7 %
|style="text-align:center; background: #F6CEEC;"| 41.0 %
|style="text-align:center; background: #F6CEEC;"| 33.4 %
|-
|style="text-align:left; background: #F6CEEC;"| Endometriosis
|style="text-align:center; background: #F6CEEC;"| 13.5 %
|style="text-align:center; background: #F6CEEC;"| 13.5 %
|style="text-align:center; background: #F6CEEC;"| 10.7 %
|-
|style="text-align:left; background: #F6CEEC;"| Ovulation Disorders
|style="text-align:center; background: #F6CEEC;"| 14.0 %
|style="text-align:center; background: #F6CEEC;"| 29.5 %
|style="text-align:center; background: #F6CEEC;"| 22.4 %
|-
|style="text-align:left; background: #F6CEEC;"| Diminished ovarian reserve
|style="text-align:center; background: #F6CEEC;"| 16.9 %
|style="text-align:center; background: #F6CEEC;"| 3.2 %
|style="text-align:center; background: #F6CEEC;"| 2.4 %
|-
|style="text-align:left; background: #F6CEEC;"| Tubal factors
|style="text-align:center; background: #F6CEEC;"| 20.4 %
|style="text-align:center; background: #F6CEEC;"| 22.6 %
|style="text-align:center; background: #F6CEEC;"| 22.3 %
|-
|style="text-align:left; background: #F6CEEC;"| Uterine factors
|style="text-align:center; background: #F6CEEC;"| 5.1 %
|style="text-align:center; background: #F6CEEC;"| 4.3 %
|style="text-align:center; background: #F6CEEC;"| 3.1 %
|-
|style="text-align:left; background: #F6CEEC;"| Other factors
|style="text-align:center; background: #F6CEEC;"| 13.9 %
|style="text-align:center; background: #F6CEEC;"| 13.1 %
|style="text-align:center; background: #F6CEEC;"| 10.4 %
|-
|style="text-align:left; background: #F6CEEC;"| Unexplained factor
|style="text-align:center; background: #F6CEEC;"| 12.7 %
|style="text-align:center; background: #F6CEEC;"| 11.8 %
|style="text-align:center; background: #F6CEEC;"| 18.6 %
|-
|}
</div>

==Causative Agents==
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[[File:Follicular Development.jpeg|right|thumbnail|500px|Infertility treatments aim to facilitate follicular development and induce ovulation to improve chances of fertilisation <ref name="PMID24717179"><pubmed>24717179</pubmed></ref>]]

Normally a woman produces one egg per month from the ovaries, which travel down the Fallopian tube to be fertilized or be released from the body. In cases where women have difficulty falling pregnant, they are given medication which help them to produce and release eggs (as shown in the diagram to the right), further increasing their chances of fertilization and pregnancy <ref><pubmed>19573285</pubmed></ref>. Ovarian Hyper stimulation Syndrome generally occurs during infertility treatments when the ovaries are overstimulated by the fertility medication which causes the ovaries to swell and leak fluids into the belly and abdomen. The prevalence of OHSS onset is linked with excessive number of follicle development in response to the administration of injectable Follicle Stimulating Hormones (FSH) followed by the '''Human Chorionic Gonadotrophins''' (hCG) which triggers the release of the oocytes <ref><pubmed>26190539</pubmed></ref>.

'''Follicle Stimulating Hormones''' (FSH) <ref name="PMID9020850"><pubmed>9020850</pubmed></ref> are glycoprotein hormones that are produced and secreted from the Anterior Pituitary gland into the bloodstream, which regulate the developmental, growth, maturation and the reproductive processes within the body. In females, the Follicle Stimulating Hormones initiates the stages of growth and development of immature ovarian follicles within the ovaries before the release of an egg from a follicle at ovulation. When FSH is administered to a patient who is suffering from infertility, the increase FSH levels affect the rate of development and production, in turn increasing the amount of follicles which are ready to be released during ovulation.

</div>

==Symptoms==
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OHSS is classified based on a criteria from mild, moderate and severe <ref name="WikiOHSS" />:

'''Mild Symptoms'''- abdominal bloating, minimal weight gain, nausea, diarrhoea and a feeling of fullness.

'''Moderate Symptoms'''- Substantial weight gain (on average 2 or more pounds a day), increased abdominal girth, darkend urine and excessive thirst in addition to the mild symptoms.

'''Severe Symptoms'''- In addition to the symptoms associated with Mild and Moderate OHSS, in severe OHSS, you see shortness of breath, calf and chest pains and pleural effusion.

<span style="font-size:100%">'''Classifications of Ovarian Hyper-stimulation Syndrome:'''</span> <ref name="PMID22065820"><pubmed>22065820</pubmed></ref>
{| class="wikitable" style="text-align:center
|-
! scope="col" width="70px"| '''Classification'''
! scope="col" width="650px"| '''Symptoms'''
|-
|style="text-align:center; background: #F6CEEC;"| '''Mild'''
|style="height: 60px; background: #F6CEEC;"| '''Grade 1''' - Abdominal distention and discomfort
'''Grade 2''' - Abdominal distention, discomfort with nausea, vomiting and/or diarrhea and ovarian enlargement from 5~12cm
|-
|style="text-align:center; background: #F8E0F1;"| '''Moderate'''
|style="height: 60px; background: #F8E0F1;"| '''Grade 3''' - All features of Mild OHSS with ultrasonographic evidence of ascites
|-
|style="text-align:center; background: #F6CEEC;"| '''Severe'''
|style="height: 60px; background: #F6CEEC;"| '''Grade 4''' - All features of Moderate OHSS with the addition of clinical evidence of ascites and breathing difficulties present
'''Grade 5''' - All of the above symptoms along with a change in the blood volume, increased blood viscosity due to coagulation and diminished renal function
|}

</div>

==Diagnosis==
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Whilst symptoms of OHSS can occur as soon as 24 hours post hCG administration, they are usually seen in women 7-10 days post administration. Initially women with OHSS will present with abdominal bloating, as a result of fluid in the peritoneal cavity and an increase in ovary size. When women present with severe OHSS they are often dehydrated, due to increased vascular permeability, and have hemoconcentration. The above results in a decrease in intravascular volume, leading to '''oligouria''' <ref name="PMID22416285" />.

===History===

Initially a thorough history of the patient is taken during which the clinician looks for evidence of ovarian stimulation, followed by ovulation. During this history taking, the clinician will inquire into any weight gain noticed, urine output, and the woman's ability to maintain oral hydration. A key diagnostic tool for clinicians regarding women who are taking gonadotropins is to identify if they are at an increased risk of developing OHSS. Some risk factors include woman aged less than 30, women who have polycystic ovaries, woman with a previous history of OHSS and women who have had greater than 20 oocytes retrieved <ref name="PMID22416285" />.

===Physical Exam===
[[File:Vaginal_Ultrasonography_in_Sagittal_Plane.jpg|right|thumbnail|600px|Vaginal Ultrasonography in Sagittal plane <ref name="Wikiversity Journal of Medicine"> Häggström, Mikael. "Medical gallery of Mikael Häggström 2014". Wikiversity Journal of Medicine 1 (2). DOI:10.15347/wjm/2014.008. ISSN 20018762</ref>]]
After a history of the patient is taken, the next step is to perform a physical exam on the patient. Women who present with abdominal bloating will produce a shifting dullness upon abdominal percussion. Additionally the clinician will test the woman's vital signs, measure her abdominal girth, weight and will look for evidence of ascites or increase in calf size (usually unilateral)<ref name="PMID22416285" />.

===Investigations===

If the clinician further suspects a women of having OHSS, various investigations can be done such as an ultrasound.The intraperitoneal fluid is best imaged via vaginal ultrasound due to the enlarged ovaries making it difficult to image the pelvis using transabdominal ultrasound. The clinician can also order laboratory testing to look for urine specific gravity and and complete blood count to look for hemoconcentration with a hematocrit. Additionally, liver function tests can be ordered to look for elevated function. The clinician will also look for evidence of elevated D-dimers and fibrinogen and decreased levels of anti-thrombin 3 <ref name="SAHealth"> Government of South Australia Health [ http://www.sahealth.sa.gov.au/wps/wcm/connect/9b61ed004ee5348da663afd150ce4f37/Ovarian-hyperstimulation-syndrome-WCHN-PPG-17072012.pdf?MOD=AJPERES&CACHEID=9b61ed004ee5348da663afd150ce4f37 ], 'South Australian Paediatric Clinical Guidelines OHSS'</ref>.

====Ultrasound====

Typical appearances of the ultrasound include <ref name="Ultrasound"> Radiopaedia [ http://radiopaedia.org/articles/ovarian-hyperstimulation-syndrome-1 ], 'Ovarian Hyperstimulation Syndrome'</ref>:

*Bilaterally and symmetrically enlarged ovaries (>12cm)
* "Spoke-Wheel appearance" - presence of multiple cysts of varying size
*May also see ascites (fluid)

===Severity===

Once a clinician has deduced a women is suffering from OHSS, the severity of their condition needs to be established as either mild, moderate or severe. This is done by referring to the criteria under the sub-heading [[Symptoms]].The subsequent course of treatment for the woman will be based upon this evaluation.

{|
|-bgcolor="F6CEEC"
|
'''Further investigations''' can be done including a Chest X-ray to check for pleural effusions and oedema and USS with Doppler's to check for ascites or possible ovary torsion. <ref name="PMID22416285"><pubmed>22416285</pubmed></ref>
|}

===Differential Diagnosis===

Conditions presenting with similar symptoms or ultrasound images include <ref name="Ultrasound" />:

*Polycystic Ovaries (PO)
:: The difference is that with PO is that the cycts are typically smaller than OHSS cysts and there is no evidence of ascited or pleural effusion
*Mucinous Ovarian Malignancy
:: A type of Ovarian Epithelial tumour
*Ectopic Pregnancy <ref name="Casereport"> Australian Medical Student Journal [ http://www.amsj.org/wpcontent/uploads/files/articles/amsj_v2_i1/AMSJ_v2_i1_pg58-60.pdf ], 'Ovarian hyperstimulation syndrome'</ref>
::A pregnancy in which the foetus develops outside of the uterus e.g. in the fallopian tube

</div>

==Pathophysiology==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

[[File:Pathogenesis_of_OHSS.png|600px|thumb|Pathogenesis of OHSS <ref name="PMID20416867"><pubmed>20416867</pubmed></ref>]]

The definition of Ovarian Stimulation is enlarged ovaries with many luteinized cysts, that can present with secondary complications. What distinguishes Ovarian Stimulation from OHSS is the presence of vascular hyper-permeability that results in fluids being redirected elsewhere in the body.

The key process to OHSS appears to be caused by '''Vascular Endothelial Growth Factor''' (VEGF), that is released along with other cytokines, estrogen and progesterone, due to the ovary undergoing luteinization as a result of stimulation by hCG. VEGF increases vascular permeability and as a result the capillaries become more "leaky" to the fluids in them. These fluids can then escape the capillaries and accumulate in the pleural and abdominal cavities as ascites. The woman then becomes hypovolemic and is at an increased risk of circulatory, renal and respiratory issues such as arterial thromboembolism due to the thickening of the blood. Note, the blood is thickened as fluid is leaving the capillaries, leaving behind red blood cells and other cellular components of the blood <ref name="WikiOHSS" />.

The increase in expression of VEGF and VEGF Receptor 2 (VEGFR2) is attributed to the greatly increased amount of their mRNA present in the body after stimulation with hCG <ref name="PMID21082502"><pubmed>21082502</pubmed></ref>. VEGF interacts with VEGF2 and VEGF Receptor 1 (VEGFR1) to create a strong angiogenic effect. Both VEGFR2 and VEGFR1 belong to a family of receptors called tyrosine kinases. VEGF2 is involved in the regulation of angiogenesis and vascular permeability whilst VEGF1 has a slightly contradictory role in that is is involved in the maintenance of the tight junctions between endothelial cells in blood vessels. A study by Gómez ''et. al.'' <ref name="PMID21082502" /> showed that women experiencing OHSS had substantially higher plasma levels of VEGF and lower levels of VEGFR1.

</div>

==Complications==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

Ovarian torsion or rupture, renal insufficiency and thrombophlebitis can all complicate OHSS. If a pregnancy occurs, symptoms may persist longer than the usual 1 to 2 weeks and become more severe, however, even with severe OHSS, they do not extend past the first trimester <ref name="WikiOHSS" />.

<span style="color:#FA58D0"> '''1-2% of women who undergo ovarian stimulation develop a severe form of OHSS''' </span>. Complications from severe OHSS include:

*Fluid collection in the abdomen
*Electrolyte disturbances (sodium and potassium)
*Kidney failure
*Ovary twisting
*Rupture of a cyst in an ovary
*Breathing problems
*Blood clots in large vessels (most commonly the legs)
*Pregnancy loss from miscarriage or termination
*Rarely, death

A study by Nouri ''et. al.'' <ref name="PMID24996451"><pubmed>24996451</pubmed></ref> found that women with '''Polycystic Ovarian Syndrome''' (PCOS) and those that were induced with hCG experienced longer recovery times from severe OHSS than women who were not pregnant. They looked at a cohort of women hospitalised for the first time with severe OHSS and subject them to the same treatments. Based on a defined criteria, they established the recovery time of these women and compared the times between those that were pregnant to those that were not pregnant. They also found that whether a woman had PCOS or ovulation induction did not affect her risk of developing OHSS if she was not pregnant. It is only a risk factor for pregnant women.

===Thromboembolic events===

A frequent and deadly complication of OHSS are thromboembolic events due to increased blood clotting. This increase in blood clotting has been attributed to a variety of complications such as hemoconcentration (which thickens the blood), hypovolemia and an increase in the permeability of blood vessels as a result of increased vasoactive substances in the body of ovarian origin. Thromboembolic events include venous thromboses often in the upper extremities and arterial thromboses such as those in the cerebrovascular region. These events can lead to amputations of extremities, brain damage, miscarriage and death. To avoid this, anti-coagulants are given to pateitns with OHSS and they are fitted with compression stockings (see [[Treatment]]) <ref name="PMID23378404"><pubmed>23378404</pubmed></ref>.

{|
|-bgcolor="F8E0F1"
|
The risk of a woman developing OHSS is higher if she is having a '''twin pregnancy''', as she is exposed to higher concentration of hCG. <ref name="PMID9756273"><pubmed>9756273</pubmed></ref>
|}

</div>

==Treatment==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

'''General treatment
'''
*''Acetaminophen'' with or without a narcotic agent- used to treat abdominal discomfort
*Women are encouraged to drink 2-3 litres of water a day to prevent hemoconcentration
*Women are advised to avoid sexual intercourse and vigorous exercise at the risk of torsion or rupture of the ovaries
*NSAID's with anti-platelet properties should NOT be used as they may effect renal function in a women with OHSS
*Patients with significantly painful ascites or breathing problems may undergo ''Paracentesis'' (drainage of the ascites)
*''Culdocentesis'' (extraction of fluid from recto-uterine pouch) can be done to decrease the likelihood of a woman with moderate OHSS progressing to severe OHSS.<ref name="PMID22416285" />

===Mild to Moderate OHSS===

Mild OHSS can often resolve on its own, however, moderate OHSS may include treatments such as<ref name="WikiOHSS" />:

*Anti-nausea medication and prescription painkillers
*Regular physical examinations and ultrasounds
*Daily weigh-ins and waist measurements
*Measuring the amount of urine produced each day
*Frequent blood tests for monitoring dehydration and electrolyte imbalance
*Maintaining a high balance of fluids
*Drainage of excess abdominal fluid by inserting a needle in the abdominal cavity
*Wearing support stockings which help prevent blood clots/thrombosis

===Severe OHSS===

Severe OHSS requires hospital care in order for constant monitoring and treatment such as <ref name="WikiOHSS" />:

*Intravenous fluids with a crystalloid solution (100-150mL/hr)
*Intravenous Albumin is administered is IV fluids are insufficient (15-20mL/hr of 25% albumin for 4 hrs)
*In addition to Acetaminophen, ''Opioid analgesics'' can be administered for pain relief
*''Antiemetics'' can be used to subside nauseas and/or vomiting
*Woman administered to hospital of OHSS are considered at high risk of thromboembolic complications and are given low molecular weight ''heparin'', an anti-coagulant
*''Cabergoline''- lessens OHSS symptoms
*''GnRH agonist''- suppresses ovarian activity
**If at risk of OHSS, alternates include using a GnRH agonist instead of hCG however its effects on pregnancy rates are questionable. Using a GnRH agonist to replace the use of hCG for final oocyte stimulation will see a 6% decrease in delivery rate.

*Daily monitoring of creatine, urea, creatine clearance C-reactive protein (to rule out infection) are all required in combination with weekly tests such as liver and renal function tests and chest x-rays (to check for pleural effusion) <ref name="PMID12638783" />.

If there are serious complications then additional treatments are required:

*Surgery for a ruptured ovarian cyst
*Intensive care for the liver or lung complications

====Paracentesis====

For women with severe/grade 3 OHSS, paracentesis, the removal of fluid from the body using an aspiration needle, can be undertaken. It is a diagnostic and a therapeutic method that can be done trans-abdominally and trans-vaginally. It is used to relieve symptoms, improve haemodynamics e.g. Urinary output, and shorten the women's hospital stay. Complications of paracentesis include bleeding, infection and organ injury, however are note common <ref name="Paracentesis"> S. Monica Soni, HMS 3, Gillian Lieberman, MD [ http://eradiology.bidmc.harvard.edu/LearningLab/genito/Soni.pdf ], 'Ovarian Hyperstimulation Syndrome'</ref>.

{|
|-bgcolor="F8E0F1"
|
The most important aspect of treatment for any women with OHSS is close and constant '''monitoring''' with her healthcare professional. Counselling may also be provided to women and their partners or families in order to provide them with the best possible knowledge base to manage and treat their OHSS. It is important to note that there is '''no one cure or treatment''' for OHSS. Treatment involves managing and eliminating the symptoms until such time as the syndrome resolves itself <ref name="WikiOHSS" />.
|}

</div>

==Prevention==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

There are three key avenues through which the incidence of OHSS may be prevented. These include identifying risk factors to predict OHSS development, modifying treatment regimes on the basis of the identified risk factors and intervention to prevent progression to OHSS once the patient has undergone '''Controlled Ovarian Stimulation''' (COS).

=== Risk factors===

'''Primary risk factors'''

Pre-existing factors likely to exacerbate the ovarian stimulation response. Primary risk factors include <ref name="PMID26074966"><pubmed>26074966</pubmed></ref>:

*Young age
*Low body weight
*History of elevated response to gonadotropins
*Polycystic Ovary Syndrome (PCOS)
*Isolated PCOS characteristic
*A previous history of OHSS.
*Hormonal markers (e.g. Anti-Mullerian Hormone markers)
*Ultrasonographic markers (e.g. Antral Follicle Count)

'''Secondary risk factors'''

Secondary risk factors involve the monitoring of ovarian response parameters once COS has been initiated. These parameters are monitored for <ref name="PMID19007627"><pubmed>19007627</pubmed></ref>:

*rapidly rising E2 levels
*E2 concentration larger than 2500 pg/mL
*large number of developing follicles (10-14mm) on the day hCG is administered
*large number of oocytes retrieved

These factors in combination, act as a predictive tool to assess the likelihood of severe OHSS development, with a 83% sensitivity and 84% specificity. <ref name="PMID19007627"/>

=== Primary Prevention===

Primary Prevention involves the modification of treatment regimens on the basis of OHSS risk classifications, in order to prevent OHSS occurrence.

'''Ovulation Induction'''

Unifollicular Ovulation Induction through Ovulation Induction (OI) is a primary means of avoiding OHSS in women with Polycystic Ovarian Syndrome, who are at an increased risk. In order to promote unifollicular development, the ovaries are stimulated with a low starting dose of FSH (75 IU).<ref name="PMID20416867"><pubmed>20416867</pubmed></ref> Studies suggests that a minimum gonadotropin dose lowers OHSS risk and thus a step-up regimen is utilised to achieve an ovarian response, whereby the FSH dosage is increased every 7 days until follicular development of greater than 10mm is noted.<ref name="PMID26074966" /> Alternatively, a step-down regimen may be followed, whereby a high initial FSH dosage is lowered according to the ovarian response. Another method to increase FSH levels during OI, is through Aromatase Inhibitors which promote folliculogenesis by increasing pituitary secretion of FSH, and downregulate oestrogen production through a negative feedback loop. However, Aromatase Inhibitors have not been shown to reduce OHSS incidence in comparison to other methods of OI.<ref name="PMID26074966" /> During OI, a key objective is to prevent early cycle cancellation due to premature luteinisation from pituitary secretion of LH. In order to downregulate LH secretion, Gonadotropin-releasing hormone agonists (GnRHa) are administered in addition to gonadotropins. Alternatively, GnRH antagonists may be administered to downregulate endogenous LH secretion. Comparative studies have shown that the GnRH antagonist protocol has a greater effect in lowering the incidence of mild to severe OHSS. However due to the rare nature of OHSS, and insufficient sample sizes, the difference was not found to be significant. <ref name="PMID21082508"><pubmed>21082508</pubmed></ref>. Generally, the duration of exposure to gonadotropins and subsequent risk of OHSS may be minimised through mild stimulation protocols which administer FSH only in the mid to late follicular phase.<ref name="PMID20416867" />

'''Adjuvant Metformin Therapy'''

Adjuvant Metformin Therapy has been found to lower the risk of OHSS by 63%.<ref name="PMID25406011"><pubmed>25406011</pubmed></ref> It involves the administration of metformin at a daily dosage of 1000 to 2000mg, 2 months prior to Controlled Ovarian Stimulation <ref name="PMID26074966"/>. Metformin lowers the elevated insulin levels in PCOS which consequently reduce intraovarian androgen levels. This leads to a reduced sensitivity and expression of granulosa cell-follicle stimulating hormone receptors which result in a less exaggerated response to gonadotropins. Furthermore, it is suggested that Metformin prevents OHSS by controlling vascular permeability through the inhibition of various vasoactive molecules, including VEGF.

'''Avoiding hCG during Luteal Phase Support

Following Controlled Ovarian Stimulation, the steroid levels of E2 and P4 are reduced during the luteal phase due to the negative feedback on the pituitary. This leads to low endogenous LH levels, which consequently reduce endometrial receptivity as well as the luteal phase duration itself. As a result, implantation and pregnancy rates are reduced and early pregnancy loss rates are increased.<ref name="PMID20416867" /> Luteal Phase Support (LPS) serves to combat these adverse events with the use of hCG. However, hCG has been found to increase the risk of OHSS. Alternatively, the use of progesterone has been found to not only halve the risk of OHSS, but also induce similar improvements in pregnancy and miscarriage rates as hCG.<ref name="PMID26148507"><pubmed>26148507</pubmed></ref>

===Secondary Prevention===

Secondary Prevention aims to prevent progression to OHSS once COS has been initiated and the patient has been found to mount an exaggerated response. <ref name="PMID20416867" />

'''Coasting'''

Coasting is a first-line secondary preventative strategy. It consists of the withdrawal of gonadotrophins when a critical number of follicles and/or E2 concentration is reached. hCG is administered once the E2 concentration reduces to a safe level, before the process of oocyte retrieval commences. This preventative strategy is conducted for a period of less than 3 days in order to avoid compromising IVF outcomes.

'''Cryopreservation'''

Cryopreservation of embryos after oocyte retrieval is another avenue which may avert OHSS progression. The cryopreserved embryos are only reimplanted once the patient's hormone serum levels have normalised. Using oocyte vitrification, crystal formation within embryo tissue is avoided and so cryopreserved embryos have been found to produce better pregnancy rates with a 32% increase, than fresh embryo transfer. Recent studies suggest cryopreservation itself does not reduce OHSS rates, but must be followed by a GnRHa trigger to avert OHSS.

'''Cycle cancellation'''

Cycle cancellation is a guaranteed method to prevent early OHSS whereby hCG is withheld. This is a last resort strategy as it carries the risk of significant psychological distress and financial loss for the patient.

</div>

==Effect on the Newborn==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

</div>
Women who develop OHSS while undergoing Assisted Reproductive Technologies (ART) treatment are not only more likely to achieve a pregnancy, but have a live birth as the pregnancy outcome. This live birth is also more likely to be a multiple birth of two, three or more children. <ref name="PMID19591989"><pubmed>19591989</pubmed></ref> It has been postulated that a multifetal pregnancy leads to a more rapid increase in hCG levels, resulting in an increased risk of OHSS. However, the causal nature between multifetal pregnancy and OHSS development is disputed and further research is required to distinguish correlation from causation. <ref name="PMID19573292"><pubmed>19573292</pubmed></ref>

OHSS development is also associated with an increased risk of adverse outcomes including stillbirth, premature birth and low birthweight.<ref name="PMID19591989" /> Although the cause for the increased risk in adverse pregnancy outcomes is unknown, it is suggested that as the incidence of OHSS is reduced through various prevention strategies, the risk of such outcomes may be also be reduced.

==Genetics==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

Despite OHSS typically being of iatrogenic origin as a result of ovarian stimulation with gonadotropins, research has been conducted into the potential genetics behind OHSS as many sporadic and familial cases have been observed. '''Mutations''' in the receptor for hormones such as Follicle Simulating Hormone (FSH), Lutenizing Hormone (LH) and hCG have all been targets of OHSS genetics research. Interestingly, they too also arise from a common ancestral gene.

===Follicle Stimulating Hormome===

Dr. Botros Rizk, of the University of South Alabama College of Medicine <ref name="PMID19573286"><pubmed>19573286</pubmed></ref>, has written extensively regarding the genetics behind OHSS. In particular, he talks about '''FSH receptors''' (FSHR) and their role in the syndrome. He hypothesises that mutations in these receptors could be activating or inactivating, leading to an increased risk of developing OHSS or sterility respectively. Currently, 744 single nucleotide polymorphisms (a type of mutation) have been found in the gene encoding the FSHR, 8 of which are located in its exons (coding regions of the gene). How the ovary responds is resultant on the FSHR genotype. For example, Ser680Asn, a polymorphism in the FSHR gene has been shown to aid in predicting the severity of a woman's OHSS. Ordinarily FSH stimulates the growth of ovarian follicles, however, when mutated, it is stimulated by the hCG resulting in excessive follicle development.

Spontaneous OHSS, OHSS that arises and cannot be attributed to any form of ovarian stimulation or Assisted Reproductive Technology, has been linked to activating mutations in the FSHR <ref name="PMID23499866"><pubmed>23499866</pubmed></ref>. This familial disorder is an autosomal dominant one. In most cases the FSHR can be stimulated by the presence of Thyroid Stimulating Hormone (TSH) or hCG, in the absence of FSH (the ligand for FSHR).

===Lutenizing Hormome===

The '''Lutenizing Hormone Receptor''' (LHR) gene in humans is comprised of 11 exons. Animal studies have shown that many primates exhibit a similar gene which is comprised of only 10 exons, however a gene lacking the 10th exon has been identified and termed the type 2 LHR. Expression of the type 2 LHR has been seen in humans. The type 2 LHR, compared to the wild-type LHR appears to be repaired with regard to its function. Defects in the type 2 LHR include a decrease in efficiency of transport to the plasma membrane and irregularities in signal transduction. Inactivating mutations in the LHR have been seen to cause infertility in women as well as amenorrhoea. Activating LHR gene mutations are asymptomatic and are not associated with OHSS in women.

===Bone Morphogenic Protein===

An imporant growth factor, derived from oocytes called '''BMP-15''' (Bone Morphogenic Protein 15) is vital for female fertility. It belongs to the family of growth factors, Transforming Growth Factor β (TGF-β) and is heavily involved in folliculogenesis. It has been found that mutations in the BMP-15 gene caused infertility in female sheep. Conversely, it has also been indicated in enhanced fertility when BMP-15 is present is high amounts in follicular fluid <ref name="PMID19573286" />.

A case study done by Hanevik ''et. al.'' in 2013 <ref name="PMID21565556"><pubmed>21565556</pubmed></ref> found that a Single Nuclear Polymorphism (SNP) in the BMP-15 gene is responsible for a high response to ovarian hyper-stimulation. The aim of the study was to test the effect the SNP had on BMP-15 with regard to high and low responders buy taking blood from 53 high responders, 38 low responders and 100 non-responders (controls) and analysing 5 noted SNP's. Results from their study showed a correlation between a high response to ovarian hyper-stimulation and the BMP-15 9G allele. The article does state however, that further research is required into the molecular effects of SNP's on the function of BMP-15.

===Vascular Endothelial Growth Factor===

'''Vascular endothelial growth factor''' (VEGF) has been indicated as one of the key agents causing vascular permeability and subsequent ascites in OHSS. The gene, which is located on chromosome 12, is made up of 8 exons (coding regions), of which exons 6 and 7 do not always appear due to the exons being spliced out.The splicing of this gene allows for various isoforms of the gene to exist of which VEGF 121 and 165 appear to play a role in angiogenesis. There are two VEGF Receptors, VEGFR-1 and VEGFR-2 that belong to the tyrosine kinase family of receptors (for more information on VEGF see [[Pathophysiology]]). Because of its distinct role in OHSS, it has been targeted as an area for research for potential treatments. The idea is that if the genetic expression of VEGF and its receptors can be controlled, OHSS can be avoided or treated.<ref name="PMID19573286" />

A different study by Hanevik ''et. al.'' , <ref name="PMID22587628"><pubmed>22587628</pubmed></ref> done in 2012 involved analysing blood samples from 53 women with OHSS and 100 women without it (controls) and analysing 6 SNP's in the VEGFR2 gene to find any genetic variations. They found a correlation between women with the VEGF +405cc genotype and the development of OHSS indicating women that undergo controlled ovarian hyper-stimulation and posses his genotype, are at an increased risk of developing OHSS.

</div>

== Current Research on Animal Models==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">
{|
|-bgcolor="F8E0F1"
|
<span style="font-size:120%">'''Inhibition of Cyclooxygenase-2 (COX-2) by Meloxican decreasing the incidence of OHSS in Rat Model'''</span> <ref name="PMID18166186"><pubmed>18166186</pubmed></ref>

Reasearch was carried out to investigate the effects of selective inhibition of the enzyme COX-2 on the Ovarian Hyperstimulation Syndrome (OHSS) using Female Wistar rates as the subjects. The research aimed to find results by measuring the number of antral and luteinized follicles, ovarian weight, vascualr endothelial growth factors and COX-2 immunohistochemistry. The rats being tested were all 22 days old and were divided into four equal groups;

'''Group 1 (Control group)''' was subject to a 0.1 ml of Intraperitoneal Saline from days 22 ~ 26

'''Group 2 (Mildly-stimulated group)''' subject to 10IU of pregnant mare serum gonadotrophin (PMSG) on day 24 and then 10IU of Human Chorionic Gonadotrophin (hCG) on day 26

'''Group 3 (OHSS positive group)''' was subject to 10IU of PMSG from days 22 ~ 26 and then administered 30IU of hCG on day 26 to induce OHSS

'''Group 4 (OHSS positive variant group)''' received 15mg/ml of Meloxicam 2 hours prior to administration of 10IU PMSG from days 22 ~ 26

Results showed there was no difference in ovarian weight in samples from Group 1 and Group 2, however Group 3 showed signs of significant ovarian weight increase which in group 4 was suppressed by the introduction of Meloxicam. No differences were observed in the number of antral follicles amongst the four test groups. Results from Group 2 and Group 3 showed that the granulosa cells of preovulatory follicles and the stromal cells were highly VEGF immunoreactive, however the Meloxicam treated Group 4 showed less immunoreactivity than Group 2 and Group 3 which indicated the correlation between Meloxicam and the diminished VEGF expression. Group 3 presented an increased COS-2 immunoreactivity which was highly diminished than in Group 4.

The research concluded that in a rat model, the enzyme Meloxicam has a beneficial effect on OHSS by reducing the increase of ovarian weight and the expression of VEGF associated with OHSS, the effects of which may be mediated by the inhibitory capacity of COX-2 on Meloxicam
|}

{|
|-bgcolor="FF99FF"
|
<span style="font-size:120%">'''Inhibition of Ovarian VEGF secretion by activation of Dopamine Receptor 2'''</span> <ref name="PMID25217874"><pubmed>25217874</pubmed></ref>

This research was carried out to investigate a possibility in whether a Dopamine Receptor 2 agonist '''(D2-ag)''' can assist in the prevention of Ovarian Hyperstimulation Syndrome, using rat models, by decreasing the ovarian vascular endothelial growth factor '''(VEGF)''' production. Using Immature Wistar rats (22 days old) as their animal model, the rats were initially stimulated with Gonadotrophins to mimic the onset and effects of OHSS and then subjected to treatment with a D2-agonist and/or a D2-antagonist (D2-ant). The vascular permeability was measured at the endpoint after day 26 by measuring the peritoneal extravasion of a previously injected dye and ovaries from all subjects were collected to assess the effects of D2-ag and D2-ant on the production of Ovarian VEGF. The expression of VEGF mRNA was measured by quantitative real time PCR and the levels of VEGF proteins were measured by Western Blots.

Results showed that the D2-ag caused a large reduction in the vascular permeability which was in turn associated with the great decreased in VEGF protein production in the OHSS rat ovaries, whereas the introduction of D2-ant showed opposite results with a increase in the vascular permeability leading to the increase of VEGF protein production in the ovaries. Ovarian VEGF mRNA levels were found to be unaffected by the introduction of these drugs in OHSS rat subjects. Conclusions were drawn on the fact that Dopamine Receptor 2 agonists prevent the increase of vascular permeability in subjects with OHSS by decreasing the ovarian production of VEGF and also that due to the dose-dependent inhibitory effect of the D2-ag on ovarian VEGF, current OHSS therapies used in humans can benefit by increasing the intraovarian concentration of D2-ag.
|}
</div>

==Glossary==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

'''Ascites''' - An accumulation of fluid in the peritoneal cavity with resultant abdominal swelling.

'''Cabergoline''' - A dopamine receptor agonist used to treat hormone imbalance.

'''Controlled Ovarian Stimulation''' - female infertility treatment using medications to stimulate the ovaries to develop follicles.

'''Gonadotropin''' - Any hormone that has a stimulating effect on the gonads.

'''GnRH antagonist''' - Gonadotropin Releasing Hormone - A class of compounds that are similar in terms of the structure of natural Gonadotropin Releasing Hormone but has a antagonistic effect.

'''hCG'''- Human Chorionic Gonadotropin

'''Hemoconcentration''' - An increase in the concentration of circulating red blood cells in response to a decrease in blood plasma volume.

'''Hypovolemic''' - A decrease in circulating blood volume.

'''Iatrogenic'''- Illness caused as a result of a medical examination or treatment.

'''Intravenous fluids''' - Is the infusion of liquid substances directly into a vein.

'''IVF'''- In-vitro Fertilization

'''NSAID'''- Non-steroidal Anti-Inflammatory Drug e.g. Ibuprofen

'''OHSS'''- Ovarian Hyper-stimulation Syndrome

'''PCOS'''- Polycystic Ovarian Syndrome. An endrocrine system disorder whereby the ovaries are enlarged with small collections of fluid.

'''FSH''' - Follicle Stimulating Hormone

'''LH''' - Luteinizing Hormone

'''Oliguria'''- Decreased urine output/small amounts of urine produced.

</div>

==References==

2015 Group Project 2

2015-10-22T22:17:01Z

Z3372824: /* Prevention */

{{ANAT2341Project2015header}}

==<span style="font-size:120%">'''Ovarian Hyper-stimulation Syndrome (OHSS)'''</span>==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

Ovarian Hyper stimulation Syndrome (OHSS) is an iatrogenic complication of '''Assisted Reproduction Technology''' (ART), in which women take medications to stimulate oocyte growth. It is generally identified by cystic enlargements of the ovaries and fluid accumulation in the peritoneal cavity due to the increased capillary permeability and ovarian neoangiogenesis <ref name="PMID22065820"><pubmed>22065820</pubmed></ref>. It is an occurrence which is dependent on the controlled stimulation of the ovaries in preparation for IVF i.e. administration of human Chorionic Gonadotropin (hCG).

OHSS was first described in 1943 as ''“syndrome d’hyperluteinisation massive
des ovaries”''. It was during this time that gonadotropins were prepared from animals such as sheep to bring on ovulation in women. The first recorded death as a result of OHSS occurred in 1951 and was due to renal failure as a result of oligouria, a complication of the syndrome <ref name="OHSS"> Marie M. Budev, DO, MPH; Alejandro C. Arroliga, MD; Tommaso Falcone, MD, [ http://utilis.net/Morning%20Topics/REI/Ovarian%20Hyperstimulation.pdf ], 'Ovarian Hyperstimulation Syndrome'</ref> <ref name="PMID12638783"><pubmed>12638783</pubmed></ref>.

<span style="color:#FA58D0">This wikipage aims to provide clear information on various areas surrounding OHSS such as diagnosis, prevention and complications and will look into the genetics behind the disorder and the various animals models used to research it.</span>

<html5media height="350" width="450">https://www.youtube.com/watch?v=aXmjJw234a4</html5media>

'''Overview of the Ovarian Hyperstimulation Syndrome''' <ref> Howcast (2013, August 27) Ovarian Hyperstimulation Syndrome | Infertility. Retrieved from https://www.youtube.com/watch?v=aXmjJw234a4</ref>

</div>

==Epidemiology==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

Ovarian Hyper-Stimulation Syndrome (OHSS) rarely occurs sporadically, and if it does, it is usually the result of an underlying genetic problem. The majority of OHSS is due to the ovaries being stimulated to mature and release an abundance of oocytes, in response to hormones Human Chorionic Gonadotropin (hCG) and Follicle Stimulating hormone (FSH), during IVF. Rarely, Clomifene Citrate therapy can cause OHSS.<ref name="WikiOHSS"> Wikipedia, [ https://en.wikipedia.org/wiki/Ovarian_hyperstimulation_syndrome ], 'Ovarian Hyperstimulation Syndrome'</ref>

OHSS only affects '''0.5-5%''' of women undergoing Ovarian Hyper-stimulation, but despite its small prevalence, it is a potentially fatal outcome of a non-vital procedure and remains a prevalent problem for fertility specialists <ref name="PMID12498425"><pubmed>12498425</pubmed></ref> <ref name="PMID12638783"><pubmed>12638783</pubmed></ref>. Age has been cited as a factor affecting those with OHSS, with younger women more at risk. Additionally, women with allergies were seen to have a higher incidence of OHSS. It is important to note that at this point in time, there is no positive correlation between gonadotropin dose and OHSS.

Of the 0.5-5% of women affected with OHSS mentioned above, 2% of those women will require hospitalisation. As of 2011, it has been reported that the incidence of OHSS was '''increasing''', resulting in approximately 3 deaths per 100,000 women undergoing ovarian stimulation per year <ref name="PMID21828116"><pubmed>21828116</pubmed></ref>. This is particularly worrying as in 2008, in the United States alone, there were around 150,000 IVF cycles undertaken.

{|
|-bgcolor="F8E0F1"
|
'''With the field of Assisted Reproductive Technologies expanding and more women partaking in IVF treatments, the threat of women developing OHSS is an ongoing and increasing one''' <ref name="PMID21828116" />.
|}
{| class="wikitable mw-collapsible mw-collapsed"
! Characteristics of women by complication group <ref name="PMID19591989"><pubmed>19591989</pubmed></ref>
|-
! scope="col" width="100px" height="60px" style="text-align:center| '''Characteristic'''
! scope="col" width="100px" height="60px" style="text-align:center| '''No Complications
(N = 212,041)'''
! scope="col" width="100px" height="60px" style="text-align:center| '''Moderate OHSS
(N = 1,523)'''
! scope="col" width="100px" height="60px" style="text-align:center| '''Severe OHSS
(N = 655)'''
|-
|style="text-align:center; background: #FF99FF;"| '''Maternal Age (Mean ± SD)'''
|style="text-align:center; background: #F6CEEC;"| 35.6 ± 4.6
|style="text-align:center; background: #F6CEEC;"| 33.0 ± 4.3
|style="text-align:center; background: #F6CEEC;"| 33.1 ± 4.4
|-
|style="text-align:center; background: #FF99FF;"| '''Maternal Age (%)'''
|-
|style="text-align:left; background: #F6CEEC;"| <30 years
|style="text-align:center; background: #F6CEEC;"| 10 %
|style="text-align:center; background: #F6CEEC;"| 21.1 %
|style="text-align:center; background: #F6CEEC;"| 20.6 %
|-
|style="text-align:left; background: #F6CEEC;"| 30-34 years
|style="text-align:center; background: #F6CEEC;"| 30.4 %
|style="text-align:center; background: #F6CEEC;"| 43.2 %
|style="text-align:center; background: #F6CEEC;"| 40.5 %
|-
|style="text-align:left; background: #F6CEEC;"| 35-39 years
|style="text-align:center; background: #F6CEEC;"| 37.8 %
|style="text-align:center; background: #F6CEEC;"| 27.2 %
|style="text-align:center; background: #F6CEEC;"| 32.5 %
|-
|style="text-align:left; background: #F6CEEC;"| >40 years
|style="text-align:center; background: #F6CEEC;"| 21.8 %
|style="text-align:center; background: #F6CEEC;"| 8.4 %
|style="text-align:center; background: #F6CEEC;"| 6.4 %
|-
|style="text-align:center; background: #FF99FF;"| '''Nulligravida (%)'''
|style="text-align:center; background: #F6CEEC;"| 45.8 %
|style="text-align:center; background: #F6CEEC;"| 51.5 %
|style="text-align:center; background: #F6CEEC;"| 51.8 %
|-
|style="text-align:center; background: #FF99FF;"| '''Infertility Diagnosis (%)'''
|-
|style="text-align:left; background: #F6CEEC;"| Male factor
|style="text-align:center; background: #F6CEEC;"| 37.7 %
|style="text-align:center; background: #F6CEEC;"| 41.0 %
|style="text-align:center; background: #F6CEEC;"| 33.4 %
|-
|style="text-align:left; background: #F6CEEC;"| Endometriosis
|style="text-align:center; background: #F6CEEC;"| 13.5 %
|style="text-align:center; background: #F6CEEC;"| 13.5 %
|style="text-align:center; background: #F6CEEC;"| 10.7 %
|-
|style="text-align:left; background: #F6CEEC;"| Ovulation Disorders
|style="text-align:center; background: #F6CEEC;"| 14.0 %
|style="text-align:center; background: #F6CEEC;"| 29.5 %
|style="text-align:center; background: #F6CEEC;"| 22.4 %
|-
|style="text-align:left; background: #F6CEEC;"| Diminished ovarian reserve
|style="text-align:center; background: #F6CEEC;"| 16.9 %
|style="text-align:center; background: #F6CEEC;"| 3.2 %
|style="text-align:center; background: #F6CEEC;"| 2.4 %
|-
|style="text-align:left; background: #F6CEEC;"| Tubal factors
|style="text-align:center; background: #F6CEEC;"| 20.4 %
|style="text-align:center; background: #F6CEEC;"| 22.6 %
|style="text-align:center; background: #F6CEEC;"| 22.3 %
|-
|style="text-align:left; background: #F6CEEC;"| Uterine factors
|style="text-align:center; background: #F6CEEC;"| 5.1 %
|style="text-align:center; background: #F6CEEC;"| 4.3 %
|style="text-align:center; background: #F6CEEC;"| 3.1 %
|-
|style="text-align:left; background: #F6CEEC;"| Other factors
|style="text-align:center; background: #F6CEEC;"| 13.9 %
|style="text-align:center; background: #F6CEEC;"| 13.1 %
|style="text-align:center; background: #F6CEEC;"| 10.4 %
|-
|style="text-align:left; background: #F6CEEC;"| Unexplained factor
|style="text-align:center; background: #F6CEEC;"| 12.7 %
|style="text-align:center; background: #F6CEEC;"| 11.8 %
|style="text-align:center; background: #F6CEEC;"| 18.6 %
|-
|}
</div>

==Causative Agents==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

[[File:Follicular Development.jpeg|right|thumbnail|500px|Infertility treatments aim to facilitate follicular development and induce ovulation to improve chances of fertilisation <ref name="PMID24717179"><pubmed>24717179</pubmed></ref>]]

Normally a woman produces one egg per month from the ovaries, which travel down the Fallopian tube to be fertilized or be released from the body. In cases where women have difficulty falling pregnant, they are given medication which help them to produce and release eggs (as shown in the diagram to the right), further increasing their chances of fertilization and pregnancy <ref><pubmed>19573285</pubmed></ref>. Ovarian Hyper stimulation Syndrome generally occurs during infertility treatments when the ovaries are overstimulated by the fertility medication which causes the ovaries to swell and leak fluids into the belly and abdomen. The prevalence of OHSS onset is linked with excessive number of follicle development in response to the administration of injectable Follicle Stimulating Hormones (FSH) followed by the '''Human Chorionic Gonadotrophins''' (hCG) which triggers the release of the oocytes <ref><pubmed>26190539</pubmed></ref>.

'''Follicle Stimulating Hormones''' (FSH) <ref name="PMID9020850"><pubmed>9020850</pubmed></ref> are glycoprotein hormones that are produced and secreted from the Anterior Pituitary gland into the bloodstream, which regulate the developmental, growth, maturation and the reproductive processes within the body. In females, the Follicle Stimulating Hormones initiates the stages of growth and development of immature ovarian follicles within the ovaries before the release of an egg from a follicle at ovulation. When FSH is administered to a patient who is suffering from infertility, the increase FSH levels affect the rate of development and production, in turn increasing the amount of follicles which are ready to be released during ovulation.

</div>

==Symptoms==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

OHSS is classified based on a criteria from mild, moderate and severe <ref name="WikiOHSS" />:

'''Mild Symptoms'''- abdominal bloating, minimal weight gain, nausea, diarrhoea and a feeling of fullness.

'''Moderate Symptoms'''- Substantial weight gain (on average 2 or more pounds a day), increased abdominal girth, darkend urine and excessive thirst in addition to the mild symptoms.

'''Severe Symptoms'''- In addition to the symptoms associated with Mild and Moderate OHSS, in severe OHSS, you see shortness of breath, calf and chest pains and pleural effusion.

<span style="font-size:100%">'''Classifications of Ovarian Hyper-stimulation Syndrome:'''</span> <ref name="PMID22065820"><pubmed>22065820</pubmed></ref>
{| class="wikitable" style="text-align:center
|-
! scope="col" width="70px"| '''Classification'''
! scope="col" width="650px"| '''Symptoms'''
|-
|style="text-align:center; background: #F6CEEC;"| '''Mild'''
|style="height: 60px; background: #F6CEEC;"| '''Grade 1''' - Abdominal distention and discomfort
'''Grade 2''' - Abdominal distention, discomfort with nausea, vomiting and/or diarrhea and ovarian enlargement from 5~12cm
|-
|style="text-align:center; background: #F8E0F1;"| '''Moderate'''
|style="height: 60px; background: #F8E0F1;"| '''Grade 3''' - All features of Mild OHSS with ultrasonographic evidence of ascites
|-
|style="text-align:center; background: #F6CEEC;"| '''Severe'''
|style="height: 60px; background: #F6CEEC;"| '''Grade 4''' - All features of Moderate OHSS with the addition of clinical evidence of ascites and breathing difficulties present
'''Grade 5''' - All of the above symptoms along with a change in the blood volume, increased blood viscosity due to coagulation and diminished renal function
|}

</div>

==Diagnosis==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

Whilst symptoms of OHSS can occur as soon as 24 hours post hCG administration, they are usually seen in women 7-10 days post administration. Initially women with OHSS will present with abdominal bloating, as a result of fluid in the peritoneal cavity and an increase in ovary size. When women present with severe OHSS they are often dehydrated, due to increased vascular permeability, and have hemoconcentration. The above results in a decrease in intravascular volume, leading to '''oligouria''' <ref name="PMID22416285" />.

===History===

Initially a thorough history of the patient is taken during which the clinician looks for evidence of ovarian stimulation, followed by ovulation. During this history taking, the clinician will inquire into any weight gain noticed, urine output, and the woman's ability to maintain oral hydration. A key diagnostic tool for clinicians regarding women who are taking gonadotropins is to identify if they are at an increased risk of developing OHSS. Some risk factors include woman aged less than 30, women who have polycystic ovaries, woman with a previous history of OHSS and women who have had greater than 20 oocytes retrieved <ref name="PMID22416285" />.

===Physical Exam===
[[File:Vaginal_Ultrasonography_in_Sagittal_Plane.jpg|right|thumbnail|600px|Vaginal Ultrasonography in Sagittal plane <ref name="Wikiversity Journal of Medicine"> Häggström, Mikael. "Medical gallery of Mikael Häggström 2014". Wikiversity Journal of Medicine 1 (2). DOI:10.15347/wjm/2014.008. ISSN 20018762</ref>]]
After a history of the patient is taken, the next step is to perform a physical exam on the patient. Women who present with abdominal bloating will produce a shifting dullness upon abdominal percussion. Additionally the clinician will test the woman's vital signs, measure her abdominal girth, weight and will look for evidence of ascites or increase in calf size (usually unilateral)<ref name="PMID22416285" />.

===Investigations===

If the clinician further suspects a women of having OHSS, various investigations can be done such as an ultrasound.The intraperitoneal fluid is best imaged via vaginal ultrasound due to the enlarged ovaries making it difficult to image the pelvis using transabdominal ultrasound. The clinician can also order laboratory testing to look for urine specific gravity and and complete blood count to look for hemoconcentration with a hematocrit. Additionally, liver function tests can be ordered to look for elevated function. The clinician will also look for evidence of elevated D-dimers and fibrinogen and decreased levels of anti-thrombin 3 <ref name="SAHealth"> Government of South Australia Health [ http://www.sahealth.sa.gov.au/wps/wcm/connect/9b61ed004ee5348da663afd150ce4f37/Ovarian-hyperstimulation-syndrome-WCHN-PPG-17072012.pdf?MOD=AJPERES&CACHEID=9b61ed004ee5348da663afd150ce4f37 ], 'South Australian Paediatric Clinical Guidelines OHSS'</ref>.

====Ultrasound====

Typical appearances of the ultrasound include <ref name="Ultrasound"> Radiopaedia [ http://radiopaedia.org/articles/ovarian-hyperstimulation-syndrome-1 ], 'Ovarian Hyperstimulation Syndrome'</ref>:

*Bilaterally and symmetrically enlarged ovaries (>12cm)
* "Spoke-Wheel appearance" - presence of multiple cysts of varying size
*May also see ascites (fluid)

===Severity===

Once a clinician has deduced a women is suffering from OHSS, the severity of their condition needs to be established as either mild, moderate or severe. This is done by referring to the criteria under the sub-heading [[Symptoms]].The subsequent course of treatment for the woman will be based upon this evaluation.

{|
|-bgcolor="F6CEEC"
|
'''Further investigations''' can be done including a Chest X-ray to check for pleural effusions and oedema and USS with Doppler's to check for ascites or possible ovary torsion. <ref name="PMID22416285"><pubmed>22416285</pubmed></ref>
|}

===Differential Diagnosis===

Conditions presenting with similar symptoms or ultrasound images include <ref name="Ultrasound" />:

*Polycystic Ovaries (PO)
:: The difference is that with PO is that the cycts are typically smaller than OHSS cysts and there is no evidence of ascited or pleural effusion
*Mucinous Ovarian Malignancy
:: A type of Ovarian Epithelial tumour
*Ectopic Pregnancy <ref name="Casereport"> Australian Medical Student Journal [ http://www.amsj.org/wpcontent/uploads/files/articles/amsj_v2_i1/AMSJ_v2_i1_pg58-60.pdf ], 'Ovarian hyperstimulation syndrome'</ref>
::A pregnancy in which the foetus develops outside of the uterus e.g. in the fallopian tube

</div>

==Pathophysiology==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

[[File:Pathogenesis_of_OHSS.png|600px|thumb|Pathogenesis of OHSS <ref name="PMID20416867"><pubmed>20416867</pubmed></ref>]]

The definition of Ovarian Stimulation is enlarged ovaries with many luteinized cysts, that can present with secondary complications. What distinguishes Ovarian Stimulation from OHSS is the presence of vascular hyper-permeability that results in fluids being redirected elsewhere in the body.

The key process to OHSS appears to be caused by '''Vascular Endothelial Growth Factor''' (VEGF), that is released along with other cytokines, estrogen and progesterone, due to the ovary undergoing luteinization as a result of stimulation by hCG. VEGF increases vascular permeability and as a result the capillaries become more "leaky" to the fluids in them. These fluids can then escape the capillaries and accumulate in the pleural and abdominal cavities as ascites. The woman then becomes hypovolemic and is at an increased risk of circulatory, renal and respiratory issues such as arterial thromboembolism due to the thickening of the blood. Note, the blood is thickened as fluid is leaving the capillaries, leaving behind red blood cells and other cellular components of the blood <ref name="WikiOHSS" />.

The increase in expression of VEGF and VEGF Receptor 2 (VEGFR2) is attributed to the greatly increased amount of their mRNA present in the body after stimulation with hCG <ref name="PMID21082502"><pubmed>21082502</pubmed></ref>. VEGF interacts with VEGF2 and VEGF Receptor 1 (VEGFR1) to create a strong angiogenic effect. Both VEGFR2 and VEGFR1 belong to a family of receptors called tyrosine kinases. VEGF2 is involved in the regulation of angiogenesis and vascular permeability whilst VEGF1 has a slightly contradictory role in that is is involved in the maintenance of the tight junctions between endothelial cells in blood vessels. A study by Gómez ''et. al.'' <ref name="PMID21082502" /> showed that women experiencing OHSS had substantially higher plasma levels of VEGF and lower levels of VEGFR1.

</div>

==Complications==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

Ovarian torsion or rupture, renal insufficiency and thrombophlebitis can all complicate OHSS. If a pregnancy occurs, symptoms may persist longer than the usual 1 to 2 weeks and become more severe, however, even with severe OHSS, they do not extend past the first trimester <ref name="WikiOHSS" />.

<span style="color:#FA58D0"> '''1-2% of women who undergo ovarian stimulation develop a severe form of OHSS''' </span>. Complications from severe OHSS include:

*Fluid collection in the abdomen
*Electrolyte disturbances (sodium and potassium)
*Kidney failure
*Ovary twisting
*Rupture of a cyst in an ovary
*Breathing problems
*Blood clots in large vessels (most commonly the legs)
*Pregnancy loss from miscarriage or termination
*Rarely, death

A study by Nouri ''et. al.'' <ref name="PMID24996451"><pubmed>24996451</pubmed></ref> found that women with '''Polycystic Ovarian Syndrome''' (PCOS) and those that were induced with hCG experienced longer recovery times from severe OHSS than women who were not pregnant. They looked at a cohort of women hospitalised for the first time with severe OHSS and subject them to the same treatments. Based on a defined criteria, they established the recovery time of these women and compared the times between those that were pregnant to those that were not pregnant. They also found that whether a woman had PCOS or ovulation induction did not affect her risk of developing OHSS if she was not pregnant. It is only a risk factor for pregnant women.

===Thromboembolic events===

A frequent and deadly complication of OHSS are thromboembolic events due to increased blood clotting. This increase in blood clotting has been attributed to a variety of complications such as hemoconcentration (which thickens the blood), hypovolemia and an increase in the permeability of blood vessels as a result of increased vasoactive substances in the body of ovarian origin. Thromboembolic events include venous thromboses often in the upper extremities and arterial thromboses such as those in the cerebrovascular region. These events can lead to amputations of extremities, brain damage, miscarriage and death. To avoid this, anti-coagulants are given to pateitns with OHSS and they are fitted with compression stockings (see [[Treatment]]) <ref name="PMID23378404"><pubmed>23378404</pubmed></ref>.

{|
|-bgcolor="F8E0F1"
|
The risk of a woman developing OHSS is higher if she is having a '''twin pregnancy''', as she is exposed to higher concentration of hCG. <ref name="PMID9756273"><pubmed>9756273</pubmed></ref>
|}

</div>

==Treatment==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

'''General treatment
'''
*''Acetaminophen'' with or without a narcotic agent- used to treat abdominal discomfort
*Women are encouraged to drink 2-3 litres of water a day to prevent hemoconcentration
*Women are advised to avoid sexual intercourse and vigorous exercise at the risk of torsion or rupture of the ovaries
*NSAID's with anti-platelet properties should NOT be used as they may effect renal function in a women with OHSS
*Patients with significantly painful ascites or breathing problems may undergo ''Paracentesis'' (drainage of the ascites)
*''Culdocentesis'' (extraction of fluid from recto-uterine pouch) can be done to decrease the likelihood of a woman with moderate OHSS progressing to severe OHSS.<ref name="PMID22416285" />

===Mild to Moderate OHSS===

Mild OHSS can often resolve on its own, however, moderate OHSS may include treatments such as<ref name="WikiOHSS" />:

*Anti-nausea medication and prescription painkillers
*Regular physical examinations and ultrasounds
*Daily weigh-ins and waist measurements
*Measuring the amount of urine produced each day
*Frequent blood tests for monitoring dehydration and electrolyte imbalance
*Maintaining a high balance of fluids
*Drainage of excess abdominal fluid by inserting a needle in the abdominal cavity
*Wearing support stockings which help prevent blood clots/thrombosis

===Severe OHSS===

Severe OHSS requires hospital care in order for constant monitoring and treatment such as <ref name="WikiOHSS" />:

*Intravenous fluids with a crystalloid solution (100-150mL/hr)
*Intravenous Albumin is administered is IV fluids are insufficient (15-20mL/hr of 25% albumin for 4 hrs)
*In addition to Acetaminophen, ''Opioid analgesics'' can be administered for pain relief
*''Antiemetics'' can be used to subside nauseas and/or vomiting
*Woman administered to hospital of OHSS are considered at high risk of thromboembolic complications and are given low molecular weight ''heparin'', an anti-coagulant
*''Cabergoline''- lessens OHSS symptoms
*''GnRH agonist''- suppresses ovarian activity
**If at risk of OHSS, alternates include using a GnRH agonist instead of hCG however its effects on pregnancy rates are questionable. Using a GnRH agonist to replace the use of hCG for final oocyte stimulation will see a 6% decrease in delivery rate.

*Daily monitoring of creatine, urea, creatine clearance C-reactive protein (to rule out infection) are all required in combination with weekly tests such as liver and renal function tests and chest x-rays (to check for pleural effusion) <ref name="PMID12638783" />.

If there are serious complications then additional treatments are required:

*Surgery for a ruptured ovarian cyst
*Intensive care for the liver or lung complications

====Paracentesis====

For women with severe/grade 3 OHSS, paracentesis, the removal of fluid from the body using an aspiration needle, can be undertaken. It is a diagnostic and a therapeutic method that can be done trans-abdominally and trans-vaginally. It is used to relieve symptoms, improve haemodynamics e.g. Urinary output, and shorten the women's hospital stay. Complications of paracentesis include bleeding, infection and organ injury, however are note common <ref name="Paracentesis"> S. Monica Soni, HMS 3, Gillian Lieberman, MD [ http://eradiology.bidmc.harvard.edu/LearningLab/genito/Soni.pdf ], 'Ovarian Hyperstimulation Syndrome'</ref>.

{|
|-bgcolor="F8E0F1"
|
The most important aspect of treatment for any women with OHSS is close and constant '''monitoring''' with her healthcare professional. Counselling may also be provided to women and their partners or families in order to provide them with the best possible knowledge base to manage and treat their OHSS. It is important to note that there is '''no one cure or treatment''' for OHSS. Treatment involves managing and eliminating the symptoms until such time as the syndrome resolves itself <ref name="WikiOHSS" />.
|}

</div>

==Prevention==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

There are three key avenues through which the incidence of OHSS may be prevented. These include identifying risk factors to predict OHSS development, modifying treatment regimes on the basis of the identified risk factors and intervention to prevent progression to OHSS once the patient has undergone '''Controlled Ovarian Stimulation''' (COS).

=== Risk factors===

'''Primary risk factors'''

Pre-existing factors likely to exacerbate the ovarian stimulation response. Primary risk factors include <ref name="PMID26074966"><pubmed>26074966</pubmed></ref>:

*Young age
*Low body weight
*History of elevated response to gonadotropins
*Polycystic Ovary Syndrome (PCOS)
*Isolated PCOS characteristic
*A previous history of OHSS.
*Hormonal markers (e.g. Anti-Mullerian Hormone markers)
*Ultrasonographic markers (e.g. Antral Follicle Count)

'''Secondary risk factors'''

Secondary risk factors involve the monitoring of ovarian response parameters once COS has been initiated. These parameters are monitored for <ref name="PMID19007627"><pubmed>19007627</pubmed></ref>:

*rapidly rising E2 levels
*E2 concentration larger than 2500 pg/mL
*large number of developing follicles (10-14mm) on the day hCG is administered
*large number of oocytes retrieved

These factors in combination, act as a predictive tool to assess the likelihood of severe OHSS development, with a 83% sensitivity and 84% specificity. <ref name="PMID19007627"/>

=== Primary Prevention===

Primary Prevention involves the modification of treatment regimens on the basis of OHSS risk classifications, in order to prevent OHSS occurrence.

'''Ovulation Induction'''

Unifollicular Ovulation Induction through Ovulation Induction (OI) is a primary means of avoiding OHSS in women with Polycystic Ovarian Syndrome, who are at an increased risk. In order to promote unifollicular development, the ovaries are stimulated with a low starting dose of FSH (75 IU).<ref name="PMID20416867"><pubmed>20416867</pubmed></ref> Studies suggests that a minimum gonadotropin dose lowers OHSS risk and thus a step-up regimen is utilised to achieve an ovarian response, whereby the FSH dosage is increased every 7 days until follicular development of greater than 10mm is noted.<ref name="PMID26074966" /> Alternatively, a step-down regimen may be followed, whereby a high initial FSH dosage is lowered according to the ovarian response. Another method to increase FSH levels during OI, is through Aromatase Inhibitors which promote folliculogenesis by increasing pituitary secretion of FSH, and downregulate oestrogen production through a negative feedback loop. However, Aromatase Inhibitors have not been shown to reduce OHSS incidence in comparison to other methods of OI.<ref name="PMID26074966" /> During OI, a key objective is to prevent early cycle cancellation due to premature luteinisation from pituitary secretion of LH. In order to downregulate LH secretion, Gonadotropin-releasing hormone agonists (GnRHa) are administered in addition to gonadotropins. Alternatively, GnRH antagonists may be administered to downregulate endogenous LH secretion. Comparative studies have shown that the GnRH antagonist protocol has a greater effect in lowering the incidence of mild to severe OHSS. However due to the rare nature of OHSS, and insufficient sample sizes, the difference was not found to be significant. <ref name="PMID21082508"><pubmed>21082508</pubmed></ref>. Generally, the duration of exposure to gonadotropins and subsequent risk of OHSS may be minimised through mild stimulation protocols which administer FSH only in the mid to late follicular phase.<ref name="PMID20416867" />

'''Adjuvant Metformin Therapy'''

Adjuvant Metformin Therapy has been found to lower the risk of OHSS by 63%.<ref name="PMID25406011"><pubmed>25406011</pubmed></ref> It involves the administration of metformin at a daily dosage of 1000 to 2000mg, 2 months prior to Controlled Ovarian Stimulation <ref name="PMID26074966"/>. Metformin lowers the elevated insulin levels in PCOS which consequently reduce intraovarian androgen levels. This leads to a reduced sensitivity and expression of granulosa cell-follicle stimulating hormone receptors which result in a less exaggerated response to gonadotropins. Furthermore, it is suggested that Metformin prevents OHSS by controlling vascular permeability through the inhibition of various vasoactive molecules, including VEGF.

'''Avoiding hCG during Luteal Phase Support

Following Controlled Ovarian Stimulation, the steroid levels of E2 and P4 are reduced during the luteal phase due to the negative feedback on the pituitary. This leads to low endogenous LH levels, which consequently reduce endometrial receptivity as well as the luteal phase duration itself. As a result, implantation and pregnancy rates are reduced and early pregnancy loss rates are increased.<ref name="PMID20416867" /> Luteal Phase Support (LPS) serves to combat these adverse events with the use of hCG. However, hCG has been found to increase the risk of OHSS. Alternatively, the use of progesterone has been found to not only halve the risk of OHSS, but also induce similar improvements in pregnancy and miscarriage rates as hCG.<ref name="PMID26148507"><pubmed>26148507</pubmed></ref>

===Secondary Prevention===

Secondary Prevention aims to prevent progression to OHSS once COS has been initiated and the patient has been found to mount an exaggerated response. <ref name="PMID20416867" />

'''Coasting'''

Coasting is a first-line secondary preventative strategy. It consists of the withdrawal of gonadotrophins when a critical number of follicles and/or E2 concentration is reached. hCG is administered once the E2 concentration reduces to a safe level, before the process of oocyte retrieval commences. This preventative strategy is conducted for a period of less than 3 days in order to avoid compromising IVF outcomes.

'''Cryopreservation'''

Cryopreservation of embryos after oocyte retrieval is another avenue which may avert OHSS progression. The cryopreserved embryos are only reimplanted once the patient's hormone serum levels have normalised. Using oocyte vitrification, crystal formation within embryo tissue is avoided and so cryopreserved embryos have been found to produce better pregnancy rates with a 32% increase, than fresh embryo transfer. Recent studies suggest cryopreservation itself does not reduce OHSS rates, but must be followed by a GnRHa trigger to avert OHSS.

'''Cycle cancellation'''

Cycle cancellation is a guaranteed method to prevent early OHSS whereby hCG is withheld. This is a last resort strategy as it carries the risk of significant psychological distress and financial loss for the patient.

</div>

==Effect on the Newborn==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

</div>
Women who develop OHSS while undergoing Assisted Reproductive Technologies (ART) treatment are not only more likely to achieve a pregnancy, but have a live birth as the pregnancy outcome. This live birth is also more likely to be a multiple birth of two, three or more children. <ref name="PMID19591989"><pubmed>19591989</pubmed></ref> It has been postulated that a multifetal pregnancy leads to a more rapid increase in hCG levels, resulting in an increased risk of OHSS. However, the causal nature between multifetal pregnancy and OHSS development is disputed and further research is required to distinguish correlation from causation. <ref name="PMID19573292"><pubmed>19573292</pubmed></ref>

OHSS development is also associated with an increased risk of adverse outcomes including stillbirth, premature birth and low birthweight.<ref name="PMID19591989" /> Although the cause for the increased risk in adverse pregnancy outcomes is unknown, it is suggested that as the incidence of OHSS is reduced through various prevention strategies, the risk of such outcomes may be also be reduced.

==Genetics==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

Despite OHSS typically being of iatrogenic origin as a result of ovarian stimulation with gonadotropins, research has been conducted into the potential genetics behind OHSS as many sporadic and familial cases have been observed. '''Mutations''' in the receptor for hormones such as Follicle Simulating Hormone (FSH), Lutenizing Hormone (LH) and hCG have all been targets of OHSS genetics research. Interestingly, they too also arise from a common ancestral gene.

===Follicle Stimulating Hormome===

Dr. Botros Rizk, of the University of South Alabama College of Medicine <ref name="PMID19573286"><pubmed>19573286</pubmed></ref>, has written extensively regarding the genetics behind OHSS. In particular, he talks about '''FSH receptors''' (FSHR) and their role in the syndrome. He hypothesises that mutations in these receptors could be activating or inactivating, leading to an increased risk of developing OHSS or sterility respectively. Currently, 744 single nucleotide polymorphisms (a type of mutation) have been found in the gene encoding the FSHR, 8 of which are located in its exons (coding regions of the gene). How the ovary responds is resultant on the FSHR genotype. For example, Ser680Asn, a polymorphism in the FSHR gene has been shown to aid in predicting the severity of a woman's OHSS. Ordinarily FSH stimulates the growth of ovarian follicles, however, when mutated, it is stimulated by the hCG resulting in excessive follicle development.

Spontaneous OHSS, OHSS that arises and cannot be attributed to any form of ovarian stimulation or Assisted Reproductive Technology, has been linked to activating mutations in the FSHR <ref name="PMID23499866"><pubmed>23499866</pubmed></ref>. This familial disorder is an autosomal dominant one. In most cases the FSHR can be stimulated by the presence of Thyroid Stimulating Hormone (TSH) or hCG, in the absence of FSH (the ligand for FSHR).

===Lutenizing Hormome===

The '''Lutenizing Hormone Receptor''' (LHR) gene in humans is comprised of 11 exons. Animal studies have shown that many primates exhibit a similar gene which is comprised of only 10 exons, however a gene lacking the 10th exon has been identified and termed the type 2 LHR. Expression of the type 2 LHR has been seen in humans. The type 2 LHR, compared to the wild-type LHR appears to be repaired with regard to its function. Defects in the type 2 LHR include a decrease in efficiency of transport to the plasma membrane and irregularities in signal transduction. Inactivating mutations in the LHR have been seen to cause infertility in women as well as amenorrhoea. Activating LHR gene mutations are asymptomatic and are not associated with OHSS in women.

===Bone Morphogenic Protein===

An imporant growth factor, derived from oocytes called '''BMP-15''' (Bone Morphogenic Protein 15) is vital for female fertility. It belongs to the family of growth factors, Transforming Growth Factor β (TGF-β) and is heavily involved in folliculogenesis. It has been found that mutations in the BMP-15 gene caused infertility in female sheep. Conversely, it has also been indicated in enhanced fertility when BMP-15 is present is high amounts in follicular fluid <ref name="PMID19573286" />.

A case study done by Hanevik ''et. al.'' in 2013 <ref name="PMID21565556"><pubmed>21565556</pubmed></ref> found that a Single Nuclear Polymorphism (SNP) in the BMP-15 gene is responsible for a high response to ovarian hyper-stimulation. The aim of the study was to test the effect the SNP had on BMP-15 with regard to high and low responders buy taking blood from 53 high responders, 38 low responders and 100 non-responders (controls) and analysing 5 noted SNP's. Results from their study showed a correlation between a high response to ovarian hyper-stimulation and the BMP-15 9G allele. The article does state however, that further research is required into the molecular effects of SNP's on the function of BMP-15.

===Vascular Endothelial Growth Factor===

'''Vascular endothelial growth factor''' (VEGF) has been indicated as one of the key agents causing vascular permeability and subsequent ascites in OHSS. The gene, which is located on chromosome 12, is made up of 8 exons (coding regions), of which exons 6 and 7 do not always appear due to the exons being spliced out.The splicing of this gene allows for various isoforms of the gene to exist of which VEGF 121 and 165 appear to play a role in angiogenesis. There are two VEGF Receptors, VEGFR-1 and VEGFR-2 that belong to the tyrosine kinase family of receptors (for more information on VEGF see [[Pathophysiology]]). Because of its distinct role in OHSS, it has been targeted as an area for research for potential treatments. The idea is that if the genetic expression of VEGF and its receptors can be controlled, OHSS can be avoided or treated.<ref name="PMID19573286" />

A different study by Hanevik ''et. al.'' , <ref name="PMID22587628"><pubmed>22587628</pubmed></ref> done in 2012 involved analysing blood samples from 53 women with OHSS and 100 women without it (controls) and analysing 6 SNP's in the VEGFR2 gene to find any genetic variations. They found a correlation between women with the VEGF +405cc genotype and the development of OHSS indicating women that undergo controlled ovarian hyper-stimulation and posses his genotype, are at an increased risk of developing OHSS.

</div>

== Current Research on Animal Models==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">
{|
|-bgcolor="F8E0F1"
|
<span style="font-size:120%">'''Inhibition of Cyclooxygenase-2 (COX-2) by Meloxican decreasing the incidence of OHSS in Rat Model'''</span> <ref name="PMID18166186"><pubmed>18166186</pubmed></ref>

Reasearch was carried out to investigate the effects of selective inhibition of the enzyme COX-2 on the Ovarian Hyperstimulation Syndrome (OHSS) using Female Wistar rates as the subjects. The research aimed to find results by measuring the number of antral and luteinized follicles, ovarian weight, vascualr endothelial growth factors and COX-2 immunohistochemistry. The rats being tested were all 22 days old and were divided into four equal groups;

'''Group 1 (Control group)''' was subject to a 0.1 ml of Intraperitoneal Saline from days 22 ~ 26

'''Group 2 (Mildly-stimulated group)''' subject to 10IU of pregnant mare serum gonadotrophin (PMSG) on day 24 and then 10IU of Human Chorionic Gonadotrophin (hCG) on day 26

'''Group 3 (OHSS positive group)''' was subject to 10IU of PMSG from days 22 ~ 26 and then administered 30IU of hCG on day 26 to induce OHSS

'''Group 4 (OHSS positive variant group)''' received 15mg/ml of Meloxicam 2 hours prior to administration of 10IU PMSG from days 22 ~ 26

Results showed there was no difference in ovarian weight in samples from Group 1 and Group 2, however Group 3 showed signs of significant ovarian weight increase which in group 4 was suppressed by the introduction of Meloxicam. No differences were observed in the number of antral follicles amongst the four test groups. Results from Group 2 and Group 3 showed that the granulosa cells of preovulatory follicles and the stromal cells were highly VEGF immunoreactive, however the Meloxicam treated Group 4 showed less immunoreactivity than Group 2 and Group 3 which indicated the correlation between Meloxicam and the diminished VEGF expression. Group 3 presented an increased COS-2 immunoreactivity which was highly diminished than in Group 4.

The research concluded that in a rat model, the enzyme Meloxicam has a beneficial effect on OHSS by reducing the increase of ovarian weight and the expression of VEGF associated with OHSS, the effects of which may be mediated by the inhibitory capacity of COX-2 on Meloxicam
|}

{|
|-bgcolor="FF99FF"
|
<span style="font-size:120%">'''Inhibition of Ovarian VEGF secretion by activation of Dopamine Receptor 2'''</span> <ref name="PMID25217874"><pubmed>25217874</pubmed></ref>

This research was carried out to investigate a possibility in whether a Dopamine Receptor 2 agonist '''(D2-ag)''' can assist in the prevention of Ovarian Hyperstimulation Syndrome, using rat models, by decreasing the ovarian vascular endothelial growth factor '''(VEGF)''' production. Using Immature Wistar rats (22 days old) as their animal model, the rats were initially stimulated with Gonadotrophins to mimic the onset and effects of OHSS and then subjected to treatment with a D2-agonist and/or a D2-antagonist (D2-ant). The vascular permeability was measured at the endpoint after day 26 by measuring the peritoneal extravasion of a previously injected dye and ovaries from all subjects were collected to assess the effects of D2-ag and D2-ant on the production of Ovarian VEGF. The expression of VEGF mRNA was measured by quantitative real time PCR and the levels of VEGF proteins were measured by Western Blots.

Results showed that the D2-ag caused a large reduction in the vascular permeability which was in turn associated with the great decreased in VEGF protein production in the OHSS rat ovaries, whereas the introduction of D2-ant showed opposite results with a increase in the vascular permeability leading to the increase of VEGF protein production in the ovaries. Ovarian VEGF mRNA levels were found to be unaffected by the introduction of these drugs in OHSS rat subjects. Conclusions were drawn on the fact that Dopamine Receptor 2 agonists prevent the increase of vascular permeability in subjects with OHSS by decreasing the ovarian production of VEGF and also that due to the dose-dependent inhibitory effect of the D2-ag on ovarian VEGF, current OHSS therapies used in humans can benefit by increasing the intraovarian concentration of D2-ag.
|}
</div>

==Glossary==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

'''Ascites'''- An accumulation of fluid in the peritoneal cavity with resultant abdominal swelling

'''Cabergoline''' - A dopamine receptor agonist used to treat hormone imbalance.

'''Controlled Ovarian Stimulation''' - female infertility treatment using medications to stimulate the ovaries to develop follicles

'''GnRH antagonist''' - Gonadotropin Releasing Hormone - A class of compounds that are similar in terms of the structure of natural Gonadotropin Releasing Hormone but has a antagonistic effect.

'''hCG'''- Human Chorionic Gonadotropin

'''Hemoconcentration'''- An increase in the concentration of circulating red blood cells in response to a decrease in blood plasma volume

'''Hypovolemic'''- A decrease in circulating blood volume

'''Iatrogenic'''- Illness caused as a result of a medical examination or treatment

'''Intravenous fluids''' - Is the infusion of liquid substances directly into a vein.

'''IVF'''- In-vitro Fertilization

'''NSAID'''- Non-steroidal Anti-Inflammatory Drug e.g. Ibuprofen

'''OHSS'''- Ovarian Hyper-stimulation Syndrome

'''FSH''' - Follicle Stimulating Hormone

'''LH''' - Luteinizing Hormone

'''Oliguria'''- Decreased urine output/small amounts of urine produced

</div>

==References==

2015 Group Project 2

2015-10-22T22:15:34Z

Z3372824: /* Glossary */

{{ANAT2341Project2015header}}

==<span style="font-size:120%">'''Ovarian Hyper-stimulation Syndrome (OHSS)'''</span>==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

Ovarian Hyper stimulation Syndrome (OHSS) is an iatrogenic complication of '''Assisted Reproduction Technology''' (ART), in which women take medications to stimulate oocyte growth. It is generally identified by cystic enlargements of the ovaries and fluid accumulation in the peritoneal cavity due to the increased capillary permeability and ovarian neoangiogenesis <ref name="PMID22065820"><pubmed>22065820</pubmed></ref>. It is an occurrence which is dependent on the controlled stimulation of the ovaries in preparation for IVF i.e. administration of human Chorionic Gonadotropin (hCG).

OHSS was first described in 1943 as ''“syndrome d’hyperluteinisation massive
des ovaries”''. It was during this time that gonadotropins were prepared from animals such as sheep to bring on ovulation in women. The first recorded death as a result of OHSS occurred in 1951 and was due to renal failure as a result of oligouria, a complication of the syndrome <ref name="OHSS"> Marie M. Budev, DO, MPH; Alejandro C. Arroliga, MD; Tommaso Falcone, MD, [ http://utilis.net/Morning%20Topics/REI/Ovarian%20Hyperstimulation.pdf ], 'Ovarian Hyperstimulation Syndrome'</ref> <ref name="PMID12638783"><pubmed>12638783</pubmed></ref>.

<span style="color:#FA58D0">This wikipage aims to provide clear information on various areas surrounding OHSS such as diagnosis, prevention and complications and will look into the genetics behind the disorder and the various animals models used to research it.</span>

<html5media height="350" width="450">https://www.youtube.com/watch?v=aXmjJw234a4</html5media>

'''Overview of the Ovarian Hyperstimulation Syndrome''' <ref> Howcast (2013, August 27) Ovarian Hyperstimulation Syndrome | Infertility. Retrieved from https://www.youtube.com/watch?v=aXmjJw234a4</ref>

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==Epidemiology==
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Ovarian Hyper-Stimulation Syndrome (OHSS) rarely occurs sporadically, and if it does, it is usually the result of an underlying genetic problem. The majority of OHSS is due to the ovaries being stimulated to mature and release an abundance of oocytes, in response to hormones Human Chorionic Gonadotropin (hCG) and Follicle Stimulating hormone (FSH), during IVF. Rarely, Clomifene Citrate therapy can cause OHSS.<ref name="WikiOHSS"> Wikipedia, [ https://en.wikipedia.org/wiki/Ovarian_hyperstimulation_syndrome ], 'Ovarian Hyperstimulation Syndrome'</ref>

OHSS only affects '''0.5-5%''' of women undergoing Ovarian Hyper-stimulation, but despite its small prevalence, it is a potentially fatal outcome of a non-vital procedure and remains a prevalent problem for fertility specialists <ref name="PMID12498425"><pubmed>12498425</pubmed></ref> <ref name="PMID12638783"><pubmed>12638783</pubmed></ref>. Age has been cited as a factor affecting those with OHSS, with younger women more at risk. Additionally, women with allergies were seen to have a higher incidence of OHSS. It is important to note that at this point in time, there is no positive correlation between gonadotropin dose and OHSS.

Of the 0.5-5% of women affected with OHSS mentioned above, 2% of those women will require hospitalisation. As of 2011, it has been reported that the incidence of OHSS was '''increasing''', resulting in approximately 3 deaths per 100,000 women undergoing ovarian stimulation per year <ref name="PMID21828116"><pubmed>21828116</pubmed></ref>. This is particularly worrying as in 2008, in the United States alone, there were around 150,000 IVF cycles undertaken.

{|
|-bgcolor="F8E0F1"
|
'''With the field of Assisted Reproductive Technologies expanding and more women partaking in IVF treatments, the threat of women developing OHSS is an ongoing and increasing one''' <ref name="PMID21828116" />.
|}
{| class="wikitable mw-collapsible mw-collapsed"
! Characteristics of women by complication group <ref name="PMID19591989"><pubmed>19591989</pubmed></ref>
|-
! scope="col" width="100px" height="60px" style="text-align:center| '''Characteristic'''
! scope="col" width="100px" height="60px" style="text-align:center| '''No Complications
(N = 212,041)'''
! scope="col" width="100px" height="60px" style="text-align:center| '''Moderate OHSS
(N = 1,523)'''
! scope="col" width="100px" height="60px" style="text-align:center| '''Severe OHSS
(N = 655)'''
|-
|style="text-align:center; background: #FF99FF;"| '''Maternal Age (Mean ± SD)'''
|style="text-align:center; background: #F6CEEC;"| 35.6 ± 4.6
|style="text-align:center; background: #F6CEEC;"| 33.0 ± 4.3
|style="text-align:center; background: #F6CEEC;"| 33.1 ± 4.4
|-
|style="text-align:center; background: #FF99FF;"| '''Maternal Age (%)'''
|-
|style="text-align:left; background: #F6CEEC;"| <30 years
|style="text-align:center; background: #F6CEEC;"| 10 %
|style="text-align:center; background: #F6CEEC;"| 21.1 %
|style="text-align:center; background: #F6CEEC;"| 20.6 %
|-
|style="text-align:left; background: #F6CEEC;"| 30-34 years
|style="text-align:center; background: #F6CEEC;"| 30.4 %
|style="text-align:center; background: #F6CEEC;"| 43.2 %
|style="text-align:center; background: #F6CEEC;"| 40.5 %
|-
|style="text-align:left; background: #F6CEEC;"| 35-39 years
|style="text-align:center; background: #F6CEEC;"| 37.8 %
|style="text-align:center; background: #F6CEEC;"| 27.2 %
|style="text-align:center; background: #F6CEEC;"| 32.5 %
|-
|style="text-align:left; background: #F6CEEC;"| >40 years
|style="text-align:center; background: #F6CEEC;"| 21.8 %
|style="text-align:center; background: #F6CEEC;"| 8.4 %
|style="text-align:center; background: #F6CEEC;"| 6.4 %
|-
|style="text-align:center; background: #FF99FF;"| '''Nulligravida (%)'''
|style="text-align:center; background: #F6CEEC;"| 45.8 %
|style="text-align:center; background: #F6CEEC;"| 51.5 %
|style="text-align:center; background: #F6CEEC;"| 51.8 %
|-
|style="text-align:center; background: #FF99FF;"| '''Infertility Diagnosis (%)'''
|-
|style="text-align:left; background: #F6CEEC;"| Male factor
|style="text-align:center; background: #F6CEEC;"| 37.7 %
|style="text-align:center; background: #F6CEEC;"| 41.0 %
|style="text-align:center; background: #F6CEEC;"| 33.4 %
|-
|style="text-align:left; background: #F6CEEC;"| Endometriosis
|style="text-align:center; background: #F6CEEC;"| 13.5 %
|style="text-align:center; background: #F6CEEC;"| 13.5 %
|style="text-align:center; background: #F6CEEC;"| 10.7 %
|-
|style="text-align:left; background: #F6CEEC;"| Ovulation Disorders
|style="text-align:center; background: #F6CEEC;"| 14.0 %
|style="text-align:center; background: #F6CEEC;"| 29.5 %
|style="text-align:center; background: #F6CEEC;"| 22.4 %
|-
|style="text-align:left; background: #F6CEEC;"| Diminished ovarian reserve
|style="text-align:center; background: #F6CEEC;"| 16.9 %
|style="text-align:center; background: #F6CEEC;"| 3.2 %
|style="text-align:center; background: #F6CEEC;"| 2.4 %
|-
|style="text-align:left; background: #F6CEEC;"| Tubal factors
|style="text-align:center; background: #F6CEEC;"| 20.4 %
|style="text-align:center; background: #F6CEEC;"| 22.6 %
|style="text-align:center; background: #F6CEEC;"| 22.3 %
|-
|style="text-align:left; background: #F6CEEC;"| Uterine factors
|style="text-align:center; background: #F6CEEC;"| 5.1 %
|style="text-align:center; background: #F6CEEC;"| 4.3 %
|style="text-align:center; background: #F6CEEC;"| 3.1 %
|-
|style="text-align:left; background: #F6CEEC;"| Other factors
|style="text-align:center; background: #F6CEEC;"| 13.9 %
|style="text-align:center; background: #F6CEEC;"| 13.1 %
|style="text-align:center; background: #F6CEEC;"| 10.4 %
|-
|style="text-align:left; background: #F6CEEC;"| Unexplained factor
|style="text-align:center; background: #F6CEEC;"| 12.7 %
|style="text-align:center; background: #F6CEEC;"| 11.8 %
|style="text-align:center; background: #F6CEEC;"| 18.6 %
|-
|}
</div>

==Causative Agents==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

[[File:Follicular Development.jpeg|right|thumbnail|500px|Infertility treatments aim to facilitate follicular development and induce ovulation to improve chances of fertilisation <ref name="PMID24717179"><pubmed>24717179</pubmed></ref>]]

Normally a woman produces one egg per month from the ovaries, which travel down the Fallopian tube to be fertilized or be released from the body. In cases where women have difficulty falling pregnant, they are given medication which help them to produce and release eggs (as shown in the diagram to the right), further increasing their chances of fertilization and pregnancy <ref><pubmed>19573285</pubmed></ref>. Ovarian Hyper stimulation Syndrome generally occurs during infertility treatments when the ovaries are overstimulated by the fertility medication which causes the ovaries to swell and leak fluids into the belly and abdomen. The prevalence of OHSS onset is linked with excessive number of follicle development in response to the administration of injectable Follicle Stimulating Hormones (FSH) followed by the '''Human Chorionic Gonadotrophins''' (hCG) which triggers the release of the oocytes <ref><pubmed>26190539</pubmed></ref>.

'''Follicle Stimulating Hormones''' (FSH) <ref name="PMID9020850"><pubmed>9020850</pubmed></ref> are glycoprotein hormones that are produced and secreted from the Anterior Pituitary gland into the bloodstream, which regulate the developmental, growth, maturation and the reproductive processes within the body. In females, the Follicle Stimulating Hormones initiates the stages of growth and development of immature ovarian follicles within the ovaries before the release of an egg from a follicle at ovulation. When FSH is administered to a patient who is suffering from infertility, the increase FSH levels affect the rate of development and production, in turn increasing the amount of follicles which are ready to be released during ovulation.

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==Symptoms==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

OHSS is classified based on a criteria from mild, moderate and severe <ref name="WikiOHSS" />:

'''Mild Symptoms'''- abdominal bloating, minimal weight gain, nausea, diarrhoea and a feeling of fullness.

'''Moderate Symptoms'''- Substantial weight gain (on average 2 or more pounds a day), increased abdominal girth, darkend urine and excessive thirst in addition to the mild symptoms.

'''Severe Symptoms'''- In addition to the symptoms associated with Mild and Moderate OHSS, in severe OHSS, you see shortness of breath, calf and chest pains and pleural effusion.

<span style="font-size:100%">'''Classifications of Ovarian Hyper-stimulation Syndrome:'''</span> <ref name="PMID22065820"><pubmed>22065820</pubmed></ref>
{| class="wikitable" style="text-align:center
|-
! scope="col" width="70px"| '''Classification'''
! scope="col" width="650px"| '''Symptoms'''
|-
|style="text-align:center; background: #F6CEEC;"| '''Mild'''
|style="height: 60px; background: #F6CEEC;"| '''Grade 1''' - Abdominal distention and discomfort
'''Grade 2''' - Abdominal distention, discomfort with nausea, vomiting and/or diarrhea and ovarian enlargement from 5~12cm
|-
|style="text-align:center; background: #F8E0F1;"| '''Moderate'''
|style="height: 60px; background: #F8E0F1;"| '''Grade 3''' - All features of Mild OHSS with ultrasonographic evidence of ascites
|-
|style="text-align:center; background: #F6CEEC;"| '''Severe'''
|style="height: 60px; background: #F6CEEC;"| '''Grade 4''' - All features of Moderate OHSS with the addition of clinical evidence of ascites and breathing difficulties present
'''Grade 5''' - All of the above symptoms along with a change in the blood volume, increased blood viscosity due to coagulation and diminished renal function
|}

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==Diagnosis==
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Whilst symptoms of OHSS can occur as soon as 24 hours post hCG administration, they are usually seen in women 7-10 days post administration. Initially women with OHSS will present with abdominal bloating, as a result of fluid in the peritoneal cavity and an increase in ovary size. When women present with severe OHSS they are often dehydrated, due to increased vascular permeability, and have hemoconcentration. The above results in a decrease in intravascular volume, leading to '''oligouria''' <ref name="PMID22416285" />.

===History===

Initially a thorough history of the patient is taken during which the clinician looks for evidence of ovarian stimulation, followed by ovulation. During this history taking, the clinician will inquire into any weight gain noticed, urine output, and the woman's ability to maintain oral hydration. A key diagnostic tool for clinicians regarding women who are taking gonadotropins is to identify if they are at an increased risk of developing OHSS. Some risk factors include woman aged less than 30, women who have polycystic ovaries, woman with a previous history of OHSS and women who have had greater than 20 oocytes retrieved <ref name="PMID22416285" />.

===Physical Exam===
[[File:Vaginal_Ultrasonography_in_Sagittal_Plane.jpg|right|thumbnail|600px|Vaginal Ultrasonography in Sagittal plane <ref name="Wikiversity Journal of Medicine"> Häggström, Mikael. "Medical gallery of Mikael Häggström 2014". Wikiversity Journal of Medicine 1 (2). DOI:10.15347/wjm/2014.008. ISSN 20018762</ref>]]
After a history of the patient is taken, the next step is to perform a physical exam on the patient. Women who present with abdominal bloating will produce a shifting dullness upon abdominal percussion. Additionally the clinician will test the woman's vital signs, measure her abdominal girth, weight and will look for evidence of ascites or increase in calf size (usually unilateral)<ref name="PMID22416285" />.

===Investigations===

If the clinician further suspects a women of having OHSS, various investigations can be done such as an ultrasound.The intraperitoneal fluid is best imaged via vaginal ultrasound due to the enlarged ovaries making it difficult to image the pelvis using transabdominal ultrasound. The clinician can also order laboratory testing to look for urine specific gravity and and complete blood count to look for hemoconcentration with a hematocrit. Additionally, liver function tests can be ordered to look for elevated function. The clinician will also look for evidence of elevated D-dimers and fibrinogen and decreased levels of anti-thrombin 3 <ref name="SAHealth"> Government of South Australia Health [ http://www.sahealth.sa.gov.au/wps/wcm/connect/9b61ed004ee5348da663afd150ce4f37/Ovarian-hyperstimulation-syndrome-WCHN-PPG-17072012.pdf?MOD=AJPERES&CACHEID=9b61ed004ee5348da663afd150ce4f37 ], 'South Australian Paediatric Clinical Guidelines OHSS'</ref>.

====Ultrasound====

Typical appearances of the ultrasound include <ref name="Ultrasound"> Radiopaedia [ http://radiopaedia.org/articles/ovarian-hyperstimulation-syndrome-1 ], 'Ovarian Hyperstimulation Syndrome'</ref>:

*Bilaterally and symmetrically enlarged ovaries (>12cm)
* "Spoke-Wheel appearance" - presence of multiple cysts of varying size
*May also see ascites (fluid)

===Severity===

Once a clinician has deduced a women is suffering from OHSS, the severity of their condition needs to be established as either mild, moderate or severe. This is done by referring to the criteria under the sub-heading [[Symptoms]].The subsequent course of treatment for the woman will be based upon this evaluation.

{|
|-bgcolor="F6CEEC"
|
'''Further investigations''' can be done including a Chest X-ray to check for pleural effusions and oedema and USS with Doppler's to check for ascites or possible ovary torsion. <ref name="PMID22416285"><pubmed>22416285</pubmed></ref>
|}

===Differential Diagnosis===

Conditions presenting with similar symptoms or ultrasound images include <ref name="Ultrasound" />:

*Polycystic Ovaries (PO)
:: The difference is that with PO is that the cycts are typically smaller than OHSS cysts and there is no evidence of ascited or pleural effusion
*Mucinous Ovarian Malignancy
:: A type of Ovarian Epithelial tumour
*Ectopic Pregnancy <ref name="Casereport"> Australian Medical Student Journal [ http://www.amsj.org/wpcontent/uploads/files/articles/amsj_v2_i1/AMSJ_v2_i1_pg58-60.pdf ], 'Ovarian hyperstimulation syndrome'</ref>
::A pregnancy in which the foetus develops outside of the uterus e.g. in the fallopian tube

</div>

==Pathophysiology==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

[[File:Pathogenesis_of_OHSS.png|600px|thumb|Pathogenesis of OHSS <ref name="PMID20416867"><pubmed>20416867</pubmed></ref>]]

The definition of Ovarian Stimulation is enlarged ovaries with many luteinized cysts, that can present with secondary complications. What distinguishes Ovarian Stimulation from OHSS is the presence of vascular hyper-permeability that results in fluids being redirected elsewhere in the body.

The key process to OHSS appears to be caused by '''Vascular Endothelial Growth Factor''' (VEGF), that is released along with other cytokines, estrogen and progesterone, due to the ovary undergoing luteinization as a result of stimulation by hCG. VEGF increases vascular permeability and as a result the capillaries become more "leaky" to the fluids in them. These fluids can then escape the capillaries and accumulate in the pleural and abdominal cavities as ascites. The woman then becomes hypovolemic and is at an increased risk of circulatory, renal and respiratory issues such as arterial thromboembolism due to the thickening of the blood. Note, the blood is thickened as fluid is leaving the capillaries, leaving behind red blood cells and other cellular components of the blood <ref name="WikiOHSS" />.

The increase in expression of VEGF and VEGF Receptor 2 (VEGFR2) is attributed to the greatly increased amount of their mRNA present in the body after stimulation with hCG <ref name="PMID21082502"><pubmed>21082502</pubmed></ref>. VEGF interacts with VEGF2 and VEGF Receptor 1 (VEGFR1) to create a strong angiogenic effect. Both VEGFR2 and VEGFR1 belong to a family of receptors called tyrosine kinases. VEGF2 is involved in the regulation of angiogenesis and vascular permeability whilst VEGF1 has a slightly contradictory role in that is is involved in the maintenance of the tight junctions between endothelial cells in blood vessels. A study by Gómez ''et. al.'' <ref name="PMID21082502" /> showed that women experiencing OHSS had substantially higher plasma levels of VEGF and lower levels of VEGFR1.

</div>

==Complications==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

Ovarian torsion or rupture, renal insufficiency and thrombophlebitis can all complicate OHSS. If a pregnancy occurs, symptoms may persist longer than the usual 1 to 2 weeks and become more severe, however, even with severe OHSS, they do not extend past the first trimester <ref name="WikiOHSS" />.

<span style="color:#FA58D0"> '''1-2% of women who undergo ovarian stimulation develop a severe form of OHSS''' </span>. Complications from severe OHSS include:

*Fluid collection in the abdomen
*Electrolyte disturbances (sodium and potassium)
*Kidney failure
*Ovary twisting
*Rupture of a cyst in an ovary
*Breathing problems
*Blood clots in large vessels (most commonly the legs)
*Pregnancy loss from miscarriage or termination
*Rarely, death

A study by Nouri ''et. al.'' <ref name="PMID24996451"><pubmed>24996451</pubmed></ref> found that women with '''Polycystic Ovarian Syndrome''' (PCOS) and those that were induced with hCG experienced longer recovery times from severe OHSS than women who were not pregnant. They looked at a cohort of women hospitalised for the first time with severe OHSS and subject them to the same treatments. Based on a defined criteria, they established the recovery time of these women and compared the times between those that were pregnant to those that were not pregnant. They also found that whether a woman had PCOS or ovulation induction did not affect her risk of developing OHSS if she was not pregnant. It is only a risk factor for pregnant women.

===Thromboembolic events===

A frequent and deadly complication of OHSS are thromboembolic events due to increased blood clotting. This increase in blood clotting has been attributed to a variety of complications such as hemoconcentration (which thickens the blood), hypovolemia and an increase in the permeability of blood vessels as a result of increased vasoactive substances in the body of ovarian origin. Thromboembolic events include venous thromboses often in the upper extremities and arterial thromboses such as those in the cerebrovascular region. These events can lead to amputations of extremities, brain damage, miscarriage and death. To avoid this, anti-coagulants are given to pateitns with OHSS and they are fitted with compression stockings (see [[Treatment]]) <ref name="PMID23378404"><pubmed>23378404</pubmed></ref>.

{|
|-bgcolor="F8E0F1"
|
The risk of a woman developing OHSS is higher if she is having a '''twin pregnancy''', as she is exposed to higher concentration of hCG. <ref name="PMID9756273"><pubmed>9756273</pubmed></ref>
|}

</div>

==Treatment==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

'''General treatment
'''
*''Acetaminophen'' with or without a narcotic agent- used to treat abdominal discomfort
*Women are encouraged to drink 2-3 litres of water a day to prevent hemoconcentration
*Women are advised to avoid sexual intercourse and vigorous exercise at the risk of torsion or rupture of the ovaries
*NSAID's with anti-platelet properties should NOT be used as they may effect renal function in a women with OHSS
*Patients with significantly painful ascites or breathing problems may undergo ''Paracentesis'' (drainage of the ascites)
*''Culdocentesis'' (extraction of fluid from recto-uterine pouch) can be done to decrease the likelihood of a woman with moderate OHSS progressing to severe OHSS.<ref name="PMID22416285" />

===Mild to Moderate OHSS===

Mild OHSS can often resolve on its own, however, moderate OHSS may include treatments such as<ref name="WikiOHSS" />:

*Anti-nausea medication and prescription painkillers
*Regular physical examinations and ultrasounds
*Daily weigh-ins and waist measurements
*Measuring the amount of urine produced each day
*Frequent blood tests for monitoring dehydration and electrolyte imbalance
*Maintaining a high balance of fluids
*Drainage of excess abdominal fluid by inserting a needle in the abdominal cavity
*Wearing support stockings which help prevent blood clots/thrombosis

===Severe OHSS===

Severe OHSS requires hospital care in order for constant monitoring and treatment such as <ref name="WikiOHSS" />:

*Intravenous fluids with a crystalloid solution (100-150mL/hr)
*Intravenous Albumin is administered is IV fluids are insufficient (15-20mL/hr of 25% albumin for 4 hrs)
*In addition to Acetaminophen, ''Opioid analgesics'' can be administered for pain relief
*''Antiemetics'' can be used to subside nauseas and/or vomiting
*Woman administered to hospital of OHSS are considered at high risk of thromboembolic complications and are given low molecular weight ''heparin'', an anti-coagulant
*''Cabergoline''- lessens OHSS symptoms
*''GnRH agonist''- suppresses ovarian activity
**If at risk of OHSS, alternates include using a GnRH agonist instead of hCG however its effects on pregnancy rates are questionable. Using a GnRH agonist to replace the use of hCG for final oocyte stimulation will see a 6% decrease in delivery rate.

*Daily monitoring of creatine, urea, creatine clearance C-reactive protein (to rule out infection) are all required in combination with weekly tests such as liver and renal function tests and chest x-rays (to check for pleural effusion) <ref name="PMID12638783" />.

If there are serious complications then additional treatments are required:

*Surgery for a ruptured ovarian cyst
*Intensive care for the liver or lung complications

====Paracentesis====

For women with severe/grade 3 OHSS, paracentesis, the removal of fluid from the body using an aspiration needle, can be undertaken. It is a diagnostic and a therapeutic method that can be done trans-abdominally and trans-vaginally. It is used to relieve symptoms, improve haemodynamics e.g. Urinary output, and shorten the women's hospital stay. Complications of paracentesis include bleeding, infection and organ injury, however are note common <ref name="Paracentesis"> S. Monica Soni, HMS 3, Gillian Lieberman, MD [ http://eradiology.bidmc.harvard.edu/LearningLab/genito/Soni.pdf ], 'Ovarian Hyperstimulation Syndrome'</ref>.

{|
|-bgcolor="F8E0F1"
|
The most important aspect of treatment for any women with OHSS is close and constant '''monitoring''' with her healthcare professional. Counselling may also be provided to women and their partners or families in order to provide them with the best possible knowledge base to manage and treat their OHSS. It is important to note that there is '''no one cure or treatment''' for OHSS. Treatment involves managing and eliminating the symptoms until such time as the syndrome resolves itself <ref name="WikiOHSS" />.
|}

</div>

==Prevention==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

There are three key avenues through which the incidence of OHSS may be prevented. These include identifying risk factors to predict OHSS development, modifying treatment regimes on the basis of the identified risk factors and intervention to prevent progression to OHSS once the patient has undergone Controlled Ovarian Stimulation.

=== Risk factors===

'''Primary risk factors'''

Pre-existing factors likely to exacerbate the ovarian stimulation response. Primary risk factors include <ref name="PMID26074966"><pubmed>26074966</pubmed></ref>:

*Young age
*Low body weight
*History of elevated response to gonadotropins
*Polycystic Ovary Syndrome (PCOS)
*Isolated PCOS characteristic
*A previous history of OHSS.
*Hormonal markers (e.g. Anti-Mullerian Hormone markers)
*Ultrasonographic markers (e.g. Antral Follicle Count)

'''Secondary risk factors'''

Secondary risk factors involve the monitoring of ovarian response parameters once COS has been initiated. These parameters are monitored for <ref name="PMID19007627"><pubmed>19007627</pubmed></ref>:

*rapidly rising E2 levels
*E2 concentration larger than 2500 pg/mL
*large number of developing follicles (10-14mm) on the day hCG is administered
*large number of oocytes retrieved

These factors in combination, act as a predictive tool to assess the likelihood of severe OHSS development, with a 83% sensitivity and 84% specificity. <ref name="PMID19007627"/>

=== Primary Prevention===

Primary Prevention involves the modification of treatment regimens on the basis of OHSS risk classifications, in order to prevent OHSS occurrence.

'''Ovulation Induction'''

Unifollicular Ovulation Induction through Ovulation Induction (OI) is a primary means of avoiding OHSS in women with Polycystic Ovarian Syndrome, who are at an increased risk. In order to promote unifollicular development, the ovaries are stimulated with a low starting dose of FSH (75 IU).<ref name="PMID20416867"><pubmed>20416867</pubmed></ref> Studies suggests that a minimum gonadotropin dose lowers OHSS risk and thus a step-up regimen is utilised to achieve an ovarian response, whereby the FSH dosage is increased every 7 days until follicular development of greater than 10mm is noted.<ref name="PMID26074966" /> Alternatively, a step-down regimen may be followed, whereby a high initial FSH dosage is lowered according to the ovarian response. Another method to increase FSH levels during OI, is through Aromatase Inhibitors which promote folliculogenesis by increasing pituitary secretion of FSH, and downregulate oestrogen production through a negative feedback loop. However, Aromatase Inhibitors have not been shown to reduce OHSS incidence in comparison to other methods of OI.<ref name="PMID26074966" /> During OI, a key objective is to prevent early cycle cancellation due to premature luteinisation from pituitary secretion of LH. In order to downregulate LH secretion, Gonadotropin-releasing hormone agonists (GnRHa) are administered in addition to gonadotropins. Alternatively, GnRH antagonists may be administered to downregulate endogenous LH secretion. Comparative studies have shown that the GnRH antagonist protocol has a greater effect in lowering the incidence of mild to severe OHSS. However due to the rare nature of OHSS, and insufficient sample sizes, the difference was not found to be significant. <ref name="PMID21082508"><pubmed>21082508</pubmed></ref>. Generally, the duration of exposure to gonadotropins and subsequent risk of OHSS may be minimised through mild stimulation protocols which administer FSH only in the mid to late follicular phase.<ref name="PMID20416867" />

'''Adjuvant Metformin Therapy'''

Adjuvant Metformin Therapy has been found to lower the risk of OHSS by 63%.<ref name="PMID25406011"><pubmed>25406011</pubmed></ref> It involves the administration of metformin at a daily dosage of 1000 to 2000mg, 2 months prior to Controlled Ovarian Stimulation <ref name="PMID26074966"/>. Metformin lowers the elevated insulin levels in PCOS which consequently reduce intraovarian androgen levels. This leads to a reduced sensitivity and expression of granulosa cell-follicle stimulating hormone receptors which result in a less exaggerated response to gonadotropins. Furthermore, it is suggested that Metformin prevents OHSS by controlling vascular permeability through the inhibition of various vasoactive molecules, including VEGF.

'''Avoiding hCG during Luteal Phase Support

Following Controlled Ovarian Stimulation, the steroid levels of E2 and P4 are reduced during the luteal phase due to the negative feedback on the pituitary. This leads to low endogenous LH levels, which consequently reduce endometrial receptivity as well as the luteal phase duration itself. As a result, implantation and pregnancy rates are reduced and early pregnancy loss rates are increased.<ref name="PMID20416867" /> Luteal Phase Support (LPS) serves to combat these adverse events with the use of hCG. However, hCG has been found to increase the risk of OHSS. Alternatively, the use of progesterone has been found to not only halve the risk of OHSS, but also induce similar improvements in pregnancy and miscarriage rates as hCG.<ref name="PMID26148507"><pubmed>26148507</pubmed></ref>

===Secondary Prevention===

Secondary Prevention aims to prevent progression to OHSS once COS has been initiated and the patient has been found to mount an exaggerated response. <ref name="PMID20416867" />

'''Coasting'''

Coasting is a first-line secondary preventative strategy. It consists of the withdrawal of gonadotrophins when a critical number of follicles and/or E2 concentration is reached. hCG is administered once the E2 concentration reduces to a safe level, before the process of oocyte retrieval commences. This preventative strategy is conducted for a period of less than 3 days in order to avoid compromising IVF outcomes.

'''Cryopreservation'''

Cryopreservation of embryos after oocyte retrieval is another avenue which may avert OHSS progression. The cryopreserved embryos are only reimplanted once the patient's hormone serum levels have normalised. Using oocyte vitrification, crystal formation within embryo tissue is avoided and so cryopreserved embryos have been found to produce better pregnancy rates with a 32% increase, than fresh embryo transfer. Recent studies suggest cryopreservation itself does not reduce OHSS rates, but must be followed by a GnRHa trigger to avert OHSS.

'''Cycle cancellation'''

Cycle cancellation is a guaranteed method to prevent early OHSS whereby hCG is withheld. This is a last resort strategy as it carries the risk of significant psychological distress and financial loss for the patient.

</div>

==Effect on the Newborn==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

</div>
Women who develop OHSS while undergoing Assisted Reproductive Technologies (ART) treatment are not only more likely to achieve a pregnancy, but have a live birth as the pregnancy outcome. This live birth is also more likely to be a multiple birth of two, three or more children. <ref name="PMID19591989"><pubmed>19591989</pubmed></ref> It has been postulated that a multifetal pregnancy leads to a more rapid increase in hCG levels, resulting in an increased risk of OHSS. However, the causal nature between multifetal pregnancy and OHSS development is disputed and further research is required to distinguish correlation from causation. <ref name="PMID19573292"><pubmed>19573292</pubmed></ref>

OHSS development is also associated with an increased risk of adverse outcomes including stillbirth, premature birth and low birthweight.<ref name="PMID19591989" /> Although the cause for the increased risk in adverse pregnancy outcomes is unknown, it is suggested that as the incidence of OHSS is reduced through various prevention strategies, the risk of such outcomes may be also be reduced.

==Genetics==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

Despite OHSS typically being of iatrogenic origin as a result of ovarian stimulation with gonadotropins, research has been conducted into the potential genetics behind OHSS as many sporadic and familial cases have been observed. '''Mutations''' in the receptor for hormones such as Follicle Simulating Hormone (FSH), Lutenizing Hormone (LH) and hCG have all been targets of OHSS genetics research. Interestingly, they too also arise from a common ancestral gene.

===Follicle Stimulating Hormome===

Dr. Botros Rizk, of the University of South Alabama College of Medicine <ref name="PMID19573286"><pubmed>19573286</pubmed></ref>, has written extensively regarding the genetics behind OHSS. In particular, he talks about '''FSH receptors''' (FSHR) and their role in the syndrome. He hypothesises that mutations in these receptors could be activating or inactivating, leading to an increased risk of developing OHSS or sterility respectively. Currently, 744 single nucleotide polymorphisms (a type of mutation) have been found in the gene encoding the FSHR, 8 of which are located in its exons (coding regions of the gene). How the ovary responds is resultant on the FSHR genotype. For example, Ser680Asn, a polymorphism in the FSHR gene has been shown to aid in predicting the severity of a woman's OHSS. Ordinarily FSH stimulates the growth of ovarian follicles, however, when mutated, it is stimulated by the hCG resulting in excessive follicle development.

Spontaneous OHSS, OHSS that arises and cannot be attributed to any form of ovarian stimulation or Assisted Reproductive Technology, has been linked to activating mutations in the FSHR <ref name="PMID23499866"><pubmed>23499866</pubmed></ref>. This familial disorder is an autosomal dominant one. In most cases the FSHR can be stimulated by the presence of Thyroid Stimulating Hormone (TSH) or hCG, in the absence of FSH (the ligand for FSHR).

===Lutenizing Hormome===

The '''Lutenizing Hormone Receptor''' (LHR) gene in humans is comprised of 11 exons. Animal studies have shown that many primates exhibit a similar gene which is comprised of only 10 exons, however a gene lacking the 10th exon has been identified and termed the type 2 LHR. Expression of the type 2 LHR has been seen in humans. The type 2 LHR, compared to the wild-type LHR appears to be repaired with regard to its function. Defects in the type 2 LHR include a decrease in efficiency of transport to the plasma membrane and irregularities in signal transduction. Inactivating mutations in the LHR have been seen to cause infertility in women as well as amenorrhoea. Activating LHR gene mutations are asymptomatic and are not associated with OHSS in women.

===Bone Morphogenic Protein===

An imporant growth factor, derived from oocytes called '''BMP-15''' (Bone Morphogenic Protein 15) is vital for female fertility. It belongs to the family of growth factors, Transforming Growth Factor β (TGF-β) and is heavily involved in folliculogenesis. It has been found that mutations in the BMP-15 gene caused infertility in female sheep. Conversely, it has also been indicated in enhanced fertility when BMP-15 is present is high amounts in follicular fluid <ref name="PMID19573286" />.

A case study done by Hanevik ''et. al.'' in 2013 <ref name="PMID21565556"><pubmed>21565556</pubmed></ref> found that a Single Nuclear Polymorphism (SNP) in the BMP-15 gene is responsible for a high response to ovarian hyper-stimulation. The aim of the study was to test the effect the SNP had on BMP-15 with regard to high and low responders buy taking blood from 53 high responders, 38 low responders and 100 non-responders (controls) and analysing 5 noted SNP's. Results from their study showed a correlation between a high response to ovarian hyper-stimulation and the BMP-15 9G allele. The article does state however, that further research is required into the molecular effects of SNP's on the function of BMP-15.

===Vascular Endothelial Growth Factor===

'''Vascular endothelial growth factor''' (VEGF) has been indicated as one of the key agents causing vascular permeability and subsequent ascites in OHSS. The gene, which is located on chromosome 12, is made up of 8 exons (coding regions), of which exons 6 and 7 do not always appear due to the exons being spliced out.The splicing of this gene allows for various isoforms of the gene to exist of which VEGF 121 and 165 appear to play a role in angiogenesis. There are two VEGF Receptors, VEGFR-1 and VEGFR-2 that belong to the tyrosine kinase family of receptors (for more information on VEGF see [[Pathophysiology]]). Because of its distinct role in OHSS, it has been targeted as an area for research for potential treatments. The idea is that if the genetic expression of VEGF and its receptors can be controlled, OHSS can be avoided or treated.<ref name="PMID19573286" />

A different study by Hanevik ''et. al.'' , <ref name="PMID22587628"><pubmed>22587628</pubmed></ref> done in 2012 involved analysing blood samples from 53 women with OHSS and 100 women without it (controls) and analysing 6 SNP's in the VEGFR2 gene to find any genetic variations. They found a correlation between women with the VEGF +405cc genotype and the development of OHSS indicating women that undergo controlled ovarian hyper-stimulation and posses his genotype, are at an increased risk of developing OHSS.

</div>

== Current Research on Animal Models==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">
{|
|-bgcolor="F8E0F1"
|
<span style="font-size:120%">'''Inhibition of Cyclooxygenase-2 (COX-2) by Meloxican decreasing the incidence of OHSS in Rat Model'''</span> <ref name="PMID18166186"><pubmed>18166186</pubmed></ref>

Reasearch was carried out to investigate the effects of selective inhibition of the enzyme COX-2 on the Ovarian Hyperstimulation Syndrome (OHSS) using Female Wistar rates as the subjects. The research aimed to find results by measuring the number of antral and luteinized follicles, ovarian weight, vascualr endothelial growth factors and COX-2 immunohistochemistry. The rats being tested were all 22 days old and were divided into four equal groups;

'''Group 1 (Control group)''' was subject to a 0.1 ml of Intraperitoneal Saline from days 22 ~ 26

'''Group 2 (Mildly-stimulated group)''' subject to 10IU of pregnant mare serum gonadotrophin (PMSG) on day 24 and then 10IU of Human Chorionic Gonadotrophin (hCG) on day 26

'''Group 3 (OHSS positive group)''' was subject to 10IU of PMSG from days 22 ~ 26 and then administered 30IU of hCG on day 26 to induce OHSS

'''Group 4 (OHSS positive variant group)''' received 15mg/ml of Meloxicam 2 hours prior to administration of 10IU PMSG from days 22 ~ 26

Results showed there was no difference in ovarian weight in samples from Group 1 and Group 2, however Group 3 showed signs of significant ovarian weight increase which in group 4 was suppressed by the introduction of Meloxicam. No differences were observed in the number of antral follicles amongst the four test groups. Results from Group 2 and Group 3 showed that the granulosa cells of preovulatory follicles and the stromal cells were highly VEGF immunoreactive, however the Meloxicam treated Group 4 showed less immunoreactivity than Group 2 and Group 3 which indicated the correlation between Meloxicam and the diminished VEGF expression. Group 3 presented an increased COS-2 immunoreactivity which was highly diminished than in Group 4.

The research concluded that in a rat model, the enzyme Meloxicam has a beneficial effect on OHSS by reducing the increase of ovarian weight and the expression of VEGF associated with OHSS, the effects of which may be mediated by the inhibitory capacity of COX-2 on Meloxicam
|}

{|
|-bgcolor="FF99FF"
|
<span style="font-size:120%">'''Inhibition of Ovarian VEGF secretion by activation of Dopamine Receptor 2'''</span> <ref name="PMID25217874"><pubmed>25217874</pubmed></ref>

This research was carried out to investigate a possibility in whether a Dopamine Receptor 2 agonist '''(D2-ag)''' can assist in the prevention of Ovarian Hyperstimulation Syndrome, using rat models, by decreasing the ovarian vascular endothelial growth factor '''(VEGF)''' production. Using Immature Wistar rats (22 days old) as their animal model, the rats were initially stimulated with Gonadotrophins to mimic the onset and effects of OHSS and then subjected to treatment with a D2-agonist and/or a D2-antagonist (D2-ant). The vascular permeability was measured at the endpoint after day 26 by measuring the peritoneal extravasion of a previously injected dye and ovaries from all subjects were collected to assess the effects of D2-ag and D2-ant on the production of Ovarian VEGF. The expression of VEGF mRNA was measured by quantitative real time PCR and the levels of VEGF proteins were measured by Western Blots.

Results showed that the D2-ag caused a large reduction in the vascular permeability which was in turn associated with the great decreased in VEGF protein production in the OHSS rat ovaries, whereas the introduction of D2-ant showed opposite results with a increase in the vascular permeability leading to the increase of VEGF protein production in the ovaries. Ovarian VEGF mRNA levels were found to be unaffected by the introduction of these drugs in OHSS rat subjects. Conclusions were drawn on the fact that Dopamine Receptor 2 agonists prevent the increase of vascular permeability in subjects with OHSS by decreasing the ovarian production of VEGF and also that due to the dose-dependent inhibitory effect of the D2-ag on ovarian VEGF, current OHSS therapies used in humans can benefit by increasing the intraovarian concentration of D2-ag.
|}
</div>

==Glossary==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

'''Ascites'''- An accumulation of fluid in the peritoneal cavity with resultant abdominal swelling

'''Cabergoline''' - A dopamine receptor agonist used to treat hormone imbalance.

'''Controlled Ovarian Stimulation''' - female infertility treatment using medications to stimulate the ovaries to develop follicles

'''GnRH antagonist''' - Gonadotropin Releasing Hormone - A class of compounds that are similar in terms of the structure of natural Gonadotropin Releasing Hormone but has a antagonistic effect.

'''hCG'''- Human Chorionic Gonadotropin

'''Hemoconcentration'''- An increase in the concentration of circulating red blood cells in response to a decrease in blood plasma volume

'''Hypovolemic'''- A decrease in circulating blood volume

'''Iatrogenic'''- Illness caused as a result of a medical examination or treatment

'''Intravenous fluids''' - Is the infusion of liquid substances directly into a vein.

'''IVF'''- In-vitro Fertilization

'''NSAID'''- Non-steroidal Anti-Inflammatory Drug e.g. Ibuprofen

'''OHSS'''- Ovarian Hyper-stimulation Syndrome

'''FSH''' - Follicle Stimulating Hormone

'''LH''' - Luteinizing Hormone

'''Oliguria'''- Decreased urine output/small amounts of urine produced

</div>

==References==

2015 Group Project 2

2015-10-22T22:12:41Z

Z3372824: /* Thromboembolic events */

{{ANAT2341Project2015header}}

==<span style="font-size:120%">'''Ovarian Hyper-stimulation Syndrome (OHSS)'''</span>==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

Ovarian Hyper stimulation Syndrome (OHSS) is an iatrogenic complication of '''Assisted Reproduction Technology''' (ART), in which women take medications to stimulate oocyte growth. It is generally identified by cystic enlargements of the ovaries and fluid accumulation in the peritoneal cavity due to the increased capillary permeability and ovarian neoangiogenesis <ref name="PMID22065820"><pubmed>22065820</pubmed></ref>. It is an occurrence which is dependent on the controlled stimulation of the ovaries in preparation for IVF i.e. administration of human Chorionic Gonadotropin (hCG).

OHSS was first described in 1943 as ''“syndrome d’hyperluteinisation massive
des ovaries”''. It was during this time that gonadotropins were prepared from animals such as sheep to bring on ovulation in women. The first recorded death as a result of OHSS occurred in 1951 and was due to renal failure as a result of oligouria, a complication of the syndrome <ref name="OHSS"> Marie M. Budev, DO, MPH; Alejandro C. Arroliga, MD; Tommaso Falcone, MD, [ http://utilis.net/Morning%20Topics/REI/Ovarian%20Hyperstimulation.pdf ], 'Ovarian Hyperstimulation Syndrome'</ref> <ref name="PMID12638783"><pubmed>12638783</pubmed></ref>.

<span style="color:#FA58D0">This wikipage aims to provide clear information on various areas surrounding OHSS such as diagnosis, prevention and complications and will look into the genetics behind the disorder and the various animals models used to research it.</span>

<html5media height="350" width="450">https://www.youtube.com/watch?v=aXmjJw234a4</html5media>

'''Overview of the Ovarian Hyperstimulation Syndrome''' <ref> Howcast (2013, August 27) Ovarian Hyperstimulation Syndrome | Infertility. Retrieved from https://www.youtube.com/watch?v=aXmjJw234a4</ref>

</div>

==Epidemiology==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

Ovarian Hyper-Stimulation Syndrome (OHSS) rarely occurs sporadically, and if it does, it is usually the result of an underlying genetic problem. The majority of OHSS is due to the ovaries being stimulated to mature and release an abundance of oocytes, in response to hormones Human Chorionic Gonadotropin (hCG) and Follicle Stimulating hormone (FSH), during IVF. Rarely, Clomifene Citrate therapy can cause OHSS.<ref name="WikiOHSS"> Wikipedia, [ https://en.wikipedia.org/wiki/Ovarian_hyperstimulation_syndrome ], 'Ovarian Hyperstimulation Syndrome'</ref>

OHSS only affects '''0.5-5%''' of women undergoing Ovarian Hyper-stimulation, but despite its small prevalence, it is a potentially fatal outcome of a non-vital procedure and remains a prevalent problem for fertility specialists <ref name="PMID12498425"><pubmed>12498425</pubmed></ref> <ref name="PMID12638783"><pubmed>12638783</pubmed></ref>. Age has been cited as a factor affecting those with OHSS, with younger women more at risk. Additionally, women with allergies were seen to have a higher incidence of OHSS. It is important to note that at this point in time, there is no positive correlation between gonadotropin dose and OHSS.

Of the 0.5-5% of women affected with OHSS mentioned above, 2% of those women will require hospitalisation. As of 2011, it has been reported that the incidence of OHSS was '''increasing''', resulting in approximately 3 deaths per 100,000 women undergoing ovarian stimulation per year <ref name="PMID21828116"><pubmed>21828116</pubmed></ref>. This is particularly worrying as in 2008, in the United States alone, there were around 150,000 IVF cycles undertaken.

{|
|-bgcolor="F8E0F1"
|
'''With the field of Assisted Reproductive Technologies expanding and more women partaking in IVF treatments, the threat of women developing OHSS is an ongoing and increasing one''' <ref name="PMID21828116" />.
|}
{| class="wikitable mw-collapsible mw-collapsed"
! Characteristics of women by complication group <ref name="PMID19591989"><pubmed>19591989</pubmed></ref>
|-
! scope="col" width="100px" height="60px" style="text-align:center| '''Characteristic'''
! scope="col" width="100px" height="60px" style="text-align:center| '''No Complications
(N = 212,041)'''
! scope="col" width="100px" height="60px" style="text-align:center| '''Moderate OHSS
(N = 1,523)'''
! scope="col" width="100px" height="60px" style="text-align:center| '''Severe OHSS
(N = 655)'''
|-
|style="text-align:center; background: #FF99FF;"| '''Maternal Age (Mean ± SD)'''
|style="text-align:center; background: #F6CEEC;"| 35.6 ± 4.6
|style="text-align:center; background: #F6CEEC;"| 33.0 ± 4.3
|style="text-align:center; background: #F6CEEC;"| 33.1 ± 4.4
|-
|style="text-align:center; background: #FF99FF;"| '''Maternal Age (%)'''
|-
|style="text-align:left; background: #F6CEEC;"| <30 years
|style="text-align:center; background: #F6CEEC;"| 10 %
|style="text-align:center; background: #F6CEEC;"| 21.1 %
|style="text-align:center; background: #F6CEEC;"| 20.6 %
|-
|style="text-align:left; background: #F6CEEC;"| 30-34 years
|style="text-align:center; background: #F6CEEC;"| 30.4 %
|style="text-align:center; background: #F6CEEC;"| 43.2 %
|style="text-align:center; background: #F6CEEC;"| 40.5 %
|-
|style="text-align:left; background: #F6CEEC;"| 35-39 years
|style="text-align:center; background: #F6CEEC;"| 37.8 %
|style="text-align:center; background: #F6CEEC;"| 27.2 %
|style="text-align:center; background: #F6CEEC;"| 32.5 %
|-
|style="text-align:left; background: #F6CEEC;"| >40 years
|style="text-align:center; background: #F6CEEC;"| 21.8 %
|style="text-align:center; background: #F6CEEC;"| 8.4 %
|style="text-align:center; background: #F6CEEC;"| 6.4 %
|-
|style="text-align:center; background: #FF99FF;"| '''Nulligravida (%)'''
|style="text-align:center; background: #F6CEEC;"| 45.8 %
|style="text-align:center; background: #F6CEEC;"| 51.5 %
|style="text-align:center; background: #F6CEEC;"| 51.8 %
|-
|style="text-align:center; background: #FF99FF;"| '''Infertility Diagnosis (%)'''
|-
|style="text-align:left; background: #F6CEEC;"| Male factor
|style="text-align:center; background: #F6CEEC;"| 37.7 %
|style="text-align:center; background: #F6CEEC;"| 41.0 %
|style="text-align:center; background: #F6CEEC;"| 33.4 %
|-
|style="text-align:left; background: #F6CEEC;"| Endometriosis
|style="text-align:center; background: #F6CEEC;"| 13.5 %
|style="text-align:center; background: #F6CEEC;"| 13.5 %
|style="text-align:center; background: #F6CEEC;"| 10.7 %
|-
|style="text-align:left; background: #F6CEEC;"| Ovulation Disorders
|style="text-align:center; background: #F6CEEC;"| 14.0 %
|style="text-align:center; background: #F6CEEC;"| 29.5 %
|style="text-align:center; background: #F6CEEC;"| 22.4 %
|-
|style="text-align:left; background: #F6CEEC;"| Diminished ovarian reserve
|style="text-align:center; background: #F6CEEC;"| 16.9 %
|style="text-align:center; background: #F6CEEC;"| 3.2 %
|style="text-align:center; background: #F6CEEC;"| 2.4 %
|-
|style="text-align:left; background: #F6CEEC;"| Tubal factors
|style="text-align:center; background: #F6CEEC;"| 20.4 %
|style="text-align:center; background: #F6CEEC;"| 22.6 %
|style="text-align:center; background: #F6CEEC;"| 22.3 %
|-
|style="text-align:left; background: #F6CEEC;"| Uterine factors
|style="text-align:center; background: #F6CEEC;"| 5.1 %
|style="text-align:center; background: #F6CEEC;"| 4.3 %
|style="text-align:center; background: #F6CEEC;"| 3.1 %
|-
|style="text-align:left; background: #F6CEEC;"| Other factors
|style="text-align:center; background: #F6CEEC;"| 13.9 %
|style="text-align:center; background: #F6CEEC;"| 13.1 %
|style="text-align:center; background: #F6CEEC;"| 10.4 %
|-
|style="text-align:left; background: #F6CEEC;"| Unexplained factor
|style="text-align:center; background: #F6CEEC;"| 12.7 %
|style="text-align:center; background: #F6CEEC;"| 11.8 %
|style="text-align:center; background: #F6CEEC;"| 18.6 %
|-
|}
</div>

==Causative Agents==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

[[File:Follicular Development.jpeg|right|thumbnail|500px|Infertility treatments aim to facilitate follicular development and induce ovulation to improve chances of fertilisation <ref name="PMID24717179"><pubmed>24717179</pubmed></ref>]]

Normally a woman produces one egg per month from the ovaries, which travel down the Fallopian tube to be fertilized or be released from the body. In cases where women have difficulty falling pregnant, they are given medication which help them to produce and release eggs (as shown in the diagram to the right), further increasing their chances of fertilization and pregnancy <ref><pubmed>19573285</pubmed></ref>. Ovarian Hyper stimulation Syndrome generally occurs during infertility treatments when the ovaries are overstimulated by the fertility medication which causes the ovaries to swell and leak fluids into the belly and abdomen. The prevalence of OHSS onset is linked with excessive number of follicle development in response to the administration of injectable Follicle Stimulating Hormones (FSH) followed by the '''Human Chorionic Gonadotrophins''' (hCG) which triggers the release of the oocytes <ref><pubmed>26190539</pubmed></ref>.

'''Follicle Stimulating Hormones''' (FSH) <ref name="PMID9020850"><pubmed>9020850</pubmed></ref> are glycoprotein hormones that are produced and secreted from the Anterior Pituitary gland into the bloodstream, which regulate the developmental, growth, maturation and the reproductive processes within the body. In females, the Follicle Stimulating Hormones initiates the stages of growth and development of immature ovarian follicles within the ovaries before the release of an egg from a follicle at ovulation. When FSH is administered to a patient who is suffering from infertility, the increase FSH levels affect the rate of development and production, in turn increasing the amount of follicles which are ready to be released during ovulation.

</div>

==Symptoms==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

OHSS is classified based on a criteria from mild, moderate and severe <ref name="WikiOHSS" />:

'''Mild Symptoms'''- abdominal bloating, minimal weight gain, nausea, diarrhoea and a feeling of fullness.

'''Moderate Symptoms'''- Substantial weight gain (on average 2 or more pounds a day), increased abdominal girth, darkend urine and excessive thirst in addition to the mild symptoms.

'''Severe Symptoms'''- In addition to the symptoms associated with Mild and Moderate OHSS, in severe OHSS, you see shortness of breath, calf and chest pains and pleural effusion.

<span style="font-size:100%">'''Classifications of Ovarian Hyper-stimulation Syndrome:'''</span> <ref name="PMID22065820"><pubmed>22065820</pubmed></ref>
{| class="wikitable" style="text-align:center
|-
! scope="col" width="70px"| '''Classification'''
! scope="col" width="650px"| '''Symptoms'''
|-
|style="text-align:center; background: #F6CEEC;"| '''Mild'''
|style="height: 60px; background: #F6CEEC;"| '''Grade 1''' - Abdominal distention and discomfort
'''Grade 2''' - Abdominal distention, discomfort with nausea, vomiting and/or diarrhea and ovarian enlargement from 5~12cm
|-
|style="text-align:center; background: #F8E0F1;"| '''Moderate'''
|style="height: 60px; background: #F8E0F1;"| '''Grade 3''' - All features of Mild OHSS with ultrasonographic evidence of ascites
|-
|style="text-align:center; background: #F6CEEC;"| '''Severe'''
|style="height: 60px; background: #F6CEEC;"| '''Grade 4''' - All features of Moderate OHSS with the addition of clinical evidence of ascites and breathing difficulties present
'''Grade 5''' - All of the above symptoms along with a change in the blood volume, increased blood viscosity due to coagulation and diminished renal function
|}

</div>

==Diagnosis==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

Whilst symptoms of OHSS can occur as soon as 24 hours post hCG administration, they are usually seen in women 7-10 days post administration. Initially women with OHSS will present with abdominal bloating, as a result of fluid in the peritoneal cavity and an increase in ovary size. When women present with severe OHSS they are often dehydrated, due to increased vascular permeability, and have hemoconcentration. The above results in a decrease in intravascular volume, leading to '''oligouria''' <ref name="PMID22416285" />.

===History===

Initially a thorough history of the patient is taken during which the clinician looks for evidence of ovarian stimulation, followed by ovulation. During this history taking, the clinician will inquire into any weight gain noticed, urine output, and the woman's ability to maintain oral hydration. A key diagnostic tool for clinicians regarding women who are taking gonadotropins is to identify if they are at an increased risk of developing OHSS. Some risk factors include woman aged less than 30, women who have polycystic ovaries, woman with a previous history of OHSS and women who have had greater than 20 oocytes retrieved <ref name="PMID22416285" />.

===Physical Exam===
[[File:Vaginal_Ultrasonography_in_Sagittal_Plane.jpg|right|thumbnail|600px|Vaginal Ultrasonography in Sagittal plane <ref name="Wikiversity Journal of Medicine"> Häggström, Mikael. "Medical gallery of Mikael Häggström 2014". Wikiversity Journal of Medicine 1 (2). DOI:10.15347/wjm/2014.008. ISSN 20018762</ref>]]
After a history of the patient is taken, the next step is to perform a physical exam on the patient. Women who present with abdominal bloating will produce a shifting dullness upon abdominal percussion. Additionally the clinician will test the woman's vital signs, measure her abdominal girth, weight and will look for evidence of ascites or increase in calf size (usually unilateral)<ref name="PMID22416285" />.

===Investigations===

If the clinician further suspects a women of having OHSS, various investigations can be done such as an ultrasound.The intraperitoneal fluid is best imaged via vaginal ultrasound due to the enlarged ovaries making it difficult to image the pelvis using transabdominal ultrasound. The clinician can also order laboratory testing to look for urine specific gravity and and complete blood count to look for hemoconcentration with a hematocrit. Additionally, liver function tests can be ordered to look for elevated function. The clinician will also look for evidence of elevated D-dimers and fibrinogen and decreased levels of anti-thrombin 3 <ref name="SAHealth"> Government of South Australia Health [ http://www.sahealth.sa.gov.au/wps/wcm/connect/9b61ed004ee5348da663afd150ce4f37/Ovarian-hyperstimulation-syndrome-WCHN-PPG-17072012.pdf?MOD=AJPERES&CACHEID=9b61ed004ee5348da663afd150ce4f37 ], 'South Australian Paediatric Clinical Guidelines OHSS'</ref>.

====Ultrasound====

Typical appearances of the ultrasound include <ref name="Ultrasound"> Radiopaedia [ http://radiopaedia.org/articles/ovarian-hyperstimulation-syndrome-1 ], 'Ovarian Hyperstimulation Syndrome'</ref>:

*Bilaterally and symmetrically enlarged ovaries (>12cm)
* "Spoke-Wheel appearance" - presence of multiple cysts of varying size
*May also see ascites (fluid)

===Severity===

Once a clinician has deduced a women is suffering from OHSS, the severity of their condition needs to be established as either mild, moderate or severe. This is done by referring to the criteria under the sub-heading [[Symptoms]].The subsequent course of treatment for the woman will be based upon this evaluation.

{|
|-bgcolor="F6CEEC"
|
'''Further investigations''' can be done including a Chest X-ray to check for pleural effusions and oedema and USS with Doppler's to check for ascites or possible ovary torsion. <ref name="PMID22416285"><pubmed>22416285</pubmed></ref>
|}

===Differential Diagnosis===

Conditions presenting with similar symptoms or ultrasound images include <ref name="Ultrasound" />:

*Polycystic Ovaries (PO)
:: The difference is that with PO is that the cycts are typically smaller than OHSS cysts and there is no evidence of ascited or pleural effusion
*Mucinous Ovarian Malignancy
:: A type of Ovarian Epithelial tumour
*Ectopic Pregnancy <ref name="Casereport"> Australian Medical Student Journal [ http://www.amsj.org/wpcontent/uploads/files/articles/amsj_v2_i1/AMSJ_v2_i1_pg58-60.pdf ], 'Ovarian hyperstimulation syndrome'</ref>
::A pregnancy in which the foetus develops outside of the uterus e.g. in the fallopian tube

</div>

==Pathophysiology==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

[[File:Pathogenesis_of_OHSS.png|600px|thumb|Pathogenesis of OHSS <ref name="PMID20416867"><pubmed>20416867</pubmed></ref>]]

The definition of Ovarian Stimulation is enlarged ovaries with many luteinized cysts, that can present with secondary complications. What distinguishes Ovarian Stimulation from OHSS is the presence of vascular hyper-permeability that results in fluids being redirected elsewhere in the body.

The key process to OHSS appears to be caused by '''Vascular Endothelial Growth Factor''' (VEGF), that is released along with other cytokines, estrogen and progesterone, due to the ovary undergoing luteinization as a result of stimulation by hCG. VEGF increases vascular permeability and as a result the capillaries become more "leaky" to the fluids in them. These fluids can then escape the capillaries and accumulate in the pleural and abdominal cavities as ascites. The woman then becomes hypovolemic and is at an increased risk of circulatory, renal and respiratory issues such as arterial thromboembolism due to the thickening of the blood. Note, the blood is thickened as fluid is leaving the capillaries, leaving behind red blood cells and other cellular components of the blood <ref name="WikiOHSS" />.

The increase in expression of VEGF and VEGF Receptor 2 (VEGFR2) is attributed to the greatly increased amount of their mRNA present in the body after stimulation with hCG <ref name="PMID21082502"><pubmed>21082502</pubmed></ref>. VEGF interacts with VEGF2 and VEGF Receptor 1 (VEGFR1) to create a strong angiogenic effect. Both VEGFR2 and VEGFR1 belong to a family of receptors called tyrosine kinases. VEGF2 is involved in the regulation of angiogenesis and vascular permeability whilst VEGF1 has a slightly contradictory role in that is is involved in the maintenance of the tight junctions between endothelial cells in blood vessels. A study by Gómez ''et. al.'' <ref name="PMID21082502" /> showed that women experiencing OHSS had substantially higher plasma levels of VEGF and lower levels of VEGFR1.

</div>

==Complications==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

Ovarian torsion or rupture, renal insufficiency and thrombophlebitis can all complicate OHSS. If a pregnancy occurs, symptoms may persist longer than the usual 1 to 2 weeks and become more severe, however, even with severe OHSS, they do not extend past the first trimester <ref name="WikiOHSS" />.

<span style="color:#FA58D0"> '''1-2% of women who undergo ovarian stimulation develop a severe form of OHSS''' </span>. Complications from severe OHSS include:

*Fluid collection in the abdomen
*Electrolyte disturbances (sodium and potassium)
*Kidney failure
*Ovary twisting
*Rupture of a cyst in an ovary
*Breathing problems
*Blood clots in large vessels (most commonly the legs)
*Pregnancy loss from miscarriage or termination
*Rarely, death

A study by Nouri ''et. al.'' <ref name="PMID24996451"><pubmed>24996451</pubmed></ref> found that women with '''Polycystic Ovarian Syndrome''' (PCOS) and those that were induced with hCG experienced longer recovery times from severe OHSS than women who were not pregnant. They looked at a cohort of women hospitalised for the first time with severe OHSS and subject them to the same treatments. Based on a defined criteria, they established the recovery time of these women and compared the times between those that were pregnant to those that were not pregnant. They also found that whether a woman had PCOS or ovulation induction did not affect her risk of developing OHSS if she was not pregnant. It is only a risk factor for pregnant women.

===Thromboembolic events===

A frequent and deadly complication of OHSS are thromboembolic events due to increased blood clotting. This increase in blood clotting has been attributed to a variety of complications such as hemoconcentration (which thickens the blood), hypovolemia and an increase in the permeability of blood vessels as a result of increased vasoactive substances in the body of ovarian origin. Thromboembolic events include venous thromboses often in the upper extremities and arterial thromboses such as those in the cerebrovascular region. These events can lead to amputations of extremities, brain damage, miscarriage and death. To avoid this, anti-coagulants are given to pateitns with OHSS and they are fitted with compression stockings (see [[Treatment]]) <ref name="PMID23378404"><pubmed>23378404</pubmed></ref>.

{|
|-bgcolor="F8E0F1"
|
The risk of a woman developing OHSS is higher if she is having a '''twin pregnancy''', as she is exposed to higher concentration of hCG. <ref name="PMID9756273"><pubmed>9756273</pubmed></ref>
|}

</div>

==Treatment==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

'''General treatment
'''
*''Acetaminophen'' with or without a narcotic agent- used to treat abdominal discomfort
*Women are encouraged to drink 2-3 litres of water a day to prevent hemoconcentration
*Women are advised to avoid sexual intercourse and vigorous exercise at the risk of torsion or rupture of the ovaries
*NSAID's with anti-platelet properties should NOT be used as they may effect renal function in a women with OHSS
*Patients with significantly painful ascites or breathing problems may undergo ''Paracentesis'' (drainage of the ascites)
*''Culdocentesis'' (extraction of fluid from recto-uterine pouch) can be done to decrease the likelihood of a woman with moderate OHSS progressing to severe OHSS.<ref name="PMID22416285" />

===Mild to Moderate OHSS===

Mild OHSS can often resolve on its own, however, moderate OHSS may include treatments such as<ref name="WikiOHSS" />:

*Anti-nausea medication and prescription painkillers
*Regular physical examinations and ultrasounds
*Daily weigh-ins and waist measurements
*Measuring the amount of urine produced each day
*Frequent blood tests for monitoring dehydration and electrolyte imbalance
*Maintaining a high balance of fluids
*Drainage of excess abdominal fluid by inserting a needle in the abdominal cavity
*Wearing support stockings which help prevent blood clots/thrombosis

===Severe OHSS===

Severe OHSS requires hospital care in order for constant monitoring and treatment such as <ref name="WikiOHSS" />:

*Intravenous fluids with a crystalloid solution (100-150mL/hr)
*Intravenous Albumin is administered is IV fluids are insufficient (15-20mL/hr of 25% albumin for 4 hrs)
*In addition to Acetaminophen, ''Opioid analgesics'' can be administered for pain relief
*''Antiemetics'' can be used to subside nauseas and/or vomiting
*Woman administered to hospital of OHSS are considered at high risk of thromboembolic complications and are given low molecular weight ''heparin'', an anti-coagulant
*''Cabergoline''- lessens OHSS symptoms
*''GnRH agonist''- suppresses ovarian activity
**If at risk of OHSS, alternates include using a GnRH agonist instead of hCG however its effects on pregnancy rates are questionable. Using a GnRH agonist to replace the use of hCG for final oocyte stimulation will see a 6% decrease in delivery rate.

*Daily monitoring of creatine, urea, creatine clearance C-reactive protein (to rule out infection) are all required in combination with weekly tests such as liver and renal function tests and chest x-rays (to check for pleural effusion) <ref name="PMID12638783" />.

If there are serious complications then additional treatments are required:

*Surgery for a ruptured ovarian cyst
*Intensive care for the liver or lung complications

====Paracentesis====

For women with severe/grade 3 OHSS, paracentesis, the removal of fluid from the body using an aspiration needle, can be undertaken. It is a diagnostic and a therapeutic method that can be done trans-abdominally and trans-vaginally. It is used to relieve symptoms, improve haemodynamics e.g. Urinary output, and shorten the women's hospital stay. Complications of paracentesis include bleeding, infection and organ injury, however are note common <ref name="Paracentesis"> S. Monica Soni, HMS 3, Gillian Lieberman, MD [ http://eradiology.bidmc.harvard.edu/LearningLab/genito/Soni.pdf ], 'Ovarian Hyperstimulation Syndrome'</ref>.

{|
|-bgcolor="F8E0F1"
|
The most important aspect of treatment for any women with OHSS is close and constant '''monitoring''' with her healthcare professional. Counselling may also be provided to women and their partners or families in order to provide them with the best possible knowledge base to manage and treat their OHSS. It is important to note that there is '''no one cure or treatment''' for OHSS. Treatment involves managing and eliminating the symptoms until such time as the syndrome resolves itself <ref name="WikiOHSS" />.
|}

</div>

==Prevention==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

There are three key avenues through which the incidence of OHSS may be prevented. These include identifying risk factors to predict OHSS development, modifying treatment regimes on the basis of the identified risk factors and intervention to prevent progression to OHSS once the patient has undergone Controlled Ovarian Stimulation.

=== Risk factors===

'''Primary risk factors'''

Pre-existing factors likely to exacerbate the ovarian stimulation response. Primary risk factors include <ref name="PMID26074966"><pubmed>26074966</pubmed></ref>:

*Young age
*Low body weight
*History of elevated response to gonadotropins
*Polycystic Ovary Syndrome (PCOS)
*Isolated PCOS characteristic
*A previous history of OHSS.
*Hormonal markers (e.g. Anti-Mullerian Hormone markers)
*Ultrasonographic markers (e.g. Antral Follicle Count)

'''Secondary risk factors'''

Secondary risk factors involve the monitoring of ovarian response parameters once COS has been initiated. These parameters are monitored for <ref name="PMID19007627"><pubmed>19007627</pubmed></ref>:

*rapidly rising E2 levels
*E2 concentration larger than 2500 pg/mL
*large number of developing follicles (10-14mm) on the day hCG is administered
*large number of oocytes retrieved

These factors in combination, act as a predictive tool to assess the likelihood of severe OHSS development, with a 83% sensitivity and 84% specificity. <ref name="PMID19007627"/>

=== Primary Prevention===

Primary Prevention involves the modification of treatment regimens on the basis of OHSS risk classifications, in order to prevent OHSS occurrence.

'''Ovulation Induction'''

Unifollicular Ovulation Induction through Ovulation Induction (OI) is a primary means of avoiding OHSS in women with Polycystic Ovarian Syndrome, who are at an increased risk. In order to promote unifollicular development, the ovaries are stimulated with a low starting dose of FSH (75 IU).<ref name="PMID20416867"><pubmed>20416867</pubmed></ref> Studies suggests that a minimum gonadotropin dose lowers OHSS risk and thus a step-up regimen is utilised to achieve an ovarian response, whereby the FSH dosage is increased every 7 days until follicular development of greater than 10mm is noted.<ref name="PMID26074966" /> Alternatively, a step-down regimen may be followed, whereby a high initial FSH dosage is lowered according to the ovarian response. Another method to increase FSH levels during OI, is through Aromatase Inhibitors which promote folliculogenesis by increasing pituitary secretion of FSH, and downregulate oestrogen production through a negative feedback loop. However, Aromatase Inhibitors have not been shown to reduce OHSS incidence in comparison to other methods of OI.<ref name="PMID26074966" /> During OI, a key objective is to prevent early cycle cancellation due to premature luteinisation from pituitary secretion of LH. In order to downregulate LH secretion, Gonadotropin-releasing hormone agonists (GnRHa) are administered in addition to gonadotropins. Alternatively, GnRH antagonists may be administered to downregulate endogenous LH secretion. Comparative studies have shown that the GnRH antagonist protocol has a greater effect in lowering the incidence of mild to severe OHSS. However due to the rare nature of OHSS, and insufficient sample sizes, the difference was not found to be significant. <ref name="PMID21082508"><pubmed>21082508</pubmed></ref>. Generally, the duration of exposure to gonadotropins and subsequent risk of OHSS may be minimised through mild stimulation protocols which administer FSH only in the mid to late follicular phase.<ref name="PMID20416867" />

'''Adjuvant Metformin Therapy'''

Adjuvant Metformin Therapy has been found to lower the risk of OHSS by 63%.<ref name="PMID25406011"><pubmed>25406011</pubmed></ref> It involves the administration of metformin at a daily dosage of 1000 to 2000mg, 2 months prior to Controlled Ovarian Stimulation <ref name="PMID26074966"/>. Metformin lowers the elevated insulin levels in PCOS which consequently reduce intraovarian androgen levels. This leads to a reduced sensitivity and expression of granulosa cell-follicle stimulating hormone receptors which result in a less exaggerated response to gonadotropins. Furthermore, it is suggested that Metformin prevents OHSS by controlling vascular permeability through the inhibition of various vasoactive molecules, including VEGF.

'''Avoiding hCG during Luteal Phase Support

Following Controlled Ovarian Stimulation, the steroid levels of E2 and P4 are reduced during the luteal phase due to the negative feedback on the pituitary. This leads to low endogenous LH levels, which consequently reduce endometrial receptivity as well as the luteal phase duration itself. As a result, implantation and pregnancy rates are reduced and early pregnancy loss rates are increased.<ref name="PMID20416867" /> Luteal Phase Support (LPS) serves to combat these adverse events with the use of hCG. However, hCG has been found to increase the risk of OHSS. Alternatively, the use of progesterone has been found to not only halve the risk of OHSS, but also induce similar improvements in pregnancy and miscarriage rates as hCG.<ref name="PMID26148507"><pubmed>26148507</pubmed></ref>

===Secondary Prevention===

Secondary Prevention aims to prevent progression to OHSS once COS has been initiated and the patient has been found to mount an exaggerated response. <ref name="PMID20416867" />

'''Coasting'''

Coasting is a first-line secondary preventative strategy. It consists of the withdrawal of gonadotrophins when a critical number of follicles and/or E2 concentration is reached. hCG is administered once the E2 concentration reduces to a safe level, before the process of oocyte retrieval commences. This preventative strategy is conducted for a period of less than 3 days in order to avoid compromising IVF outcomes.

'''Cryopreservation'''

Cryopreservation of embryos after oocyte retrieval is another avenue which may avert OHSS progression. The cryopreserved embryos are only reimplanted once the patient's hormone serum levels have normalised. Using oocyte vitrification, crystal formation within embryo tissue is avoided and so cryopreserved embryos have been found to produce better pregnancy rates with a 32% increase, than fresh embryo transfer. Recent studies suggest cryopreservation itself does not reduce OHSS rates, but must be followed by a GnRHa trigger to avert OHSS.

'''Cycle cancellation'''

Cycle cancellation is a guaranteed method to prevent early OHSS whereby hCG is withheld. This is a last resort strategy as it carries the risk of significant psychological distress and financial loss for the patient.

</div>

==Effect on the Newborn==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

</div>
Women who develop OHSS while undergoing Assisted Reproductive Technologies (ART) treatment are not only more likely to achieve a pregnancy, but have a live birth as the pregnancy outcome. This live birth is also more likely to be a multiple birth of two, three or more children. <ref name="PMID19591989"><pubmed>19591989</pubmed></ref> It has been postulated that a multifetal pregnancy leads to a more rapid increase in hCG levels, resulting in an increased risk of OHSS. However, the causal nature between multifetal pregnancy and OHSS development is disputed and further research is required to distinguish correlation from causation. <ref name="PMID19573292"><pubmed>19573292</pubmed></ref>

OHSS development is also associated with an increased risk of adverse outcomes including stillbirth, premature birth and low birthweight.<ref name="PMID19591989" /> Although the cause for the increased risk in adverse pregnancy outcomes is unknown, it is suggested that as the incidence of OHSS is reduced through various prevention strategies, the risk of such outcomes may be also be reduced.

==Genetics==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

Despite OHSS typically being of iatrogenic origin as a result of ovarian stimulation with gonadotropins, research has been conducted into the potential genetics behind OHSS as many sporadic and familial cases have been observed. '''Mutations''' in the receptor for hormones such as Follicle Simulating Hormone (FSH), Lutenizing Hormone (LH) and hCG have all been targets of OHSS genetics research. Interestingly, they too also arise from a common ancestral gene.

===Follicle Stimulating Hormome===

Dr. Botros Rizk, of the University of South Alabama College of Medicine <ref name="PMID19573286"><pubmed>19573286</pubmed></ref>, has written extensively regarding the genetics behind OHSS. In particular, he talks about '''FSH receptors''' (FSHR) and their role in the syndrome. He hypothesises that mutations in these receptors could be activating or inactivating, leading to an increased risk of developing OHSS or sterility respectively. Currently, 744 single nucleotide polymorphisms (a type of mutation) have been found in the gene encoding the FSHR, 8 of which are located in its exons (coding regions of the gene). How the ovary responds is resultant on the FSHR genotype. For example, Ser680Asn, a polymorphism in the FSHR gene has been shown to aid in predicting the severity of a woman's OHSS. Ordinarily FSH stimulates the growth of ovarian follicles, however, when mutated, it is stimulated by the hCG resulting in excessive follicle development.

Spontaneous OHSS, OHSS that arises and cannot be attributed to any form of ovarian stimulation or Assisted Reproductive Technology, has been linked to activating mutations in the FSHR <ref name="PMID23499866"><pubmed>23499866</pubmed></ref>. This familial disorder is an autosomal dominant one. In most cases the FSHR can be stimulated by the presence of Thyroid Stimulating Hormone (TSH) or hCG, in the absence of FSH (the ligand for FSHR).

===Lutenizing Hormome===

The '''Lutenizing Hormone Receptor''' (LHR) gene in humans is comprised of 11 exons. Animal studies have shown that many primates exhibit a similar gene which is comprised of only 10 exons, however a gene lacking the 10th exon has been identified and termed the type 2 LHR. Expression of the type 2 LHR has been seen in humans. The type 2 LHR, compared to the wild-type LHR appears to be repaired with regard to its function. Defects in the type 2 LHR include a decrease in efficiency of transport to the plasma membrane and irregularities in signal transduction. Inactivating mutations in the LHR have been seen to cause infertility in women as well as amenorrhoea. Activating LHR gene mutations are asymptomatic and are not associated with OHSS in women.

===Bone Morphogenic Protein===

An imporant growth factor, derived from oocytes called '''BMP-15''' (Bone Morphogenic Protein 15) is vital for female fertility. It belongs to the family of growth factors, Transforming Growth Factor β (TGF-β) and is heavily involved in folliculogenesis. It has been found that mutations in the BMP-15 gene caused infertility in female sheep. Conversely, it has also been indicated in enhanced fertility when BMP-15 is present is high amounts in follicular fluid <ref name="PMID19573286" />.

A case study done by Hanevik ''et. al.'' in 2013 <ref name="PMID21565556"><pubmed>21565556</pubmed></ref> found that a Single Nuclear Polymorphism (SNP) in the BMP-15 gene is responsible for a high response to ovarian hyper-stimulation. The aim of the study was to test the effect the SNP had on BMP-15 with regard to high and low responders buy taking blood from 53 high responders, 38 low responders and 100 non-responders (controls) and analysing 5 noted SNP's. Results from their study showed a correlation between a high response to ovarian hyper-stimulation and the BMP-15 9G allele. The article does state however, that further research is required into the molecular effects of SNP's on the function of BMP-15.

===Vascular Endothelial Growth Factor===

'''Vascular endothelial growth factor''' (VEGF) has been indicated as one of the key agents causing vascular permeability and subsequent ascites in OHSS. The gene, which is located on chromosome 12, is made up of 8 exons (coding regions), of which exons 6 and 7 do not always appear due to the exons being spliced out.The splicing of this gene allows for various isoforms of the gene to exist of which VEGF 121 and 165 appear to play a role in angiogenesis. There are two VEGF Receptors, VEGFR-1 and VEGFR-2 that belong to the tyrosine kinase family of receptors (for more information on VEGF see [[Pathophysiology]]). Because of its distinct role in OHSS, it has been targeted as an area for research for potential treatments. The idea is that if the genetic expression of VEGF and its receptors can be controlled, OHSS can be avoided or treated.<ref name="PMID19573286" />

A different study by Hanevik ''et. al.'' , <ref name="PMID22587628"><pubmed>22587628</pubmed></ref> done in 2012 involved analysing blood samples from 53 women with OHSS and 100 women without it (controls) and analysing 6 SNP's in the VEGFR2 gene to find any genetic variations. They found a correlation between women with the VEGF +405cc genotype and the development of OHSS indicating women that undergo controlled ovarian hyper-stimulation and posses his genotype, are at an increased risk of developing OHSS.

</div>

== Current Research on Animal Models==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">
{|
|-bgcolor="F8E0F1"
|
<span style="font-size:120%">'''Inhibition of Cyclooxygenase-2 (COX-2) by Meloxican decreasing the incidence of OHSS in Rat Model'''</span> <ref name="PMID18166186"><pubmed>18166186</pubmed></ref>

Reasearch was carried out to investigate the effects of selective inhibition of the enzyme COX-2 on the Ovarian Hyperstimulation Syndrome (OHSS) using Female Wistar rates as the subjects. The research aimed to find results by measuring the number of antral and luteinized follicles, ovarian weight, vascualr endothelial growth factors and COX-2 immunohistochemistry. The rats being tested were all 22 days old and were divided into four equal groups;

'''Group 1 (Control group)''' was subject to a 0.1 ml of Intraperitoneal Saline from days 22 ~ 26

'''Group 2 (Mildly-stimulated group)''' subject to 10IU of pregnant mare serum gonadotrophin (PMSG) on day 24 and then 10IU of Human Chorionic Gonadotrophin (hCG) on day 26

'''Group 3 (OHSS positive group)''' was subject to 10IU of PMSG from days 22 ~ 26 and then administered 30IU of hCG on day 26 to induce OHSS

'''Group 4 (OHSS positive variant group)''' received 15mg/ml of Meloxicam 2 hours prior to administration of 10IU PMSG from days 22 ~ 26

Results showed there was no difference in ovarian weight in samples from Group 1 and Group 2, however Group 3 showed signs of significant ovarian weight increase which in group 4 was suppressed by the introduction of Meloxicam. No differences were observed in the number of antral follicles amongst the four test groups. Results from Group 2 and Group 3 showed that the granulosa cells of preovulatory follicles and the stromal cells were highly VEGF immunoreactive, however the Meloxicam treated Group 4 showed less immunoreactivity than Group 2 and Group 3 which indicated the correlation between Meloxicam and the diminished VEGF expression. Group 3 presented an increased COS-2 immunoreactivity which was highly diminished than in Group 4.

The research concluded that in a rat model, the enzyme Meloxicam has a beneficial effect on OHSS by reducing the increase of ovarian weight and the expression of VEGF associated with OHSS, the effects of which may be mediated by the inhibitory capacity of COX-2 on Meloxicam
|}

{|
|-bgcolor="FF99FF"
|
<span style="font-size:120%">'''Inhibition of Ovarian VEGF secretion by activation of Dopamine Receptor 2'''</span> <ref name="PMID25217874"><pubmed>25217874</pubmed></ref>

This research was carried out to investigate a possibility in whether a Dopamine Receptor 2 agonist '''(D2-ag)''' can assist in the prevention of Ovarian Hyperstimulation Syndrome, using rat models, by decreasing the ovarian vascular endothelial growth factor '''(VEGF)''' production. Using Immature Wistar rats (22 days old) as their animal model, the rats were initially stimulated with Gonadotrophins to mimic the onset and effects of OHSS and then subjected to treatment with a D2-agonist and/or a D2-antagonist (D2-ant). The vascular permeability was measured at the endpoint after day 26 by measuring the peritoneal extravasion of a previously injected dye and ovaries from all subjects were collected to assess the effects of D2-ag and D2-ant on the production of Ovarian VEGF. The expression of VEGF mRNA was measured by quantitative real time PCR and the levels of VEGF proteins were measured by Western Blots.

Results showed that the D2-ag caused a large reduction in the vascular permeability which was in turn associated with the great decreased in VEGF protein production in the OHSS rat ovaries, whereas the introduction of D2-ant showed opposite results with a increase in the vascular permeability leading to the increase of VEGF protein production in the ovaries. Ovarian VEGF mRNA levels were found to be unaffected by the introduction of these drugs in OHSS rat subjects. Conclusions were drawn on the fact that Dopamine Receptor 2 agonists prevent the increase of vascular permeability in subjects with OHSS by decreasing the ovarian production of VEGF and also that due to the dose-dependent inhibitory effect of the D2-ag on ovarian VEGF, current OHSS therapies used in humans can benefit by increasing the intraovarian concentration of D2-ag.
|}
</div>

==Glossary==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

'''Ascites'''- An accumulation of fluid in the peritoneal cavity with resultant abdominal swelling

'''Cabergoline''' - A dopamine receptor agonist used to treat hormone imbalance.

'''GnRH antagonist''' - Gonadotropin Releasing Hormone - A class of compounds that are similar in terms of the structure of natural Gonadotropin Releasing Hormone but has a antagonistic effect.

'''hCG'''- Human Chorionic Gonadotropin

'''Hemoconcentration'''- An increase in the concentration of circulating red blood cells in response to a decrease in blood plasma volume

'''Hypovolemic'''- A decrease in circulating blood volume

'''Iatrogenic'''- Illness caused as a result of a medical examination or treatment

'''Intravenous fluids''' - Is the infusion of liquid substances directly into a vein.

'''IVF'''- In-vitro Fertilization

'''NSAID'''- Non-steroidal Anti-Inflammatory Drug e.g. Ibuprofen

'''OHSS'''- Ovarian Hyper-stimulation Syndrome

'''FSH''' - Follicle Stimulating Hormone

'''LH''' - Luteinizing Hormone

'''Oliguria'''- Decreased urine output/small amounts of urine produced

</div>

==References==

2015 Group Project 2

2015-10-22T22:09:49Z

Z3372824: /* Diagnosis */

{{ANAT2341Project2015header}}

==<span style="font-size:120%">'''Ovarian Hyper-stimulation Syndrome (OHSS)'''</span>==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

Ovarian Hyper stimulation Syndrome (OHSS) is an iatrogenic complication of '''Assisted Reproduction Technology''' (ART), in which women take medications to stimulate oocyte growth. It is generally identified by cystic enlargements of the ovaries and fluid accumulation in the peritoneal cavity due to the increased capillary permeability and ovarian neoangiogenesis <ref name="PMID22065820"><pubmed>22065820</pubmed></ref>. It is an occurrence which is dependent on the controlled stimulation of the ovaries in preparation for IVF i.e. administration of human Chorionic Gonadotropin (hCG).

OHSS was first described in 1943 as ''“syndrome d’hyperluteinisation massive
des ovaries”''. It was during this time that gonadotropins were prepared from animals such as sheep to bring on ovulation in women. The first recorded death as a result of OHSS occurred in 1951 and was due to renal failure as a result of oligouria, a complication of the syndrome <ref name="OHSS"> Marie M. Budev, DO, MPH; Alejandro C. Arroliga, MD; Tommaso Falcone, MD, [ http://utilis.net/Morning%20Topics/REI/Ovarian%20Hyperstimulation.pdf ], 'Ovarian Hyperstimulation Syndrome'</ref> <ref name="PMID12638783"><pubmed>12638783</pubmed></ref>.

<span style="color:#FA58D0">This wikipage aims to provide clear information on various areas surrounding OHSS such as diagnosis, prevention and complications and will look into the genetics behind the disorder and the various animals models used to research it.</span>

<html5media height="350" width="450">https://www.youtube.com/watch?v=aXmjJw234a4</html5media>

'''Overview of the Ovarian Hyperstimulation Syndrome''' <ref> Howcast (2013, August 27) Ovarian Hyperstimulation Syndrome | Infertility. Retrieved from https://www.youtube.com/watch?v=aXmjJw234a4</ref>

</div>

==Epidemiology==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

Ovarian Hyper-Stimulation Syndrome (OHSS) rarely occurs sporadically, and if it does, it is usually the result of an underlying genetic problem. The majority of OHSS is due to the ovaries being stimulated to mature and release an abundance of oocytes, in response to hormones Human Chorionic Gonadotropin (hCG) and Follicle Stimulating hormone (FSH), during IVF. Rarely, Clomifene Citrate therapy can cause OHSS.<ref name="WikiOHSS"> Wikipedia, [ https://en.wikipedia.org/wiki/Ovarian_hyperstimulation_syndrome ], 'Ovarian Hyperstimulation Syndrome'</ref>

OHSS only affects '''0.5-5%''' of women undergoing Ovarian Hyper-stimulation, but despite its small prevalence, it is a potentially fatal outcome of a non-vital procedure and remains a prevalent problem for fertility specialists <ref name="PMID12498425"><pubmed>12498425</pubmed></ref> <ref name="PMID12638783"><pubmed>12638783</pubmed></ref>. Age has been cited as a factor affecting those with OHSS, with younger women more at risk. Additionally, women with allergies were seen to have a higher incidence of OHSS. It is important to note that at this point in time, there is no positive correlation between gonadotropin dose and OHSS.

Of the 0.5-5% of women affected with OHSS mentioned above, 2% of those women will require hospitalisation. As of 2011, it has been reported that the incidence of OHSS was '''increasing''', resulting in approximately 3 deaths per 100,000 women undergoing ovarian stimulation per year <ref name="PMID21828116"><pubmed>21828116</pubmed></ref>. This is particularly worrying as in 2008, in the United States alone, there were around 150,000 IVF cycles undertaken.

{|
|-bgcolor="F8E0F1"
|
'''With the field of Assisted Reproductive Technologies expanding and more women partaking in IVF treatments, the threat of women developing OHSS is an ongoing and increasing one''' <ref name="PMID21828116" />.
|}
{| class="wikitable mw-collapsible mw-collapsed"
! Characteristics of women by complication group <ref name="PMID19591989"><pubmed>19591989</pubmed></ref>
|-
! scope="col" width="100px" height="60px" style="text-align:center| '''Characteristic'''
! scope="col" width="100px" height="60px" style="text-align:center| '''No Complications
(N = 212,041)'''
! scope="col" width="100px" height="60px" style="text-align:center| '''Moderate OHSS
(N = 1,523)'''
! scope="col" width="100px" height="60px" style="text-align:center| '''Severe OHSS
(N = 655)'''
|-
|style="text-align:center; background: #FF99FF;"| '''Maternal Age (Mean ± SD)'''
|style="text-align:center; background: #F6CEEC;"| 35.6 ± 4.6
|style="text-align:center; background: #F6CEEC;"| 33.0 ± 4.3
|style="text-align:center; background: #F6CEEC;"| 33.1 ± 4.4
|-
|style="text-align:center; background: #FF99FF;"| '''Maternal Age (%)'''
|-
|style="text-align:left; background: #F6CEEC;"| <30 years
|style="text-align:center; background: #F6CEEC;"| 10 %
|style="text-align:center; background: #F6CEEC;"| 21.1 %
|style="text-align:center; background: #F6CEEC;"| 20.6 %
|-
|style="text-align:left; background: #F6CEEC;"| 30-34 years
|style="text-align:center; background: #F6CEEC;"| 30.4 %
|style="text-align:center; background: #F6CEEC;"| 43.2 %
|style="text-align:center; background: #F6CEEC;"| 40.5 %
|-
|style="text-align:left; background: #F6CEEC;"| 35-39 years
|style="text-align:center; background: #F6CEEC;"| 37.8 %
|style="text-align:center; background: #F6CEEC;"| 27.2 %
|style="text-align:center; background: #F6CEEC;"| 32.5 %
|-
|style="text-align:left; background: #F6CEEC;"| >40 years
|style="text-align:center; background: #F6CEEC;"| 21.8 %
|style="text-align:center; background: #F6CEEC;"| 8.4 %
|style="text-align:center; background: #F6CEEC;"| 6.4 %
|-
|style="text-align:center; background: #FF99FF;"| '''Nulligravida (%)'''
|style="text-align:center; background: #F6CEEC;"| 45.8 %
|style="text-align:center; background: #F6CEEC;"| 51.5 %
|style="text-align:center; background: #F6CEEC;"| 51.8 %
|-
|style="text-align:center; background: #FF99FF;"| '''Infertility Diagnosis (%)'''
|-
|style="text-align:left; background: #F6CEEC;"| Male factor
|style="text-align:center; background: #F6CEEC;"| 37.7 %
|style="text-align:center; background: #F6CEEC;"| 41.0 %
|style="text-align:center; background: #F6CEEC;"| 33.4 %
|-
|style="text-align:left; background: #F6CEEC;"| Endometriosis
|style="text-align:center; background: #F6CEEC;"| 13.5 %
|style="text-align:center; background: #F6CEEC;"| 13.5 %
|style="text-align:center; background: #F6CEEC;"| 10.7 %
|-
|style="text-align:left; background: #F6CEEC;"| Ovulation Disorders
|style="text-align:center; background: #F6CEEC;"| 14.0 %
|style="text-align:center; background: #F6CEEC;"| 29.5 %
|style="text-align:center; background: #F6CEEC;"| 22.4 %
|-
|style="text-align:left; background: #F6CEEC;"| Diminished ovarian reserve
|style="text-align:center; background: #F6CEEC;"| 16.9 %
|style="text-align:center; background: #F6CEEC;"| 3.2 %
|style="text-align:center; background: #F6CEEC;"| 2.4 %
|-
|style="text-align:left; background: #F6CEEC;"| Tubal factors
|style="text-align:center; background: #F6CEEC;"| 20.4 %
|style="text-align:center; background: #F6CEEC;"| 22.6 %
|style="text-align:center; background: #F6CEEC;"| 22.3 %
|-
|style="text-align:left; background: #F6CEEC;"| Uterine factors
|style="text-align:center; background: #F6CEEC;"| 5.1 %
|style="text-align:center; background: #F6CEEC;"| 4.3 %
|style="text-align:center; background: #F6CEEC;"| 3.1 %
|-
|style="text-align:left; background: #F6CEEC;"| Other factors
|style="text-align:center; background: #F6CEEC;"| 13.9 %
|style="text-align:center; background: #F6CEEC;"| 13.1 %
|style="text-align:center; background: #F6CEEC;"| 10.4 %
|-
|style="text-align:left; background: #F6CEEC;"| Unexplained factor
|style="text-align:center; background: #F6CEEC;"| 12.7 %
|style="text-align:center; background: #F6CEEC;"| 11.8 %
|style="text-align:center; background: #F6CEEC;"| 18.6 %
|-
|}
</div>

==Causative Agents==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

[[File:Follicular Development.jpeg|right|thumbnail|500px|Infertility treatments aim to facilitate follicular development and induce ovulation to improve chances of fertilisation <ref name="PMID24717179"><pubmed>24717179</pubmed></ref>]]

Normally a woman produces one egg per month from the ovaries, which travel down the Fallopian tube to be fertilized or be released from the body. In cases where women have difficulty falling pregnant, they are given medication which help them to produce and release eggs (as shown in the diagram to the right), further increasing their chances of fertilization and pregnancy <ref><pubmed>19573285</pubmed></ref>. Ovarian Hyper stimulation Syndrome generally occurs during infertility treatments when the ovaries are overstimulated by the fertility medication which causes the ovaries to swell and leak fluids into the belly and abdomen. The prevalence of OHSS onset is linked with excessive number of follicle development in response to the administration of injectable Follicle Stimulating Hormones (FSH) followed by the '''Human Chorionic Gonadotrophins''' (hCG) which triggers the release of the oocytes <ref><pubmed>26190539</pubmed></ref>.

'''Follicle Stimulating Hormones''' (FSH) <ref name="PMID9020850"><pubmed>9020850</pubmed></ref> are glycoprotein hormones that are produced and secreted from the Anterior Pituitary gland into the bloodstream, which regulate the developmental, growth, maturation and the reproductive processes within the body. In females, the Follicle Stimulating Hormones initiates the stages of growth and development of immature ovarian follicles within the ovaries before the release of an egg from a follicle at ovulation. When FSH is administered to a patient who is suffering from infertility, the increase FSH levels affect the rate of development and production, in turn increasing the amount of follicles which are ready to be released during ovulation.

</div>

==Symptoms==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

OHSS is classified based on a criteria from mild, moderate and severe <ref name="WikiOHSS" />:

'''Mild Symptoms'''- abdominal bloating, minimal weight gain, nausea, diarrhoea and a feeling of fullness.

'''Moderate Symptoms'''- Substantial weight gain (on average 2 or more pounds a day), increased abdominal girth, darkend urine and excessive thirst in addition to the mild symptoms.

'''Severe Symptoms'''- In addition to the symptoms associated with Mild and Moderate OHSS, in severe OHSS, you see shortness of breath, calf and chest pains and pleural effusion.

<span style="font-size:100%">'''Classifications of Ovarian Hyper-stimulation Syndrome:'''</span> <ref name="PMID22065820"><pubmed>22065820</pubmed></ref>
{| class="wikitable" style="text-align:center
|-
! scope="col" width="70px"| '''Classification'''
! scope="col" width="650px"| '''Symptoms'''
|-
|style="text-align:center; background: #F6CEEC;"| '''Mild'''
|style="height: 60px; background: #F6CEEC;"| '''Grade 1''' - Abdominal distention and discomfort
'''Grade 2''' - Abdominal distention, discomfort with nausea, vomiting and/or diarrhea and ovarian enlargement from 5~12cm
|-
|style="text-align:center; background: #F8E0F1;"| '''Moderate'''
|style="height: 60px; background: #F8E0F1;"| '''Grade 3''' - All features of Mild OHSS with ultrasonographic evidence of ascites
|-
|style="text-align:center; background: #F6CEEC;"| '''Severe'''
|style="height: 60px; background: #F6CEEC;"| '''Grade 4''' - All features of Moderate OHSS with the addition of clinical evidence of ascites and breathing difficulties present
'''Grade 5''' - All of the above symptoms along with a change in the blood volume, increased blood viscosity due to coagulation and diminished renal function
|}

</div>

==Diagnosis==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

Whilst symptoms of OHSS can occur as soon as 24 hours post hCG administration, they are usually seen in women 7-10 days post administration. Initially women with OHSS will present with abdominal bloating, as a result of fluid in the peritoneal cavity and an increase in ovary size. When women present with severe OHSS they are often dehydrated, due to increased vascular permeability, and have hemoconcentration. The above results in a decrease in intravascular volume, leading to '''oligouria''' <ref name="PMID22416285" />.

===History===

Initially a thorough history of the patient is taken during which the clinician looks for evidence of ovarian stimulation, followed by ovulation. During this history taking, the clinician will inquire into any weight gain noticed, urine output, and the woman's ability to maintain oral hydration. A key diagnostic tool for clinicians regarding women who are taking gonadotropins is to identify if they are at an increased risk of developing OHSS. Some risk factors include woman aged less than 30, women who have polycystic ovaries, woman with a previous history of OHSS and women who have had greater than 20 oocytes retrieved <ref name="PMID22416285" />.

===Physical Exam===
[[File:Vaginal_Ultrasonography_in_Sagittal_Plane.jpg|right|thumbnail|600px|Vaginal Ultrasonography in Sagittal plane <ref name="Wikiversity Journal of Medicine"> Häggström, Mikael. "Medical gallery of Mikael Häggström 2014". Wikiversity Journal of Medicine 1 (2). DOI:10.15347/wjm/2014.008. ISSN 20018762</ref>]]
After a history of the patient is taken, the next step is to perform a physical exam on the patient. Women who present with abdominal bloating will produce a shifting dullness upon abdominal percussion. Additionally the clinician will test the woman's vital signs, measure her abdominal girth, weight and will look for evidence of ascites or increase in calf size (usually unilateral)<ref name="PMID22416285" />.

===Investigations===

If the clinician further suspects a women of having OHSS, various investigations can be done such as an ultrasound.The intraperitoneal fluid is best imaged via vaginal ultrasound due to the enlarged ovaries making it difficult to image the pelvis using transabdominal ultrasound. The clinician can also order laboratory testing to look for urine specific gravity and and complete blood count to look for hemoconcentration with a hematocrit. Additionally, liver function tests can be ordered to look for elevated function. The clinician will also look for evidence of elevated D-dimers and fibrinogen and decreased levels of anti-thrombin 3 <ref name="SAHealth"> Government of South Australia Health [ http://www.sahealth.sa.gov.au/wps/wcm/connect/9b61ed004ee5348da663afd150ce4f37/Ovarian-hyperstimulation-syndrome-WCHN-PPG-17072012.pdf?MOD=AJPERES&CACHEID=9b61ed004ee5348da663afd150ce4f37 ], 'South Australian Paediatric Clinical Guidelines OHSS'</ref>.

====Ultrasound====

Typical appearances of the ultrasound include <ref name="Ultrasound"> Radiopaedia [ http://radiopaedia.org/articles/ovarian-hyperstimulation-syndrome-1 ], 'Ovarian Hyperstimulation Syndrome'</ref>:

*Bilaterally and symmetrically enlarged ovaries (>12cm)
* "Spoke-Wheel appearance" - presence of multiple cysts of varying size
*May also see ascites (fluid)

===Severity===

Once a clinician has deduced a women is suffering from OHSS, the severity of their condition needs to be established as either mild, moderate or severe. This is done by referring to the criteria under the sub-heading [[Symptoms]].The subsequent course of treatment for the woman will be based upon this evaluation.

{|
|-bgcolor="F6CEEC"
|
'''Further investigations''' can be done including a Chest X-ray to check for pleural effusions and oedema and USS with Doppler's to check for ascites or possible ovary torsion. <ref name="PMID22416285"><pubmed>22416285</pubmed></ref>
|}

===Differential Diagnosis===

Conditions presenting with similar symptoms or ultrasound images include <ref name="Ultrasound" />:

*Polycystic Ovaries (PO)
:: The difference is that with PO is that the cycts are typically smaller than OHSS cysts and there is no evidence of ascited or pleural effusion
*Mucinous Ovarian Malignancy
:: A type of Ovarian Epithelial tumour
*Ectopic Pregnancy <ref name="Casereport"> Australian Medical Student Journal [ http://www.amsj.org/wpcontent/uploads/files/articles/amsj_v2_i1/AMSJ_v2_i1_pg58-60.pdf ], 'Ovarian hyperstimulation syndrome'</ref>
::A pregnancy in which the foetus develops outside of the uterus e.g. in the fallopian tube

</div>

==Pathophysiology==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

[[File:Pathogenesis_of_OHSS.png|600px|thumb|Pathogenesis of OHSS <ref name="PMID20416867"><pubmed>20416867</pubmed></ref>]]

The definition of Ovarian Stimulation is enlarged ovaries with many luteinized cysts, that can present with secondary complications. What distinguishes Ovarian Stimulation from OHSS is the presence of vascular hyper-permeability that results in fluids being redirected elsewhere in the body.

The key process to OHSS appears to be caused by '''Vascular Endothelial Growth Factor''' (VEGF), that is released along with other cytokines, estrogen and progesterone, due to the ovary undergoing luteinization as a result of stimulation by hCG. VEGF increases vascular permeability and as a result the capillaries become more "leaky" to the fluids in them. These fluids can then escape the capillaries and accumulate in the pleural and abdominal cavities as ascites. The woman then becomes hypovolemic and is at an increased risk of circulatory, renal and respiratory issues such as arterial thromboembolism due to the thickening of the blood. Note, the blood is thickened as fluid is leaving the capillaries, leaving behind red blood cells and other cellular components of the blood <ref name="WikiOHSS" />.

The increase in expression of VEGF and VEGF Receptor 2 (VEGFR2) is attributed to the greatly increased amount of their mRNA present in the body after stimulation with hCG <ref name="PMID21082502"><pubmed>21082502</pubmed></ref>. VEGF interacts with VEGF2 and VEGF Receptor 1 (VEGFR1) to create a strong angiogenic effect. Both VEGFR2 and VEGFR1 belong to a family of receptors called tyrosine kinases. VEGF2 is involved in the regulation of angiogenesis and vascular permeability whilst VEGF1 has a slightly contradictory role in that is is involved in the maintenance of the tight junctions between endothelial cells in blood vessels. A study by Gómez ''et. al.'' <ref name="PMID21082502" /> showed that women experiencing OHSS had substantially higher plasma levels of VEGF and lower levels of VEGFR1.

</div>

==Complications==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

Ovarian torsion or rupture, renal insufficiency and thrombophlebitis can all complicate OHSS. If a pregnancy occurs, symptoms may persist longer than the usual 1 to 2 weeks and become more severe, however, even with severe OHSS, they do not extend past the first trimester <ref name="WikiOHSS" />.

<span style="color:#FA58D0"> '''1-2% of women who undergo ovarian stimulation develop a severe form of OHSS''' </span>. Complications from severe OHSS include:

*Fluid collection in the abdomen
*Electrolyte disturbances (sodium and potassium)
*Kidney failure
*Ovary twisting
*Rupture of a cyst in an ovary
*Breathing problems
*Blood clots in large vessels (most commonly the legs)
*Pregnancy loss from miscarriage or termination
*Rarely, death

A study by Nouri ''et. al.'' <ref name="PMID24996451"><pubmed>24996451</pubmed></ref> found that women with '''Polycystic Ovarian Syndrome''' (PCOS) and those that were induced with hCG experienced longer recovery times from severe OHSS than women who were not pregnant. They looked at a cohort of women hospitalised for the first time with severe OHSS and subject them to the same treatments. Based on a defined criteria, they established the recovery time of these women and compared the times between those that were pregnant to those that were not pregnant. They also found that whether a woman had PCOS or ovulation induction did not affect her risk of developing OHSS if she was not pregnant. It is only a risk factor for pregnant women.

===Thromboembolic events===

A frequent and deadly complication of OHSS are thromboembolic events due to increased blood clotting. This increase in blood clotting has been attributed to a variety of complications such as hemoconcentration (which thickens the blood), hypolvolemia and an increase in the permeability of blood vessels as a result of increased vasoactive substances in the body of ovarian origin. Thromboembolic events include venous thromboses often in the upper extremities and arterial thromboses such as those in the cerebrovascular region. These events can lead to amputations of extremities, brain damage, miscarriage and death. To avoid this, anti-coagulants are given to pateitns with OHSS and they are fitted with compression stockings (see [[Treatment]]) <ref name="PMID23378404"><pubmed>23378404</pubmed></ref>.

{|
|-bgcolor="F8E0F1"
|
The risk of a woman developing OHSS is higher if she is having a '''twin pregnancy''', as she is exposed to higher concentration of hCG. <ref name="PMID9756273"><pubmed>9756273</pubmed></ref>
|}

</div>

==Treatment==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

'''General treatment
'''
*''Acetaminophen'' with or without a narcotic agent- used to treat abdominal discomfort
*Women are encouraged to drink 2-3 litres of water a day to prevent hemoconcentration
*Women are advised to avoid sexual intercourse and vigorous exercise at the risk of torsion or rupture of the ovaries
*NSAID's with anti-platelet properties should NOT be used as they may effect renal function in a women with OHSS
*Patients with significantly painful ascites or breathing problems may undergo ''Paracentesis'' (drainage of the ascites)
*''Culdocentesis'' (extraction of fluid from recto-uterine pouch) can be done to decrease the likelihood of a woman with moderate OHSS progressing to severe OHSS.<ref name="PMID22416285" />

===Mild to Moderate OHSS===

Mild OHSS can often resolve on its own, however, moderate OHSS may include treatments such as<ref name="WikiOHSS" />:

*Anti-nausea medication and prescription painkillers
*Regular physical examinations and ultrasounds
*Daily weigh-ins and waist measurements
*Measuring the amount of urine produced each day
*Frequent blood tests for monitoring dehydration and electrolyte imbalance
*Maintaining a high balance of fluids
*Drainage of excess abdominal fluid by inserting a needle in the abdominal cavity
*Wearing support stockings which help prevent blood clots/thrombosis

===Severe OHSS===

Severe OHSS requires hospital care in order for constant monitoring and treatment such as <ref name="WikiOHSS" />:

*Intravenous fluids with a crystalloid solution (100-150mL/hr)
*Intravenous Albumin is administered is IV fluids are insufficient (15-20mL/hr of 25% albumin for 4 hrs)
*In addition to Acetaminophen, ''Opioid analgesics'' can be administered for pain relief
*''Antiemetics'' can be used to subside nauseas and/or vomiting
*Woman administered to hospital of OHSS are considered at high risk of thromboembolic complications and are given low molecular weight ''heparin'', an anti-coagulant
*''Cabergoline''- lessens OHSS symptoms
*''GnRH agonist''- suppresses ovarian activity
**If at risk of OHSS, alternates include using a GnRH agonist instead of hCG however its effects on pregnancy rates are questionable. Using a GnRH agonist to replace the use of hCG for final oocyte stimulation will see a 6% decrease in delivery rate.

*Daily monitoring of creatine, urea, creatine clearance C-reactive protein (to rule out infection) are all required in combination with weekly tests such as liver and renal function tests and chest x-rays (to check for pleural effusion) <ref name="PMID12638783" />.

If there are serious complications then additional treatments are required:

*Surgery for a ruptured ovarian cyst
*Intensive care for the liver or lung complications

====Paracentesis====

For women with severe/grade 3 OHSS, paracentesis, the removal of fluid from the body using an aspiration needle, can be undertaken. It is a diagnostic and a therapeutic method that can be done trans-abdominally and trans-vaginally. It is used to relieve symptoms, improve haemodynamics e.g. Urinary output, and shorten the women's hospital stay. Complications of paracentesis include bleeding, infection and organ injury, however are note common <ref name="Paracentesis"> S. Monica Soni, HMS 3, Gillian Lieberman, MD [ http://eradiology.bidmc.harvard.edu/LearningLab/genito/Soni.pdf ], 'Ovarian Hyperstimulation Syndrome'</ref>.

{|
|-bgcolor="F8E0F1"
|
The most important aspect of treatment for any women with OHSS is close and constant '''monitoring''' with her healthcare professional. Counselling may also be provided to women and their partners or families in order to provide them with the best possible knowledge base to manage and treat their OHSS. It is important to note that there is '''no one cure or treatment''' for OHSS. Treatment involves managing and eliminating the symptoms until such time as the syndrome resolves itself <ref name="WikiOHSS" />.
|}

</div>

==Prevention==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

There are three key avenues through which the incidence of OHSS may be prevented. These include identifying risk factors to predict OHSS development, modifying treatment regimes on the basis of the identified risk factors and intervention to prevent progression to OHSS once the patient has undergone Controlled Ovarian Stimulation.

=== Risk factors===

'''Primary risk factors'''

Pre-existing factors likely to exacerbate the ovarian stimulation response. Primary risk factors include <ref name="PMID26074966"><pubmed>26074966</pubmed></ref>:

*Young age
*Low body weight
*History of elevated response to gonadotropins
*Polycystic Ovary Syndrome (PCOS)
*Isolated PCOS characteristic
*A previous history of OHSS.
*Hormonal markers (e.g. Anti-Mullerian Hormone markers)
*Ultrasonographic markers (e.g. Antral Follicle Count)

'''Secondary risk factors'''

Secondary risk factors involve the monitoring of ovarian response parameters once COS has been initiated. These parameters are monitored for <ref name="PMID19007627"><pubmed>19007627</pubmed></ref>:

*rapidly rising E2 levels
*E2 concentration larger than 2500 pg/mL
*large number of developing follicles (10-14mm) on the day hCG is administered
*large number of oocytes retrieved

These factors in combination, act as a predictive tool to assess the likelihood of severe OHSS development, with a 83% sensitivity and 84% specificity. <ref name="PMID19007627"/>

=== Primary Prevention===

Primary Prevention involves the modification of treatment regimens on the basis of OHSS risk classifications, in order to prevent OHSS occurrence.

'''Ovulation Induction'''

Unifollicular Ovulation Induction through Ovulation Induction (OI) is a primary means of avoiding OHSS in women with Polycystic Ovarian Syndrome, who are at an increased risk. In order to promote unifollicular development, the ovaries are stimulated with a low starting dose of FSH (75 IU).<ref name="PMID20416867"><pubmed>20416867</pubmed></ref> Studies suggests that a minimum gonadotropin dose lowers OHSS risk and thus a step-up regimen is utilised to achieve an ovarian response, whereby the FSH dosage is increased every 7 days until follicular development of greater than 10mm is noted.<ref name="PMID26074966" /> Alternatively, a step-down regimen may be followed, whereby a high initial FSH dosage is lowered according to the ovarian response. Another method to increase FSH levels during OI, is through Aromatase Inhibitors which promote folliculogenesis by increasing pituitary secretion of FSH, and downregulate oestrogen production through a negative feedback loop. However, Aromatase Inhibitors have not been shown to reduce OHSS incidence in comparison to other methods of OI.<ref name="PMID26074966" /> During OI, a key objective is to prevent early cycle cancellation due to premature luteinisation from pituitary secretion of LH. In order to downregulate LH secretion, Gonadotropin-releasing hormone agonists (GnRHa) are administered in addition to gonadotropins. Alternatively, GnRH antagonists may be administered to downregulate endogenous LH secretion. Comparative studies have shown that the GnRH antagonist protocol has a greater effect in lowering the incidence of mild to severe OHSS. However due to the rare nature of OHSS, and insufficient sample sizes, the difference was not found to be significant. <ref name="PMID21082508"><pubmed>21082508</pubmed></ref>. Generally, the duration of exposure to gonadotropins and subsequent risk of OHSS may be minimised through mild stimulation protocols which administer FSH only in the mid to late follicular phase.<ref name="PMID20416867" />

'''Adjuvant Metformin Therapy'''

Adjuvant Metformin Therapy has been found to lower the risk of OHSS by 63%.<ref name="PMID25406011"><pubmed>25406011</pubmed></ref> It involves the administration of metformin at a daily dosage of 1000 to 2000mg, 2 months prior to Controlled Ovarian Stimulation <ref name="PMID26074966"/>. Metformin lowers the elevated insulin levels in PCOS which consequently reduce intraovarian androgen levels. This leads to a reduced sensitivity and expression of granulosa cell-follicle stimulating hormone receptors which result in a less exaggerated response to gonadotropins. Furthermore, it is suggested that Metformin prevents OHSS by controlling vascular permeability through the inhibition of various vasoactive molecules, including VEGF.

'''Avoiding hCG during Luteal Phase Support

Following Controlled Ovarian Stimulation, the steroid levels of E2 and P4 are reduced during the luteal phase due to the negative feedback on the pituitary. This leads to low endogenous LH levels, which consequently reduce endometrial receptivity as well as the luteal phase duration itself. As a result, implantation and pregnancy rates are reduced and early pregnancy loss rates are increased.<ref name="PMID20416867" /> Luteal Phase Support (LPS) serves to combat these adverse events with the use of hCG. However, hCG has been found to increase the risk of OHSS. Alternatively, the use of progesterone has been found to not only halve the risk of OHSS, but also induce similar improvements in pregnancy and miscarriage rates as hCG.<ref name="PMID26148507"><pubmed>26148507</pubmed></ref>

===Secondary Prevention===

Secondary Prevention aims to prevent progression to OHSS once COS has been initiated and the patient has been found to mount an exaggerated response. <ref name="PMID20416867" />

'''Coasting'''

Coasting is a first-line secondary preventative strategy. It consists of the withdrawal of gonadotrophins when a critical number of follicles and/or E2 concentration is reached. hCG is administered once the E2 concentration reduces to a safe level, before the process of oocyte retrieval commences. This preventative strategy is conducted for a period of less than 3 days in order to avoid compromising IVF outcomes.

'''Cryopreservation'''

Cryopreservation of embryos after oocyte retrieval is another avenue which may avert OHSS progression. The cryopreserved embryos are only reimplanted once the patient's hormone serum levels have normalised. Using oocyte vitrification, crystal formation within embryo tissue is avoided and so cryopreserved embryos have been found to produce better pregnancy rates with a 32% increase, than fresh embryo transfer. Recent studies suggest cryopreservation itself does not reduce OHSS rates, but must be followed by a GnRHa trigger to avert OHSS.

'''Cycle cancellation'''

Cycle cancellation is a guaranteed method to prevent early OHSS whereby hCG is withheld. This is a last resort strategy as it carries the risk of significant psychological distress and financial loss for the patient.

</div>

==Effect on the Newborn==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

</div>
Women who develop OHSS while undergoing Assisted Reproductive Technologies (ART) treatment are not only more likely to achieve a pregnancy, but have a live birth as the pregnancy outcome. This live birth is also more likely to be a multiple birth of two, three or more children. <ref name="PMID19591989"><pubmed>19591989</pubmed></ref> It has been postulated that a multifetal pregnancy leads to a more rapid increase in hCG levels, resulting in an increased risk of OHSS. However, the causal nature between multifetal pregnancy and OHSS development is disputed and further research is required to distinguish correlation from causation. <ref name="PMID19573292"><pubmed>19573292</pubmed></ref>

OHSS development is also associated with an increased risk of adverse outcomes including stillbirth, premature birth and low birthweight.<ref name="PMID19591989" /> Although the cause for the increased risk in adverse pregnancy outcomes is unknown, it is suggested that as the incidence of OHSS is reduced through various prevention strategies, the risk of such outcomes may be also be reduced.

==Genetics==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

Despite OHSS typically being of iatrogenic origin as a result of ovarian stimulation with gonadotropins, research has been conducted into the potential genetics behind OHSS as many sporadic and familial cases have been observed. '''Mutations''' in the receptor for hormones such as Follicle Simulating Hormone (FSH), Lutenizing Hormone (LH) and hCG have all been targets of OHSS genetics research. Interestingly, they too also arise from a common ancestral gene.

===Follicle Stimulating Hormome===

Dr. Botros Rizk, of the University of South Alabama College of Medicine <ref name="PMID19573286"><pubmed>19573286</pubmed></ref>, has written extensively regarding the genetics behind OHSS. In particular, he talks about '''FSH receptors''' (FSHR) and their role in the syndrome. He hypothesises that mutations in these receptors could be activating or inactivating, leading to an increased risk of developing OHSS or sterility respectively. Currently, 744 single nucleotide polymorphisms (a type of mutation) have been found in the gene encoding the FSHR, 8 of which are located in its exons (coding regions of the gene). How the ovary responds is resultant on the FSHR genotype. For example, Ser680Asn, a polymorphism in the FSHR gene has been shown to aid in predicting the severity of a woman's OHSS. Ordinarily FSH stimulates the growth of ovarian follicles, however, when mutated, it is stimulated by the hCG resulting in excessive follicle development.

Spontaneous OHSS, OHSS that arises and cannot be attributed to any form of ovarian stimulation or Assisted Reproductive Technology, has been linked to activating mutations in the FSHR <ref name="PMID23499866"><pubmed>23499866</pubmed></ref>. This familial disorder is an autosomal dominant one. In most cases the FSHR can be stimulated by the presence of Thyroid Stimulating Hormone (TSH) or hCG, in the absence of FSH (the ligand for FSHR).

===Lutenizing Hormome===

The '''Lutenizing Hormone Receptor''' (LHR) gene in humans is comprised of 11 exons. Animal studies have shown that many primates exhibit a similar gene which is comprised of only 10 exons, however a gene lacking the 10th exon has been identified and termed the type 2 LHR. Expression of the type 2 LHR has been seen in humans. The type 2 LHR, compared to the wild-type LHR appears to be repaired with regard to its function. Defects in the type 2 LHR include a decrease in efficiency of transport to the plasma membrane and irregularities in signal transduction. Inactivating mutations in the LHR have been seen to cause infertility in women as well as amenorrhoea. Activating LHR gene mutations are asymptomatic and are not associated with OHSS in women.

===Bone Morphogenic Protein===

An imporant growth factor, derived from oocytes called '''BMP-15''' (Bone Morphogenic Protein 15) is vital for female fertility. It belongs to the family of growth factors, Transforming Growth Factor β (TGF-β) and is heavily involved in folliculogenesis. It has been found that mutations in the BMP-15 gene caused infertility in female sheep. Conversely, it has also been indicated in enhanced fertility when BMP-15 is present is high amounts in follicular fluid <ref name="PMID19573286" />.

A case study done by Hanevik ''et. al.'' in 2013 <ref name="PMID21565556"><pubmed>21565556</pubmed></ref> found that a Single Nuclear Polymorphism (SNP) in the BMP-15 gene is responsible for a high response to ovarian hyper-stimulation. The aim of the study was to test the effect the SNP had on BMP-15 with regard to high and low responders buy taking blood from 53 high responders, 38 low responders and 100 non-responders (controls) and analysing 5 noted SNP's. Results from their study showed a correlation between a high response to ovarian hyper-stimulation and the BMP-15 9G allele. The article does state however, that further research is required into the molecular effects of SNP's on the function of BMP-15.

===Vascular Endothelial Growth Factor===

'''Vascular endothelial growth factor''' (VEGF) has been indicated as one of the key agents causing vascular permeability and subsequent ascites in OHSS. The gene, which is located on chromosome 12, is made up of 8 exons (coding regions), of which exons 6 and 7 do not always appear due to the exons being spliced out.The splicing of this gene allows for various isoforms of the gene to exist of which VEGF 121 and 165 appear to play a role in angiogenesis. There are two VEGF Receptors, VEGFR-1 and VEGFR-2 that belong to the tyrosine kinase family of receptors (for more information on VEGF see [[Pathophysiology]]). Because of its distinct role in OHSS, it has been targeted as an area for research for potential treatments. The idea is that if the genetic expression of VEGF and its receptors can be controlled, OHSS can be avoided or treated.<ref name="PMID19573286" />

A different study by Hanevik ''et. al.'' , <ref name="PMID22587628"><pubmed>22587628</pubmed></ref> done in 2012 involved analysing blood samples from 53 women with OHSS and 100 women without it (controls) and analysing 6 SNP's in the VEGFR2 gene to find any genetic variations. They found a correlation between women with the VEGF +405cc genotype and the development of OHSS indicating women that undergo controlled ovarian hyper-stimulation and posses his genotype, are at an increased risk of developing OHSS.

</div>

== Current Research on Animal Models==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">
{|
|-bgcolor="F8E0F1"
|
<span style="font-size:120%">'''Inhibition of Cyclooxygenase-2 (COX-2) by Meloxican decreasing the incidence of OHSS in Rat Model'''</span> <ref name="PMID18166186"><pubmed>18166186</pubmed></ref>

Reasearch was carried out to investigate the effects of selective inhibition of the enzyme COX-2 on the Ovarian Hyperstimulation Syndrome (OHSS) using Female Wistar rates as the subjects. The research aimed to find results by measuring the number of antral and luteinized follicles, ovarian weight, vascualr endothelial growth factors and COX-2 immunohistochemistry. The rats being tested were all 22 days old and were divided into four equal groups;

'''Group 1 (Control group)''' was subject to a 0.1 ml of Intraperitoneal Saline from days 22 ~ 26

'''Group 2 (Mildly-stimulated group)''' subject to 10IU of pregnant mare serum gonadotrophin (PMSG) on day 24 and then 10IU of Human Chorionic Gonadotrophin (hCG) on day 26

'''Group 3 (OHSS positive group)''' was subject to 10IU of PMSG from days 22 ~ 26 and then administered 30IU of hCG on day 26 to induce OHSS

'''Group 4 (OHSS positive variant group)''' received 15mg/ml of Meloxicam 2 hours prior to administration of 10IU PMSG from days 22 ~ 26

Results showed there was no difference in ovarian weight in samples from Group 1 and Group 2, however Group 3 showed signs of significant ovarian weight increase which in group 4 was suppressed by the introduction of Meloxicam. No differences were observed in the number of antral follicles amongst the four test groups. Results from Group 2 and Group 3 showed that the granulosa cells of preovulatory follicles and the stromal cells were highly VEGF immunoreactive, however the Meloxicam treated Group 4 showed less immunoreactivity than Group 2 and Group 3 which indicated the correlation between Meloxicam and the diminished VEGF expression. Group 3 presented an increased COS-2 immunoreactivity which was highly diminished than in Group 4.

The research concluded that in a rat model, the enzyme Meloxicam has a beneficial effect on OHSS by reducing the increase of ovarian weight and the expression of VEGF associated with OHSS, the effects of which may be mediated by the inhibitory capacity of COX-2 on Meloxicam
|}

{|
|-bgcolor="FF99FF"
|
<span style="font-size:120%">'''Inhibition of Ovarian VEGF secretion by activation of Dopamine Receptor 2'''</span> <ref name="PMID25217874"><pubmed>25217874</pubmed></ref>

This research was carried out to investigate a possibility in whether a Dopamine Receptor 2 agonist '''(D2-ag)''' can assist in the prevention of Ovarian Hyperstimulation Syndrome, using rat models, by decreasing the ovarian vascular endothelial growth factor '''(VEGF)''' production. Using Immature Wistar rats (22 days old) as their animal model, the rats were initially stimulated with Gonadotrophins to mimic the onset and effects of OHSS and then subjected to treatment with a D2-agonist and/or a D2-antagonist (D2-ant). The vascular permeability was measured at the endpoint after day 26 by measuring the peritoneal extravasion of a previously injected dye and ovaries from all subjects were collected to assess the effects of D2-ag and D2-ant on the production of Ovarian VEGF. The expression of VEGF mRNA was measured by quantitative real time PCR and the levels of VEGF proteins were measured by Western Blots.

Results showed that the D2-ag caused a large reduction in the vascular permeability which was in turn associated with the great decreased in VEGF protein production in the OHSS rat ovaries, whereas the introduction of D2-ant showed opposite results with a increase in the vascular permeability leading to the increase of VEGF protein production in the ovaries. Ovarian VEGF mRNA levels were found to be unaffected by the introduction of these drugs in OHSS rat subjects. Conclusions were drawn on the fact that Dopamine Receptor 2 agonists prevent the increase of vascular permeability in subjects with OHSS by decreasing the ovarian production of VEGF and also that due to the dose-dependent inhibitory effect of the D2-ag on ovarian VEGF, current OHSS therapies used in humans can benefit by increasing the intraovarian concentration of D2-ag.
|}
</div>

==Glossary==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

'''Ascites'''- An accumulation of fluid in the peritoneal cavity with resultant abdominal swelling

'''Cabergoline''' - A dopamine receptor agonist used to treat hormone imbalance.

'''GnRH antagonist''' - Gonadotropin Releasing Hormone - A class of compounds that are similar in terms of the structure of natural Gonadotropin Releasing Hormone but has a antagonistic effect.

'''hCG'''- Human Chorionic Gonadotropin

'''Hemoconcentration'''- An increase in the concentration of circulating red blood cells in response to a decrease in blood plasma volume

'''Hypovolemic'''- A decrease in circulating blood volume

'''Iatrogenic'''- Illness caused as a result of a medical examination or treatment

'''Intravenous fluids''' - Is the infusion of liquid substances directly into a vein.

'''IVF'''- In-vitro Fertilization

'''NSAID'''- Non-steroidal Anti-Inflammatory Drug e.g. Ibuprofen

'''OHSS'''- Ovarian Hyper-stimulation Syndrome

'''FSH''' - Follicle Stimulating Hormone

'''LH''' - Luteinizing Hormone

'''Oliguria'''- Decreased urine output/small amounts of urine produced

</div>

==References==

2015 Group Project 2

2015-10-22T22:05:53Z

Z3372824: /* Primary Prevention */

{{ANAT2341Project2015header}}

==<span style="font-size:120%">'''Ovarian Hyper-stimulation Syndrome (OHSS)'''</span>==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

Ovarian Hyper stimulation Syndrome (OHSS) is an iatrogenic complication of '''Assisted Reproduction Technology''' (ART), in which women take medications to stimulate oocyte growth. It is generally identified by cystic enlargements of the ovaries and fluid accumulation in the peritoneal cavity due to the increased capillary permeability and ovarian neoangiogenesis <ref name="PMID22065820"><pubmed>22065820</pubmed></ref>. It is an occurrence which is dependent on the controlled stimulation of the ovaries in preparation for IVF i.e. administration of human Chorionic Gonadotropin (hCG).

OHSS was first described in 1943 as ''“syndrome d’hyperluteinisation massive
des ovaries”''. It was during this time that gonadotropins were prepared from animals such as sheep to bring on ovulation in women. The first recorded death as a result of OHSS occurred in 1951 and was due to renal failure as a result of oligouria, a complication of the syndrome <ref name="OHSS"> Marie M. Budev, DO, MPH; Alejandro C. Arroliga, MD; Tommaso Falcone, MD, [ http://utilis.net/Morning%20Topics/REI/Ovarian%20Hyperstimulation.pdf ], 'Ovarian Hyperstimulation Syndrome'</ref> <ref name="PMID12638783"><pubmed>12638783</pubmed></ref>.

<span style="color:#FA58D0">This wikipage aims to provide clear information on various areas surrounding OHSS such as diagnosis, prevention and complications and will look into the genetics behind the disorder and the various animals models used to research it.</span>

<html5media height="350" width="450">https://www.youtube.com/watch?v=aXmjJw234a4</html5media>

'''Overview of the Ovarian Hyperstimulation Syndrome''' <ref> Howcast (2013, August 27) Ovarian Hyperstimulation Syndrome | Infertility. Retrieved from https://www.youtube.com/watch?v=aXmjJw234a4</ref>

</div>

==Epidemiology==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

Ovarian Hyper-Stimulation Syndrome (OHSS) rarely occurs sporadically, and if it does, it is usually the result of an underlying genetic problem. The majority of OHSS is due to the ovaries being stimulated to mature and release an abundance of oocytes, in response to hormones Human Chorionic Gonadotropin (hCG) and Follicle Stimulating hormone (FSH), during IVF. Rarely, Clomifene Citrate therapy can cause OHSS.<ref name="WikiOHSS"> Wikipedia, [ https://en.wikipedia.org/wiki/Ovarian_hyperstimulation_syndrome ], 'Ovarian Hyperstimulation Syndrome'</ref>

OHSS only affects '''0.5-5%''' of women undergoing Ovarian Hyper-stimulation, but despite its small prevalence, it is a potentially fatal outcome of a non-vital procedure and remains a prevalent problem for fertility specialists <ref name="PMID12498425"><pubmed>12498425</pubmed></ref> <ref name="PMID12638783"><pubmed>12638783</pubmed></ref>. Age has been cited as a factor affecting those with OHSS, with younger women more at risk. Additionally, women with allergies were seen to have a higher incidence of OHSS. It is important to note that at this point in time, there is no positive correlation between gonadotropin dose and OHSS.

Of the 0.5-5% of women affected with OHSS mentioned above, 2% of those women will require hospitalisation. As of 2011, it has been reported that the incidence of OHSS was '''increasing''', resulting in approximately 3 deaths per 100,000 women undergoing ovarian stimulation per year <ref name="PMID21828116"><pubmed>21828116</pubmed></ref>. This is particularly worrying as in 2008, in the United States alone, there were around 150,000 IVF cycles undertaken.

{|
|-bgcolor="F8E0F1"
|
'''With the field of Assisted Reproductive Technologies expanding and more women partaking in IVF treatments, the threat of women developing OHSS is an ongoing and increasing one''' <ref name="PMID21828116" />.
|}
{| class="wikitable mw-collapsible mw-collapsed"
! Characteristics of women by complication group <ref name="PMID19591989"><pubmed>19591989</pubmed></ref>
|-
! scope="col" width="100px" height="60px" style="text-align:center| '''Characteristic'''
! scope="col" width="100px" height="60px" style="text-align:center| '''No Complications
(N = 212,041)'''
! scope="col" width="100px" height="60px" style="text-align:center| '''Moderate OHSS
(N = 1,523)'''
! scope="col" width="100px" height="60px" style="text-align:center| '''Severe OHSS
(N = 655)'''
|-
|style="text-align:center; background: #FF99FF;"| '''Maternal Age (Mean ± SD)'''
|style="text-align:center; background: #F6CEEC;"| 35.6 ± 4.6
|style="text-align:center; background: #F6CEEC;"| 33.0 ± 4.3
|style="text-align:center; background: #F6CEEC;"| 33.1 ± 4.4
|-
|style="text-align:center; background: #FF99FF;"| '''Maternal Age (%)'''
|-
|style="text-align:left; background: #F6CEEC;"| <30 years
|style="text-align:center; background: #F6CEEC;"| 10 %
|style="text-align:center; background: #F6CEEC;"| 21.1 %
|style="text-align:center; background: #F6CEEC;"| 20.6 %
|-
|style="text-align:left; background: #F6CEEC;"| 30-34 years
|style="text-align:center; background: #F6CEEC;"| 30.4 %
|style="text-align:center; background: #F6CEEC;"| 43.2 %
|style="text-align:center; background: #F6CEEC;"| 40.5 %
|-
|style="text-align:left; background: #F6CEEC;"| 35-39 years
|style="text-align:center; background: #F6CEEC;"| 37.8 %
|style="text-align:center; background: #F6CEEC;"| 27.2 %
|style="text-align:center; background: #F6CEEC;"| 32.5 %
|-
|style="text-align:left; background: #F6CEEC;"| >40 years
|style="text-align:center; background: #F6CEEC;"| 21.8 %
|style="text-align:center; background: #F6CEEC;"| 8.4 %
|style="text-align:center; background: #F6CEEC;"| 6.4 %
|-
|style="text-align:center; background: #FF99FF;"| '''Nulligravida (%)'''
|style="text-align:center; background: #F6CEEC;"| 45.8 %
|style="text-align:center; background: #F6CEEC;"| 51.5 %
|style="text-align:center; background: #F6CEEC;"| 51.8 %
|-
|style="text-align:center; background: #FF99FF;"| '''Infertility Diagnosis (%)'''
|-
|style="text-align:left; background: #F6CEEC;"| Male factor
|style="text-align:center; background: #F6CEEC;"| 37.7 %
|style="text-align:center; background: #F6CEEC;"| 41.0 %
|style="text-align:center; background: #F6CEEC;"| 33.4 %
|-
|style="text-align:left; background: #F6CEEC;"| Endometriosis
|style="text-align:center; background: #F6CEEC;"| 13.5 %
|style="text-align:center; background: #F6CEEC;"| 13.5 %
|style="text-align:center; background: #F6CEEC;"| 10.7 %
|-
|style="text-align:left; background: #F6CEEC;"| Ovulation Disorders
|style="text-align:center; background: #F6CEEC;"| 14.0 %
|style="text-align:center; background: #F6CEEC;"| 29.5 %
|style="text-align:center; background: #F6CEEC;"| 22.4 %
|-
|style="text-align:left; background: #F6CEEC;"| Diminished ovarian reserve
|style="text-align:center; background: #F6CEEC;"| 16.9 %
|style="text-align:center; background: #F6CEEC;"| 3.2 %
|style="text-align:center; background: #F6CEEC;"| 2.4 %
|-
|style="text-align:left; background: #F6CEEC;"| Tubal factors
|style="text-align:center; background: #F6CEEC;"| 20.4 %
|style="text-align:center; background: #F6CEEC;"| 22.6 %
|style="text-align:center; background: #F6CEEC;"| 22.3 %
|-
|style="text-align:left; background: #F6CEEC;"| Uterine factors
|style="text-align:center; background: #F6CEEC;"| 5.1 %
|style="text-align:center; background: #F6CEEC;"| 4.3 %
|style="text-align:center; background: #F6CEEC;"| 3.1 %
|-
|style="text-align:left; background: #F6CEEC;"| Other factors
|style="text-align:center; background: #F6CEEC;"| 13.9 %
|style="text-align:center; background: #F6CEEC;"| 13.1 %
|style="text-align:center; background: #F6CEEC;"| 10.4 %
|-
|style="text-align:left; background: #F6CEEC;"| Unexplained factor
|style="text-align:center; background: #F6CEEC;"| 12.7 %
|style="text-align:center; background: #F6CEEC;"| 11.8 %
|style="text-align:center; background: #F6CEEC;"| 18.6 %
|-
|}
</div>

==Causative Agents==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

[[File:Follicular Development.jpeg|right|thumbnail|500px|Infertility treatments aim to facilitate follicular development and induce ovulation to improve chances of fertilisation <ref name="PMID24717179"><pubmed>24717179</pubmed></ref>]]

Normally a woman produces one egg per month from the ovaries, which travel down the Fallopian tube to be fertilized or be released from the body. In cases where women have difficulty falling pregnant, they are given medication which help them to produce and release eggs (as shown in the diagram to the right), further increasing their chances of fertilization and pregnancy <ref><pubmed>19573285</pubmed></ref>. Ovarian Hyper stimulation Syndrome generally occurs during infertility treatments when the ovaries are overstimulated by the fertility medication which causes the ovaries to swell and leak fluids into the belly and abdomen. The prevalence of OHSS onset is linked with excessive number of follicle development in response to the administration of injectable Follicle Stimulating Hormones (FSH) followed by the '''Human Chorionic Gonadotrophins''' (hCG) which triggers the release of the oocytes <ref><pubmed>26190539</pubmed></ref>.

'''Follicle Stimulating Hormones''' (FSH) <ref name="PMID9020850"><pubmed>9020850</pubmed></ref> are glycoprotein hormones that are produced and secreted from the Anterior Pituitary gland into the bloodstream, which regulate the developmental, growth, maturation and the reproductive processes within the body. In females, the Follicle Stimulating Hormones initiates the stages of growth and development of immature ovarian follicles within the ovaries before the release of an egg from a follicle at ovulation. When FSH is administered to a patient who is suffering from infertility, the increase FSH levels affect the rate of development and production, in turn increasing the amount of follicles which are ready to be released during ovulation.

</div>

==Symptoms==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

OHSS is classified based on a criteria from mild, moderate and severe <ref name="WikiOHSS" />:

'''Mild Symptoms'''- abdominal bloating, minimal weight gain, nausea, diarrhoea and a feeling of fullness.

'''Moderate Symptoms'''- Substantial weight gain (on average 2 or more pounds a day), increased abdominal girth, darkend urine and excessive thirst in addition to the mild symptoms.

'''Severe Symptoms'''- In addition to the symptoms associated with Mild and Moderate OHSS, in severe OHSS, you see shortness of breath, calf and chest pains and pleural effusion.

<span style="font-size:100%">'''Classifications of Ovarian Hyper-stimulation Syndrome:'''</span> <ref name="PMID22065820"><pubmed>22065820</pubmed></ref>
{| class="wikitable" style="text-align:center
|-
! scope="col" width="70px"| '''Classification'''
! scope="col" width="650px"| '''Symptoms'''
|-
|style="text-align:center; background: #F6CEEC;"| '''Mild'''
|style="height: 60px; background: #F6CEEC;"| '''Grade 1''' - Abdominal distention and discomfort
'''Grade 2''' - Abdominal distention, discomfort with nausea, vomiting and/or diarrhea and ovarian enlargement from 5~12cm
|-
|style="text-align:center; background: #F8E0F1;"| '''Moderate'''
|style="height: 60px; background: #F8E0F1;"| '''Grade 3''' - All features of Mild OHSS with ultrasonographic evidence of ascites
|-
|style="text-align:center; background: #F6CEEC;"| '''Severe'''
|style="height: 60px; background: #F6CEEC;"| '''Grade 4''' - All features of Moderate OHSS with the addition of clinical evidence of ascites and breathing difficulties present
'''Grade 5''' - All of the above symptoms along with a change in the blood volume, increased blood viscosity due to coagulation and diminished renal function
|}

</div>

==Diagnosis==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

Whilst symptoms of OHSS can occur as soon as 24 hours post hCG administration, they are usually seen in women 7-10 days post administration. Initially women with OHSS will present with abdominal bloating, as a result of fluid in the peritoneal cavity and an increase in ovary size. When women present with severe OHSS they are often dehydrated, due to increased vascular permeability, and have hemoconcentration. The above results in a decrease in intravascular volume, leading to oligouria <ref name="PMID22416285" />.

===History===

Initially a thorough history of the patient is taken during which the clinician looks for evidence of ovarian stimulation, followed by ovulation. During this history taking, the clinician will inquire into any weight gain noticed, urine output, and the woman's ability to maintain oral hydration. A key diagnostic tool for clinicians regarding women who are taking gonadotropins is to identify if they are at an increased risk of developing OHSS. Some risk factors include woman aged less than 30, women who have polycystic ovaries, woman with a previous history of OHSS and women who have had greater than 20 oocytes retrieved <ref name="PMID22416285" />.

===Physical Exam===
[[File:Vaginal_Ultrasonography_in_Sagittal_Plane.jpg|right|thumbnail|600px|Vaginal Ultrasonography in Sagittal plane <ref name="Wikiversity Journal of Medicine"> Häggström, Mikael. "Medical gallery of Mikael Häggström 2014". Wikiversity Journal of Medicine 1 (2). DOI:10.15347/wjm/2014.008. ISSN 20018762</ref>]]
After a history of the patient is taken, the next step is to perform a physical exam on the patient. Women who present with abdominal bloating will produce a shifting dullness upon abdominal percussion. Additionally the clinician will test the woman's vital signs, measure her abdominal girth, weight and will look for evidence of ascites or increase in calf size (usually unilateral)<ref name="PMID22416285" />.

===Investigations===

If the clinician further suspects a women of having OHSS, various investigations can be done such as an ultrasound.The intraperitoneal fluid is best imaged via vaginal ultrasound due to the enlarged ovaries making it difficult to image the pelvis using transabdominal ultrasound. The clinician can also order laboratory testing to look for urine specific gravity and and complete blood count to look for hemoconcentration with a hematocrit. Additionally, liver function tests can be ordered to look for elevated function. The clinician will also look for evidence of elevated D-dimers and fibrinogen and decreased levels of anti-thrombin 3 <ref name="SAHealth"> Government of South Australia Health [ http://www.sahealth.sa.gov.au/wps/wcm/connect/9b61ed004ee5348da663afd150ce4f37/Ovarian-hyperstimulation-syndrome-WCHN-PPG-17072012.pdf?MOD=AJPERES&CACHEID=9b61ed004ee5348da663afd150ce4f37 ], 'South Australian Paediatric Clinical Guidelines OHSS'</ref>.

====Ultrasound====

Typical appearances of the ultrasound include <ref name="Ultrasound"> Radiopaedia [ http://radiopaedia.org/articles/ovarian-hyperstimulation-syndrome-1 ], 'Ovarian Hyperstimulation Syndrome'</ref>:

*Bilaterally and symmetrically enlarged ovaries (>12cm)
* "Spoke-Wheel appearance" - presence of multiple cysts of varying size
*May also see ascites (fluid)

===Severity===

Once a clinician has deduced a women is suffering from OHSS, the severity of their condition needs to be established as either mild, moderate or severe. This is done by referring to the criteria under the sub-heading [[Symptoms]].The subsequent course of treatment for the woman will be based upon this evaluation.

{|
|-bgcolor="F6CEEC"
|
'''Further investigations''' can be done including a Chest X-ray to check for pleural effusions and oedema and USS with Doppler's to check for ascites or possible ovary torsion. <ref name="PMID22416285"><pubmed>22416285</pubmed></ref>
|}

===Differential Diagnosis===

Conditions presenting with similar symptoms or ultrasound images include <ref name="Ultrasound" />:

*Polycystic Ovaries (PO)
:: The difference is that with PO is that the cycts are typically smaller than OHSS cysts and there is no evidence of ascited or pleural effusion
*Mucinous Ovarian Malignancy
:: A type of Ovarian Epithelial tumour
*Ectopic Pregnancy <ref name="Casereport"> Australian Medical Student Journal [ http://www.amsj.org/wpcontent/uploads/files/articles/amsj_v2_i1/AMSJ_v2_i1_pg58-60.pdf ], 'Ovarian hyperstimulation syndrome'</ref>
::A pregnancy in which the foetus develops outside of the uterus e.g. in the fallopian tube

</div>

==Pathophysiology==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

[[File:Pathogenesis_of_OHSS.png|600px|thumb|Pathogenesis of OHSS <ref name="PMID20416867"><pubmed>20416867</pubmed></ref>]]

The definition of Ovarian Stimulation is enlarged ovaries with many luteinized cysts, that can present with secondary complications. What distinguishes Ovarian Stimulation from OHSS is the presence of vascular hyper-permeability that results in fluids being redirected elsewhere in the body.

The key process to OHSS appears to be caused by '''Vascular Endothelial Growth Factor''' (VEGF), that is released along with other cytokines, estrogen and progesterone, due to the ovary undergoing luteinization as a result of stimulation by hCG. VEGF increases vascular permeability and as a result the capillaries become more "leaky" to the fluids in them. These fluids can then escape the capillaries and accumulate in the pleural and abdominal cavities as ascites. The woman then becomes hypovolemic and is at an increased risk of circulatory, renal and respiratory issues such as arterial thromboembolism due to the thickening of the blood. Note, the blood is thickened as fluid is leaving the capillaries, leaving behind red blood cells and other cellular components of the blood <ref name="WikiOHSS" />.

The increase in expression of VEGF and VEGF Receptor 2 (VEGFR2) is attributed to the greatly increased amount of their mRNA present in the body after stimulation with hCG <ref name="PMID21082502"><pubmed>21082502</pubmed></ref>. VEGF interacts with VEGF2 and VEGF Receptor 1 (VEGFR1) to create a strong angiogenic effect. Both VEGFR2 and VEGFR1 belong to a family of receptors called tyrosine kinases. VEGF2 is involved in the regulation of angiogenesis and vascular permeability whilst VEGF1 has a slightly contradictory role in that is is involved in the maintenance of the tight junctions between endothelial cells in blood vessels. A study by Gómez ''et. al.'' <ref name="PMID21082502" /> showed that women experiencing OHSS had substantially higher plasma levels of VEGF and lower levels of VEGFR1.

</div>

==Complications==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

Ovarian torsion or rupture, renal insufficiency and thrombophlebitis can all complicate OHSS. If a pregnancy occurs, symptoms may persist longer than the usual 1 to 2 weeks and become more severe, however, even with severe OHSS, they do not extend past the first trimester <ref name="WikiOHSS" />.

<span style="color:#FA58D0"> '''1-2% of women who undergo ovarian stimulation develop a severe form of OHSS''' </span>. Complications from severe OHSS include:

*Fluid collection in the abdomen
*Electrolyte disturbances (sodium and potassium)
*Kidney failure
*Ovary twisting
*Rupture of a cyst in an ovary
*Breathing problems
*Blood clots in large vessels (most commonly the legs)
*Pregnancy loss from miscarriage or termination
*Rarely, death

A study by Nouri ''et. al.'' <ref name="PMID24996451"><pubmed>24996451</pubmed></ref> found that women with '''Polycystic Ovarian Syndrome''' (PCOS) and those that were induced with hCG experienced longer recovery times from severe OHSS than women who were not pregnant. They looked at a cohort of women hospitalised for the first time with severe OHSS and subject them to the same treatments. Based on a defined criteria, they established the recovery time of these women and compared the times between those that were pregnant to those that were not pregnant. They also found that whether a woman had PCOS or ovulation induction did not affect her risk of developing OHSS if she was not pregnant. It is only a risk factor for pregnant women.

===Thromboembolic events===

A frequent and deadly complication of OHSS are thromboembolic events due to increased blood clotting. This increase in blood clotting has been attributed to a variety of complications such as hemoconcentration (which thickens the blood), hypolvolemia and an increase in the permeability of blood vessels as a result of increased vasoactive substances in the body of ovarian origin. Thromboembolic events include venous thromboses often in the upper extremities and arterial thromboses such as those in the cerebrovascular region. These events can lead to amputations of extremities, brain damage, miscarriage and death. To avoid this, anti-coagulants are given to pateitns with OHSS and they are fitted with compression stockings (see [[Treatment]]) <ref name="PMID23378404"><pubmed>23378404</pubmed></ref>.

{|
|-bgcolor="F8E0F1"
|
The risk of a woman developing OHSS is higher if she is having a '''twin pregnancy''', as she is exposed to higher concentration of hCG. <ref name="PMID9756273"><pubmed>9756273</pubmed></ref>
|}

</div>

==Treatment==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

'''General treatment
'''
*''Acetaminophen'' with or without a narcotic agent- used to treat abdominal discomfort
*Women are encouraged to drink 2-3 litres of water a day to prevent hemoconcentration
*Women are advised to avoid sexual intercourse and vigorous exercise at the risk of torsion or rupture of the ovaries
*NSAID's with anti-platelet properties should NOT be used as they may effect renal function in a women with OHSS
*Patients with significantly painful ascites or breathing problems may undergo ''Paracentesis'' (drainage of the ascites)
*''Culdocentesis'' (extraction of fluid from recto-uterine pouch) can be done to decrease the likelihood of a woman with moderate OHSS progressing to severe OHSS.<ref name="PMID22416285" />

===Mild to Moderate OHSS===

Mild OHSS can often resolve on its own, however, moderate OHSS may include treatments such as<ref name="WikiOHSS" />:

*Anti-nausea medication and prescription painkillers
*Regular physical examinations and ultrasounds
*Daily weigh-ins and waist measurements
*Measuring the amount of urine produced each day
*Frequent blood tests for monitoring dehydration and electrolyte imbalance
*Maintaining a high balance of fluids
*Drainage of excess abdominal fluid by inserting a needle in the abdominal cavity
*Wearing support stockings which help prevent blood clots/thrombosis

===Severe OHSS===

Severe OHSS requires hospital care in order for constant monitoring and treatment such as <ref name="WikiOHSS" />:

*Intravenous fluids with a crystalloid solution (100-150mL/hr)
*Intravenous Albumin is administered is IV fluids are insufficient (15-20mL/hr of 25% albumin for 4 hrs)
*In addition to Acetaminophen, ''Opioid analgesics'' can be administered for pain relief
*''Antiemetics'' can be used to subside nauseas and/or vomiting
*Woman administered to hospital of OHSS are considered at high risk of thromboembolic complications and are given low molecular weight ''heparin'', an anti-coagulant
*''Cabergoline''- lessens OHSS symptoms
*''GnRH agonist''- suppresses ovarian activity
**If at risk of OHSS, alternates include using a GnRH agonist instead of hCG however its effects on pregnancy rates are questionable. Using a GnRH agonist to replace the use of hCG for final oocyte stimulation will see a 6% decrease in delivery rate.

*Daily monitoring of creatine, urea, creatine clearance C-reactive protein (to rule out infection) are all required in combination with weekly tests such as liver and renal function tests and chest x-rays (to check for pleural effusion) <ref name="PMID12638783" />.

If there are serious complications then additional treatments are required:

*Surgery for a ruptured ovarian cyst
*Intensive care for the liver or lung complications

====Paracentesis====

For women with severe/grade 3 OHSS, paracentesis, the removal of fluid from the body using an aspiration needle, can be undertaken. It is a diagnostic and a therapeutic method that can be done trans-abdominally and trans-vaginally. It is used to relieve symptoms, improve haemodynamics e.g. Urinary output, and shorten the women's hospital stay. Complications of paracentesis include bleeding, infection and organ injury, however are note common <ref name="Paracentesis"> S. Monica Soni, HMS 3, Gillian Lieberman, MD [ http://eradiology.bidmc.harvard.edu/LearningLab/genito/Soni.pdf ], 'Ovarian Hyperstimulation Syndrome'</ref>.

{|
|-bgcolor="F8E0F1"
|
The most important aspect of treatment for any women with OHSS is close and constant '''monitoring''' with her healthcare professional. Counselling may also be provided to women and their partners or families in order to provide them with the best possible knowledge base to manage and treat their OHSS. It is important to note that there is '''no one cure or treatment''' for OHSS. Treatment involves managing and eliminating the symptoms until such time as the syndrome resolves itself <ref name="WikiOHSS" />.
|}

</div>

==Prevention==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

There are three key avenues through which the incidence of OHSS may be prevented. These include identifying risk factors to predict OHSS development, modifying treatment regimes on the basis of the identified risk factors and intervention to prevent progression to OHSS once the patient has undergone Controlled Ovarian Stimulation.

=== Risk factors===

'''Primary risk factors'''

Pre-existing factors likely to exacerbate the ovarian stimulation response. Primary risk factors include <ref name="PMID26074966"><pubmed>26074966</pubmed></ref>:

*Young age
*Low body weight
*History of elevated response to gonadotropins
*Polycystic Ovary Syndrome (PCOS)
*Isolated PCOS characteristic
*A previous history of OHSS.
*Hormonal markers (e.g. Anti-Mullerian Hormone markers)
*Ultrasonographic markers (e.g. Antral Follicle Count)

'''Secondary risk factors'''

Secondary risk factors involve the monitoring of ovarian response parameters once COS has been initiated. These parameters are monitored for <ref name="PMID19007627"><pubmed>19007627</pubmed></ref>:

*rapidly rising E2 levels
*E2 concentration larger than 2500 pg/mL
*large number of developing follicles (10-14mm) on the day hCG is administered
*large number of oocytes retrieved

These factors in combination, act as a predictive tool to assess the likelihood of severe OHSS development, with a 83% sensitivity and 84% specificity. <ref name="PMID19007627"/>

=== Primary Prevention===

Primary Prevention involves the modification of treatment regimens on the basis of OHSS risk classifications, in order to prevent OHSS occurrence.

'''Ovulation Induction'''

Unifollicular Ovulation Induction through Ovulation Induction (OI) is a primary means of avoiding OHSS in women with Polycystic Ovarian Syndrome, who are at an increased risk. In order to promote unifollicular development, the ovaries are stimulated with a low starting dose of FSH (75 IU).<ref name="PMID20416867"><pubmed>20416867</pubmed></ref> Studies suggests that a minimum gonadotropin dose lowers OHSS risk and thus a step-up regimen is utilised to achieve an ovarian response, whereby the FSH dosage is increased every 7 days until follicular development of greater than 10mm is noted.<ref name="PMID26074966" /> Alternatively, a step-down regimen may be followed, whereby a high initial FSH dosage is lowered according to the ovarian response. Another method to increase FSH levels during OI, is through Aromatase Inhibitors which promote folliculogenesis by increasing pituitary secretion of FSH, and downregulate oestrogen production through a negative feedback loop. However, Aromatase Inhibitors have not been shown to reduce OHSS incidence in comparison to other methods of OI.<ref name="PMID26074966" /> During OI, a key objective is to prevent early cycle cancellation due to premature luteinisation from pituitary secretion of LH. In order to downregulate LH secretion, Gonadotropin-releasing hormone agonists (GnRHa) are administered in addition to gonadotropins. Alternatively, GnRH antagonists may be administered to downregulate endogenous LH secretion. Comparative studies have shown that the GnRH antagonist protocol has a greater effect in lowering the incidence of mild to severe OHSS. However due to the rare nature of OHSS, and insufficient sample sizes, the difference was not found to be significant. <ref name="PMID21082508"><pubmed>21082508</pubmed></ref>. Generally, the duration of exposure to gonadotropins and subsequent risk of OHSS may be minimised through mild stimulation protocols which administer FSH only in the mid to late follicular phase.<ref name="PMID20416867" />

'''Adjuvant Metformin Therapy'''

Adjuvant Metformin Therapy has been found to lower the risk of OHSS by 63%.<ref name="PMID25406011"><pubmed>25406011</pubmed></ref> It involves the administration of metformin at a daily dosage of 1000 to 2000mg, 2 months prior to Controlled Ovarian Stimulation <ref name="PMID26074966"/>. Metformin lowers the elevated insulin levels in PCOS which consequently reduce intraovarian androgen levels. This leads to a reduced sensitivity and expression of granulosa cell-follicle stimulating hormone receptors which result in a less exaggerated response to gonadotropins. Furthermore, it is suggested that Metformin prevents OHSS by controlling vascular permeability through the inhibition of various vasoactive molecules, including VEGF.

'''Avoiding hCG during Luteal Phase Support

Following Controlled Ovarian Stimulation, the steroid levels of E2 and P4 are reduced during the luteal phase due to the negative feedback on the pituitary. This leads to low endogenous LH levels, which consequently reduce endometrial receptivity as well as the luteal phase duration itself. As a result, implantation and pregnancy rates are reduced and early pregnancy loss rates are increased.<ref name="PMID20416867" /> Luteal Phase Support (LPS) serves to combat these adverse events with the use of hCG. However, hCG has been found to increase the risk of OHSS. Alternatively, the use of progesterone has been found to not only halve the risk of OHSS, but also induce similar improvements in pregnancy and miscarriage rates as hCG.<ref name="PMID26148507"><pubmed>26148507</pubmed></ref>

===Secondary Prevention===

Secondary Prevention aims to prevent progression to OHSS once COS has been initiated and the patient has been found to mount an exaggerated response. <ref name="PMID20416867" />

'''Coasting'''

Coasting is a first-line secondary preventative strategy. It consists of the withdrawal of gonadotrophins when a critical number of follicles and/or E2 concentration is reached. hCG is administered once the E2 concentration reduces to a safe level, before the process of oocyte retrieval commences. This preventative strategy is conducted for a period of less than 3 days in order to avoid compromising IVF outcomes.

'''Cryopreservation'''

Cryopreservation of embryos after oocyte retrieval is another avenue which may avert OHSS progression. The cryopreserved embryos are only reimplanted once the patient's hormone serum levels have normalised. Using oocyte vitrification, crystal formation within embryo tissue is avoided and so cryopreserved embryos have been found to produce better pregnancy rates with a 32% increase, than fresh embryo transfer. Recent studies suggest cryopreservation itself does not reduce OHSS rates, but must be followed by a GnRHa trigger to avert OHSS.

'''Cycle cancellation'''

Cycle cancellation is a guaranteed method to prevent early OHSS whereby hCG is withheld. This is a last resort strategy as it carries the risk of significant psychological distress and financial loss for the patient.

</div>

==Effect on the Newborn==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

</div>
Women who develop OHSS while undergoing Assisted Reproductive Technologies (ART) treatment are not only more likely to achieve a pregnancy, but have a live birth as the pregnancy outcome. This live birth is also more likely to be a multiple birth of two, three or more children. <ref name="PMID19591989"><pubmed>19591989</pubmed></ref> It has been postulated that a multifetal pregnancy leads to a more rapid increase in hCG levels, resulting in an increased risk of OHSS. However, the causal nature between multifetal pregnancy and OHSS development is disputed and further research is required to distinguish correlation from causation. <ref name="PMID19573292"><pubmed>19573292</pubmed></ref>

OHSS development is also associated with an increased risk of adverse outcomes including stillbirth, premature birth and low birthweight.<ref name="PMID19591989" /> Although the cause for the increased risk in adverse pregnancy outcomes is unknown, it is suggested that as the incidence of OHSS is reduced through various prevention strategies, the risk of such outcomes may be also be reduced.

==Genetics==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

Despite OHSS typically being of iatrogenic origin as a result of ovarian stimulation with gonadotropins, research has been conducted into the potential genetics behind OHSS as many sporadic and familial cases have been observed. '''Mutations''' in the receptor for hormones such as Follicle Simulating Hormone (FSH), Lutenizing Hormone (LH) and hCG have all been targets of OHSS genetics research. Interestingly, they too also arise from a common ancestral gene.

===Follicle Stimulating Hormome===

Dr. Botros Rizk, of the University of South Alabama College of Medicine <ref name="PMID19573286"><pubmed>19573286</pubmed></ref>, has written extensively regarding the genetics behind OHSS. In particular, he talks about '''FSH receptors''' (FSHR) and their role in the syndrome. He hypothesises that mutations in these receptors could be activating or inactivating, leading to an increased risk of developing OHSS or sterility respectively. Currently, 744 single nucleotide polymorphisms (a type of mutation) have been found in the gene encoding the FSHR, 8 of which are located in its exons (coding regions of the gene). How the ovary responds is resultant on the FSHR genotype. For example, Ser680Asn, a polymorphism in the FSHR gene has been shown to aid in predicting the severity of a woman's OHSS. Ordinarily FSH stimulates the growth of ovarian follicles, however, when mutated, it is stimulated by the hCG resulting in excessive follicle development.

Spontaneous OHSS, OHSS that arises and cannot be attributed to any form of ovarian stimulation or Assisted Reproductive Technology, has been linked to activating mutations in the FSHR <ref name="PMID23499866"><pubmed>23499866</pubmed></ref>. This familial disorder is an autosomal dominant one. In most cases the FSHR can be stimulated by the presence of Thyroid Stimulating Hormone (TSH) or hCG, in the absence of FSH (the ligand for FSHR).

===Lutenizing Hormome===

The '''Lutenizing Hormone Receptor''' (LHR) gene in humans is comprised of 11 exons. Animal studies have shown that many primates exhibit a similar gene which is comprised of only 10 exons, however a gene lacking the 10th exon has been identified and termed the type 2 LHR. Expression of the type 2 LHR has been seen in humans. The type 2 LHR, compared to the wild-type LHR appears to be repaired with regard to its function. Defects in the type 2 LHR include a decrease in efficiency of transport to the plasma membrane and irregularities in signal transduction. Inactivating mutations in the LHR have been seen to cause infertility in women as well as amenorrhoea. Activating LHR gene mutations are asymptomatic and are not associated with OHSS in women.

===Bone Morphogenic Protein===

An imporant growth factor, derived from oocytes called '''BMP-15''' (Bone Morphogenic Protein 15) is vital for female fertility. It belongs to the family of growth factors, Transforming Growth Factor β (TGF-β) and is heavily involved in folliculogenesis. It has been found that mutations in the BMP-15 gene caused infertility in female sheep. Conversely, it has also been indicated in enhanced fertility when BMP-15 is present is high amounts in follicular fluid <ref name="PMID19573286" />.

A case study done by Hanevik ''et. al.'' in 2013 <ref name="PMID21565556"><pubmed>21565556</pubmed></ref> found that a Single Nuclear Polymorphism (SNP) in the BMP-15 gene is responsible for a high response to ovarian hyper-stimulation. The aim of the study was to test the effect the SNP had on BMP-15 with regard to high and low responders buy taking blood from 53 high responders, 38 low responders and 100 non-responders (controls) and analysing 5 noted SNP's. Results from their study showed a correlation between a high response to ovarian hyper-stimulation and the BMP-15 9G allele. The article does state however, that further research is required into the molecular effects of SNP's on the function of BMP-15.

===Vascular Endothelial Growth Factor===

'''Vascular endothelial growth factor''' (VEGF) has been indicated as one of the key agents causing vascular permeability and subsequent ascites in OHSS. The gene, which is located on chromosome 12, is made up of 8 exons (coding regions), of which exons 6 and 7 do not always appear due to the exons being spliced out.The splicing of this gene allows for various isoforms of the gene to exist of which VEGF 121 and 165 appear to play a role in angiogenesis. There are two VEGF Receptors, VEGFR-1 and VEGFR-2 that belong to the tyrosine kinase family of receptors (for more information on VEGF see [[Pathophysiology]]). Because of its distinct role in OHSS, it has been targeted as an area for research for potential treatments. The idea is that if the genetic expression of VEGF and its receptors can be controlled, OHSS can be avoided or treated.<ref name="PMID19573286" />

A different study by Hanevik ''et. al.'' , <ref name="PMID22587628"><pubmed>22587628</pubmed></ref> done in 2012 involved analysing blood samples from 53 women with OHSS and 100 women without it (controls) and analysing 6 SNP's in the VEGFR2 gene to find any genetic variations. They found a correlation between women with the VEGF +405cc genotype and the development of OHSS indicating women that undergo controlled ovarian hyper-stimulation and posses his genotype, are at an increased risk of developing OHSS.

</div>

== Current Research on Animal Models==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">
{|
|-bgcolor="F8E0F1"
|
<span style="font-size:120%">'''Inhibition of Cyclooxygenase-2 (COX-2) by Meloxican decreasing the incidence of OHSS in Rat Model'''</span> <ref name="PMID18166186"><pubmed>18166186</pubmed></ref>

Reasearch was carried out to investigate the effects of selective inhibition of the enzyme COX-2 on the Ovarian Hyperstimulation Syndrome (OHSS) using Female Wistar rates as the subjects. The research aimed to find results by measuring the number of antral and luteinized follicles, ovarian weight, vascualr endothelial growth factors and COX-2 immunohistochemistry. The rats being tested were all 22 days old and were divided into four equal groups;

'''Group 1 (Control group)''' was subject to a 0.1 ml of Intraperitoneal Saline from days 22 ~ 26

'''Group 2 (Mildly-stimulated group)''' subject to 10IU of pregnant mare serum gonadotrophin (PMSG) on day 24 and then 10IU of Human Chorionic Gonadotrophin (hCG) on day 26

'''Group 3 (OHSS positive group)''' was subject to 10IU of PMSG from days 22 ~ 26 and then administered 30IU of hCG on day 26 to induce OHSS

'''Group 4 (OHSS positive variant group)''' received 15mg/ml of Meloxicam 2 hours prior to administration of 10IU PMSG from days 22 ~ 26

Results showed there was no difference in ovarian weight in samples from Group 1 and Group 2, however Group 3 showed signs of significant ovarian weight increase which in group 4 was suppressed by the introduction of Meloxicam. No differences were observed in the number of antral follicles amongst the four test groups. Results from Group 2 and Group 3 showed that the granulosa cells of preovulatory follicles and the stromal cells were highly VEGF immunoreactive, however the Meloxicam treated Group 4 showed less immunoreactivity than Group 2 and Group 3 which indicated the correlation between Meloxicam and the diminished VEGF expression. Group 3 presented an increased COS-2 immunoreactivity which was highly diminished than in Group 4.

The research concluded that in a rat model, the enzyme Meloxicam has a beneficial effect on OHSS by reducing the increase of ovarian weight and the expression of VEGF associated with OHSS, the effects of which may be mediated by the inhibitory capacity of COX-2 on Meloxicam
|}

{|
|-bgcolor="FF99FF"
|
<span style="font-size:120%">'''Inhibition of Ovarian VEGF secretion by activation of Dopamine Receptor 2'''</span> <ref name="PMID25217874"><pubmed>25217874</pubmed></ref>

This research was carried out to investigate a possibility in whether a Dopamine Receptor 2 agonist '''(D2-ag)''' can assist in the prevention of Ovarian Hyperstimulation Syndrome, using rat models, by decreasing the ovarian vascular endothelial growth factor '''(VEGF)''' production. Using Immature Wistar rats (22 days old) as their animal model, the rats were initially stimulated with Gonadotrophins to mimic the onset and effects of OHSS and then subjected to treatment with a D2-agonist and/or a D2-antagonist (D2-ant). The vascular permeability was measured at the endpoint after day 26 by measuring the peritoneal extravasion of a previously injected dye and ovaries from all subjects were collected to assess the effects of D2-ag and D2-ant on the production of Ovarian VEGF. The expression of VEGF mRNA was measured by quantitative real time PCR and the levels of VEGF proteins were measured by Western Blots.

Results showed that the D2-ag caused a large reduction in the vascular permeability which was in turn associated with the great decreased in VEGF protein production in the OHSS rat ovaries, whereas the introduction of D2-ant showed opposite results with a increase in the vascular permeability leading to the increase of VEGF protein production in the ovaries. Ovarian VEGF mRNA levels were found to be unaffected by the introduction of these drugs in OHSS rat subjects. Conclusions were drawn on the fact that Dopamine Receptor 2 agonists prevent the increase of vascular permeability in subjects with OHSS by decreasing the ovarian production of VEGF and also that due to the dose-dependent inhibitory effect of the D2-ag on ovarian VEGF, current OHSS therapies used in humans can benefit by increasing the intraovarian concentration of D2-ag.
|}
</div>

==Glossary==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

'''Ascites'''- An accumulation of fluid in the peritoneal cavity with resultant abdominal swelling

'''Cabergoline''' - A dopamine receptor agonist used to treat hormone imbalance.

'''GnRH antagonist''' - Gonadotropin Releasing Hormone - A class of compounds that are similar in terms of the structure of natural Gonadotropin Releasing Hormone but has a antagonistic effect.

'''hCG'''- Human Chorionic Gonadotropin

'''Hemoconcentration'''- An increase in the concentration of circulating red blood cells in response to a decrease in blood plasma volume

'''Hypovolemic'''- A decrease in circulating blood volume

'''Iatrogenic'''- Illness caused as a result of a medical examination or treatment

'''Intravenous fluids''' - Is the infusion of liquid substances directly into a vein.

'''IVF'''- In-vitro Fertilization

'''NSAID'''- Non-steroidal Anti-Inflammatory Drug e.g. Ibuprofen

'''OHSS'''- Ovarian Hyper-stimulation Syndrome

'''FSH''' - Follicle Stimulating Hormone

'''LH''' - Luteinizing Hormone

'''Oliguria'''- Decreased urine output/small amounts of urine produced

</div>

==References==

2015 Group Project 2

2015-10-22T21:25:44Z

Z3372824: /* Primary Prevention */

{{ANAT2341Project2015header}}

==<span style="font-size:120%">'''Ovarian Hyper-stimulation Syndrome (OHSS)'''</span>==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

Ovarian Hyper stimulation Syndrome (OHSS) is an iatrogenic complication of '''Assisted Reproduction Technology''' (ART), in which women take medications to stimulate oocyte growth. It is generally identified by cystic enlargements of the ovaries and fluid accumulation in the peritoneal cavity due to the increased capillary permeability and ovarian neoangiogenesis <ref name="PMID22065820"><pubmed>22065820</pubmed></ref>. It is an occurrence which is dependent on the controlled stimulation of the ovaries in preparation for IVF i.e. administration of human Chorionic Gonadotropin (hCG).

OHSS was first described in 1943 as ''“syndrome d’hyperluteinisation massive
des ovaries”''. It was during this time that gonadotropins were prepared from animals such as sheep to bring on ovulation in women. The first recorded death as a result of OHSS occurred in 1951 and was due to renal failure as a result of oligouria, a complication of the syndrome <ref name="OHSS"> Marie M. Budev, DO, MPH; Alejandro C. Arroliga, MD; Tommaso Falcone, MD, [ http://utilis.net/Morning%20Topics/REI/Ovarian%20Hyperstimulation.pdf ], 'Ovarian Hyperstimulation Syndrome'</ref> <ref name="PMID12638783"><pubmed>12638783</pubmed></ref>.

<span style="color:#FA58D0">This wikipage aims to provide clear information on various areas surrounding OHSS such as diagnosis, prevention and complications and will look into the genetics behind the disorder and the various animals models used to research it.</span>

<html5media height="350" width="450">https://www.youtube.com/watch?v=aXmjJw234a4</html5media>

'''Overview of the Ovarian Hyperstimulation Syndrome''' <ref> Howcast (2013, August 27) Ovarian Hyperstimulation Syndrome | Infertility. Retrieved from https://www.youtube.com/watch?v=aXmjJw234a4</ref>

</div>

==Epidemiology==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

Ovarian Hyper-Stimulation Syndrome (OHSS) rarely occurs sporadically, and if it does, it is usually the result of an underlying genetic problem. The majority of OHSS is due to the ovaries being stimulated to mature and release an abundance of oocytes, in response to hormones Human Chorionic Gonadotropin (hCG) and Follicle Stimulating hormone (FSH), during IVF. Rarely, Clomifene Citrate therapy can cause OHSS.<ref name="WikiOHSS"> Wikipedia, [ https://en.wikipedia.org/wiki/Ovarian_hyperstimulation_syndrome ], 'Ovarian Hyperstimulation Syndrome'</ref>

OHSS only affects '''0.5-5%''' of women undergoing Ovarian Hyper-stimulation, but despite its small prevalence, it is a potentially fatal outcome of a non-vital procedure and remains a prevalent problem for fertility specialists <ref name="PMID12498425"><pubmed>12498425</pubmed></ref> <ref name="PMID12638783"><pubmed>12638783</pubmed></ref>. Age has been cited as a factor affecting those with OHSS, with younger women more at risk. Additionally, women with allergies were seen to have a higher incidence of OHSS. It is important to note that at this point in time, there is no positive correlation between gonadotropin dose and OHSS.

Of the 0.5-5% of women affected with OHSS mentioned above, 2% of those women will require hospitalisation. As of 2011, it has been reported that the incidence of OHSS was '''increasing''', resulting in approximately 3 deaths per 100,000 women undergoing ovarian stimulation per year <ref name="PMID21828116"><pubmed>21828116</pubmed></ref>. This is particularly worrying as in 2008, in the United States alone, there were around 150,000 IVF cycles undertaken.

{|
|-bgcolor="F8E0F1"
|
'''With the field of Assisted Reproductive Technologies expanding and more women partaking in IVF treatments, the threat of women developing OHSS is an ongoing and increasing one''' <ref name="PMID21828116" />.
|}
{| class="wikitable mw-collapsible mw-collapsed"
! Characteristics of women by complication group <ref name="PMID19591989"><pubmed>19591989</pubmed></ref>
|-
! scope="col" width="100px" height="60px" style="text-align:center| '''Characteristic'''
! scope="col" width="100px" height="60px" style="text-align:center| '''No Complications
(N = 212,041)'''
! scope="col" width="100px" height="60px" style="text-align:center| '''Moderate OHSS
(N = 1,523)'''
! scope="col" width="100px" height="60px" style="text-align:center| '''Severe OHSS
(N = 655)'''
|-
|style="text-align:center; background: #FF99FF;"| '''Maternal Age (Mean ± SD)'''
|style="text-align:center; background: #F6CEEC;"| 35.6 ± 4.6
|style="text-align:center; background: #F6CEEC;"| 33.0 ± 4.3
|style="text-align:center; background: #F6CEEC;"| 33.1 ± 4.4
|-
|style="text-align:center; background: #FF99FF;"| '''Maternal Age (%)'''
|-
|style="text-align:left; background: #F6CEEC;"| <30 years
|style="text-align:center; background: #F6CEEC;"| 10 %
|style="text-align:center; background: #F6CEEC;"| 21.1 %
|style="text-align:center; background: #F6CEEC;"| 20.6 %
|-
|style="text-align:left; background: #F6CEEC;"| 30-34 years
|style="text-align:center; background: #F6CEEC;"| 30.4 %
|style="text-align:center; background: #F6CEEC;"| 43.2 %
|style="text-align:center; background: #F6CEEC;"| 40.5 %
|-
|style="text-align:left; background: #F6CEEC;"| 35-39 years
|style="text-align:center; background: #F6CEEC;"| 37.8 %
|style="text-align:center; background: #F6CEEC;"| 27.2 %
|style="text-align:center; background: #F6CEEC;"| 32.5 %
|-
|style="text-align:left; background: #F6CEEC;"| >40 years
|style="text-align:center; background: #F6CEEC;"| 21.8 %
|style="text-align:center; background: #F6CEEC;"| 8.4 %
|style="text-align:center; background: #F6CEEC;"| 6.4 %
|-
|style="text-align:center; background: #FF99FF;"| '''Nulligravida (%)'''
|style="text-align:center; background: #F6CEEC;"| 45.8 %
|style="text-align:center; background: #F6CEEC;"| 51.5 %
|style="text-align:center; background: #F6CEEC;"| 51.8 %
|-
|style="text-align:center; background: #FF99FF;"| '''Infertility Diagnosis (%)'''
|-
|style="text-align:left; background: #F6CEEC;"| Male factor
|style="text-align:center; background: #F6CEEC;"| 37.7 %
|style="text-align:center; background: #F6CEEC;"| 41.0 %
|style="text-align:center; background: #F6CEEC;"| 33.4 %
|-
|style="text-align:left; background: #F6CEEC;"| Endometriosis
|style="text-align:center; background: #F6CEEC;"| 13.5 %
|style="text-align:center; background: #F6CEEC;"| 13.5 %
|style="text-align:center; background: #F6CEEC;"| 10.7 %
|-
|style="text-align:left; background: #F6CEEC;"| Ovulation Disorders
|style="text-align:center; background: #F6CEEC;"| 14.0 %
|style="text-align:center; background: #F6CEEC;"| 29.5 %
|style="text-align:center; background: #F6CEEC;"| 22.4 %
|-
|style="text-align:left; background: #F6CEEC;"| Diminished ovarian reserve
|style="text-align:center; background: #F6CEEC;"| 16.9 %
|style="text-align:center; background: #F6CEEC;"| 3.2 %
|style="text-align:center; background: #F6CEEC;"| 2.4 %
|-
|style="text-align:left; background: #F6CEEC;"| Tubal factors
|style="text-align:center; background: #F6CEEC;"| 20.4 %
|style="text-align:center; background: #F6CEEC;"| 22.6 %
|style="text-align:center; background: #F6CEEC;"| 22.3 %
|-
|style="text-align:left; background: #F6CEEC;"| Uterine factors
|style="text-align:center; background: #F6CEEC;"| 5.1 %
|style="text-align:center; background: #F6CEEC;"| 4.3 %
|style="text-align:center; background: #F6CEEC;"| 3.1 %
|-
|style="text-align:left; background: #F6CEEC;"| Other factors
|style="text-align:center; background: #F6CEEC;"| 13.9 %
|style="text-align:center; background: #F6CEEC;"| 13.1 %
|style="text-align:center; background: #F6CEEC;"| 10.4 %
|-
|style="text-align:left; background: #F6CEEC;"| Unexplained factor
|style="text-align:center; background: #F6CEEC;"| 12.7 %
|style="text-align:center; background: #F6CEEC;"| 11.8 %
|style="text-align:center; background: #F6CEEC;"| 18.6 %
|-
|}
</div>

==Causative Agents==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

[[File:Follicular Development.jpeg|right|thumbnail|500px|Infertility treatments aim to facilitate follicular development and induce ovulation to improve chances of fertilisation <ref name="PMID24717179"><pubmed>24717179</pubmed></ref>]]

Normally a woman produces one egg per month from the ovaries, which travel down the Fallopian tube to be fertilized or be released from the body. In cases where women have difficulty falling pregnant, they are given medication which help them to produce and release eggs (as shown in the diagram to the right), further increasing their chances of fertilization and pregnancy <ref><pubmed>19573285</pubmed></ref>. Ovarian Hyper stimulation Syndrome generally occurs during infertility treatments when the ovaries are overstimulated by the fertility medication which causes the ovaries to swell and leak fluids into the belly and abdomen. The prevalence of OHSS onset is linked with excessive number of follicle development in response to the administration of injectable Follicle Stimulating Hormones (FSH) followed by the '''Human Chorionic Gonadotrophins''' (hCG) which triggers the release of the oocytes <ref><pubmed>26190539</pubmed></ref>.

'''Follicle Stimulating Hormones''' (FSH) <ref name="PMID9020850"><pubmed>9020850</pubmed></ref> are glycoprotein hormones that are produced and secreted from the Anterior Pituitary gland into the bloodstream, which regulate the developmental, growth, maturation and the reproductive processes within the body. In females, the Follicle Stimulating Hormones initiates the stages of growth and development of immature ovarian follicles within the ovaries before the release of an egg from a follicle at ovulation. When FSH is administered to a patient who is suffering from infertility, the increase FSH levels affect the rate of development and production, in turn increasing the amount of follicles which are ready to be released during ovulation.

</div>

==Symptoms==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

OHSS is classified based on a criteria from mild, moderate and severe <ref name="WikiOHSS" />:

'''Mild Symptoms'''- abdominal bloating, minimal weight gain, nausea, diarrhoea and a feeling of fullness.

'''Moderate Symptoms'''- Substantial weight gain (on average 2 or more pounds a day), increased abdominal girth, darkend urine and excessive thirst in addition to the mild symptoms.

'''Severe Symptoms'''- In addition to the symptoms associated with Mild and Moderate OHSS, in severe OHSS, you see shortness of breath, calf and chest pains and pleural effusion.

<span style="font-size:100%">'''Classifications of Ovarian Hyper-stimulation Syndrome:'''</span> <ref name="PMID22065820"><pubmed>22065820</pubmed></ref>
{| class="wikitable" style="text-align:center
|-
! scope="col" width="70px"| '''Classification'''
! scope="col" width="650px"| '''Symptoms'''
|-
|style="text-align:center; background: #F6CEEC;"| '''Mild'''
|style="height: 60px; background: #F6CEEC;"| '''Grade 1''' - Abdominal distention and discomfort
'''Grade 2''' - Abdominal distention, discomfort with nausea, vomiting and/or diarrhea and ovarian enlargement from 5~12cm
|-
|style="text-align:center; background: #F8E0F1;"| '''Moderate'''
|style="height: 60px; background: #F8E0F1;"| '''Grade 3''' - All features of Mild OHSS with ultrasonographic evidence of ascites
|-
|style="text-align:center; background: #F6CEEC;"| '''Severe'''
|style="height: 60px; background: #F6CEEC;"| '''Grade 4''' - All features of Moderate OHSS with the addition of clinical evidence of ascites and breathing difficulties present
'''Grade 5''' - All of the above symptoms along with a change in the blood volume, increased blood viscosity due to coagulation and diminished renal function
|}

</div>

==Diagnosis==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

Whilst symptoms of OHSS can occur as soon as 24 hours post hCG administration, they are usually seen in women 7-10 days post administration. Initially women with OHSS will present with abdominal bloating, as a result of fluid in the peritoneal cavity and an increase in ovary size. When women present with severe OHSS they are often dehydrated, due to increased vascular permeability, and have hemoconcentration. The above results in a decrease in intravascular volume, leading to oligouria <ref name="PMID22416285" />.

===History===

Initially a thorough history of the patient is taken during which the clinician looks for evidence of ovarian stimulation, followed by ovulation. During this history taking, the clinician will inquire into any weight gain noticed, urine output, and the woman's ability to maintain oral hydration. A key diagnostic tool for clinicians regarding women who are taking gonadotropins is to identify if they are at an increased risk of developing OHSS. Some risk factors include woman aged less than 30, women who have polycystic ovaries, woman with a previous history of OHSS and women who have had greater than 20 oocytes retrieved <ref name="PMID22416285" />.

===Physical Exam===
[[File:Vaginal_Ultrasonography_in_Sagittal_Plane.jpg|right|thumbnail|600px|Vaginal Ultrasonography in Sagittal plane <ref name="Wikiversity Journal of Medicine"> Häggström, Mikael. "Medical gallery of Mikael Häggström 2014". Wikiversity Journal of Medicine 1 (2). DOI:10.15347/wjm/2014.008. ISSN 20018762</ref>]]
After a history of the patient is taken, the next step is to perform a physical exam on the patient. Women who present with abdominal bloating will produce a shifting dullness upon abdominal percussion. Additionally the clinician will test the woman's vital signs, measure her abdominal girth, weight and will look for evidence of ascites or increase in calf size (usually unilateral)<ref name="PMID22416285" />.

===Investigations===

If the clinician further suspects a women of having OHSS, various investigations can be done such as an ultrasound.The intraperitoneal fluid is best imaged via vaginal ultrasound due to the enlarged ovaries making it difficult to image the pelvis using transabdominal ultrasound. The clinician can also order laboratory testing to look for urine specific gravity and and complete blood count to look for hemoconcentration with a hematocrit. Additionally, liver function tests can be ordered to look for elevated function. The clinician will also look for evidence of elevated D-dimers and fibrinogen and decreased levels of anti-thrombin 3 <ref name="SAHealth"> Government of South Australia Health [ http://www.sahealth.sa.gov.au/wps/wcm/connect/9b61ed004ee5348da663afd150ce4f37/Ovarian-hyperstimulation-syndrome-WCHN-PPG-17072012.pdf?MOD=AJPERES&CACHEID=9b61ed004ee5348da663afd150ce4f37 ], 'South Australian Paediatric Clinical Guidelines OHSS'</ref>.

====Ultrasound====

Typical appearances of the ultrasound include <ref name="Ultrasound"> Radiopaedia [ http://radiopaedia.org/articles/ovarian-hyperstimulation-syndrome-1 ], 'Ovarian Hyperstimulation Syndrome'</ref>:

*Bilaterally and symmetrically enlarged ovaries (>12cm)
* "Spoke-Wheel appearance" - presence of multiple cysts of varying size
*May also see ascites (fluid)

===Severity===

Once a clinician has deduced a women is suffering from OHSS, the severity of their condition needs to be established as either mild, moderate or severe. This is done by referring to the criteria under the sub-heading [[Symptoms]].The subsequent course of treatment for the woman will be based upon this evaluation.

{|
|-bgcolor="F6CEEC"
|
'''Further investigations''' can be done including a Chest X-ray to check for pleural effusions and oedema and USS with Doppler's to check for ascites or possible ovary torsion. <ref name="PMID22416285"><pubmed>22416285</pubmed></ref>
|}

===Differential Diagnosis===

Conditions presenting with similar symptoms or ultrasound images include <ref name="Ultrasound" />:

*Polycystic Ovaries (PO)
:: The difference is that with PO is that the cycts are typically smaller than OHSS cysts and there is no evidence of ascited or pleural effusion
*Mucinous Ovarian Malignancy
:: A type of Ovarian Epithelial tumour
*Ectopic Pregnancy <ref name="Casereport"> Australian Medical Student Journal [ http://www.amsj.org/wpcontent/uploads/files/articles/amsj_v2_i1/AMSJ_v2_i1_pg58-60.pdf ], 'Ovarian hyperstimulation syndrome'</ref>
::A pregnancy in which the foetus develops outside of the uterus e.g. in the fallopian tube

</div>

==Pathophysiology==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

[[File:Pathogenesis_of_OHSS.png|600px|thumb|Pathogenesis of OHSS <ref name="PMID20416867"><pubmed>20416867</pubmed></ref>]]

The definition of Ovarian Stimulation is enlarged ovaries with many luteinized cysts, that can present with secondary complications. What distinguishes Ovarian Stimulation from OHSS is the presence of vascular hyper-permeability that results in fluids being redirected elsewhere in the body.

The key process to OHSS appears to be caused by '''Vascular Endothelial Growth Factor''' (VEGF), that is released along with other cytokines, estrogen and progesterone, due to the ovary undergoing luteinization as a result of stimulation by hCG. VEGF increases vascular permeability and as a result the capillaries become more "leaky" to the fluids in them. These fluids can then escape the capillaries and accumulate in the pleural and abdominal cavities as ascites. The woman then becomes hypovolemic and is at an increased risk of circulatory, renal and respiratory issues such as arterial thromboembolism due to the thickening of the blood. Note, the blood is thickened as fluid is leaving the capillaries, leaving behind red blood cells and other cellular components of the blood <ref name="WikiOHSS" />.

The increase in expression of VEGF and VEGF Receptor 2 (VEGFR2) is attributed to the greatly increased amount of their mRNA present in the body after stimulation with hCG <ref name="PMID21082502"><pubmed>21082502</pubmed></ref>. VEGF interacts with VEGF2 and VEGF Receptor 1 (VEGFR1) to create a strong angiogenic effect. Both VEGFR2 and VEGFR1 belong to a family of receptors called tyrosine kinases. VEGF2 is involved in the regulation of angiogenesis and vascular permeability whilst VEGF1 has a slightly contradictory role in that is is involved in the maintenance of the tight junctions between endothelial cells in blood vessels. A study by Gómez ''et. al.'' <ref name="PMID21082502" /> showed that women experiencing OHSS had substantially higher plasma levels of VEGF and lower levels of VEGFR1.

</div>

==Complications==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

Ovarian torsion or rupture, renal insufficiency and thrombophlebitis can all complicate OHSS. If a pregnancy occurs, symptoms may persist longer than the usual 1 to 2 weeks and become more severe, however, even with severe OHSS, they do not extend past the first trimester <ref name="WikiOHSS" />.

<span style="color:#FA58D0"> '''1-2% of women who undergo ovarian stimulation develop a severe form of OHSS''' </span>. Complications from severe OHSS include:

*Fluid collection in the abdomen
*Electrolyte disturbances (sodium and potassium)
*Kidney failure
*Ovary twisting
*Rupture of a cyst in an ovary
*Breathing problems
*Blood clots in large vessels (most commonly the legs)
*Pregnancy loss from miscarriage or termination
*Rarely, death

A study by Nouri ''et. al.'' <ref name="PMID24996451"><pubmed>24996451</pubmed></ref> found that women with '''Polycystic Ovarian Syndrome''' (PCOS) and those that were induced with hCG experienced longer recovery times from severe OHSS than women who were not pregnant. They looked at a cohort of women hospitalised for the first time with severe OHSS and subject them to the same treatments. Based on a defined criteria, they established the recovery time of these women and compared the times between those that were pregnant to those that were not pregnant. They also found that whether a woman had PCOS or ovulation induction did not affect her risk of developing OHSS if she was not pregnant. It is only a risk factor for pregnant women.

===Thromboembolic events===

A frequent and deadly complication of OHSS are thromboembolic events due to increased blood clotting. This increase in blood clotting has been attributed to a variety of complications such as hemoconcentration (which thickens the blood), hypolvolemia and an increase in the permeability of blood vessels as a result of increased vasoactive substances in the body of ovarian origin. Thromboembolic events include venous thromboses often in the upper extremities and arterial thromboses such as those in the cerebrovascular region. These events can lead to amputations of extremities, brain damage, miscarriage and death. To avoid this, anti-coagulants are given to pateitns with OHSS and they are fitted with compression stockings (see [[Treatment]]) <ref name="PMID23378404"><pubmed>23378404</pubmed></ref>.

{|
|-bgcolor="F8E0F1"
|
The risk of a woman developing OHSS is higher if she is having a '''twin pregnancy''', as she is exposed to higher concentration of hCG. <ref name="PMID9756273"><pubmed>9756273</pubmed></ref>
|}

</div>

==Treatment==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

'''General treatment
'''
*''Acetaminophen'' with or without a narcotic agent- used to treat abdominal discomfort
*Women are encouraged to drink 2-3 litres of water a day to prevent hemoconcentration
*Women are advised to avoid sexual intercourse and vigorous exercise at the risk of torsion or rupture of the ovaries
*NSAID's with anti-platelet properties should NOT be used as they may effect renal function in a women with OHSS
*Patients with significantly painful ascites or breathing problems may undergo ''Paracentesis'' (drainage of the ascites)
*''Culdocentesis'' (extraction of fluid from recto-uterine pouch) can be done to decrease the likelihood of a woman with moderate OHSS progressing to severe OHSS.<ref name="PMID22416285" />

===Mild to Moderate OHSS===

Mild OHSS can often resolve on its own, however, moderate OHSS may include treatments such as<ref name="WikiOHSS" />:

*Anti-nausea medication and prescription painkillers
*Regular physical examinations and ultrasounds
*Daily weigh-ins and waist measurements
*Measuring the amount of urine produced each day
*Frequent blood tests for monitoring dehydration and electrolyte imbalance
*Maintaining a high balance of fluids
*Drainage of excess abdominal fluid by inserting a needle in the abdominal cavity
*Wearing support stockings which help prevent blood clots/thrombosis

===Severe OHSS===

Severe OHSS requires hospital care in order for constant monitoring and treatment such as <ref name="WikiOHSS" />:

*Intravenous fluids with a crystalloid solution (100-150mL/hr)
*Intravenous Albumin is administered is IV fluids are insufficient (15-20mL/hr of 25% albumin for 4 hrs)
*In addition to Acetaminophen, ''Opioid analgesics'' can be administered for pain relief
*''Antiemetics'' can be used to subside nauseas and/or vomiting
*Woman administered to hospital of OHSS are considered at high risk of thromboembolic complications and are given low molecular weight ''heparin'', an anti-coagulant
*''Cabergoline''- lessens OHSS symptoms
*''GnRH agonist''- suppresses ovarian activity
**If at risk of OHSS, alternates include using a GnRH agonist instead of hCG however its effects on pregnancy rates are questionable. Using a GnRH agonist to replace the use of hCG for final oocyte stimulation will see a 6% decrease in delivery rate.

*Daily monitoring of creatine, urea, creatine clearance C-reactive protein (to rule out infection) are all required in combination with weekly tests such as liver and renal function tests and chest x-rays (to check for pleural effusion) <ref name="PMID12638783" />.

If there are serious complications then additional treatments are required:

*Surgery for a ruptured ovarian cyst
*Intensive care for the liver or lung complications

====Paracentesis====

For women with severe/grade 3 OHSS, paracentesis, the removal of fluid from the body using an aspiration needle, can be undertaken. It is a diagnostic and a therapeutic method that can be done trans-abdominally and trans-vaginally. It is used to relieve symptoms, improve haemodynamics e.g. Urinary output, and shorten the women's hospital stay. Complications of paracentesis include bleeding, infection and organ injury, however are note common <ref name="Paracentesis"> S. Monica Soni, HMS 3, Gillian Lieberman, MD [ http://eradiology.bidmc.harvard.edu/LearningLab/genito/Soni.pdf ], 'Ovarian Hyperstimulation Syndrome'</ref>.

{|
|-bgcolor="F8E0F1"
|
The most important aspect of treatment for any women with OHSS is close and constant '''monitoring''' with her healthcare professional. Counselling may also be provided to women and their partners or families in order to provide them with the best possible knowledge base to manage and treat their OHSS. It is important to note that there is '''no one cure or treatment''' for OHSS. Treatment involves managing and eliminating the symptoms until such time as the syndrome resolves itself <ref name="WikiOHSS" />.
|}

</div>

==Prevention==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

There are three key avenues through which the incidence of OHSS may be prevented. These include identifying risk factors to predict OHSS development, modifying treatment regimes on the basis of the identified risk factors and intervention to prevent progression to OHSS once the patient has undergone Controlled Ovarian Stimulation.

=== Risk factors===

'''Primary risk factors'''

Pre-existing factors likely to exacerbate the ovarian stimulation response. Primary risk factors include <ref name="PMID26074966"><pubmed>26074966</pubmed></ref>:

*Young age
*Low body weight
*History of elevated response to gonadotropins
*Polycystic Ovary Syndrome (PCOS)
*Isolated PCOS characteristic
*A previous history of OHSS.
*Hormonal markers (e.g. Anti-Mullerian Hormone markers)
*Ultrasonographic markers (e.g. Antral Follicle Count)

'''Secondary risk factors'''

Secondary risk factors involve the monitoring of ovarian response parameters once COS has been initiated. These parameters are monitored for <ref name="PMID19007627"><pubmed>19007627</pubmed></ref>:

*rapidly rising E2 levels
*E2 concentration larger than 2500 pg/mL
*large number of developing follicles (10-14mm) on the day hCG is administered
*large number of oocytes retrieved

These factors in combination, act as a predictive tool to assess the likelihood of severe OHSS development, with a 83% sensitivity and 84% specificity. <ref name="PMID19007627"/>

=== Primary Prevention===

Primary Prevention involves the modification of treatment regimens on the basis of OHSS risk classifications, in order to prevent OHSS occurrence.

'''Ovulation Induction'''

Unifollicular Ovulation Induction through Ovulation Induction (OI) is a primary means of avoiding OHSS in women with Polycystic Ovarian Syndrome, who are at an increased risk. In order to promote unifollicular development, the ovaries are stimulated with a low starting dose of FSH (75 IU).<ref name="PMID20416867"><pubmed>20416867</pubmed></ref> Studies suggests that a minimum gonadotropin dose lowers OHSS risk and thus a step-up regimen is utilised to achieve an ovarian response, whereby the FSH dosage is increased every 7 days until follicular development of greater than 10mm is noted.<ref name="PMID26074966" /> Alternatively, a step-down regimen may be followed, whereby a high initial FSH dosage is lowered according to the ovarian response. Another method to increase FSH levels during OI, is through Aromatase Inhibitors which promote folliculogenesis by increasing pituitary secretion of FSH, and downregulate oestrogen production through a negative feedback loop. However, Aromatase Inhibitors have not been shown to reduce OHSS incidence in comparison to other methods of OI.<ref name="PMID26074966" /> During OI, a key objective is to prevent early cycle cancellation due to premature luteinisation from pituitary secretion of LH. In order to downregulate LH secretion, Gonadotropin-releasing hormone agonists (GnRHa) are administered in addition to gonadotropins. The duration of exposure to gonadotropins and subsequent risk of OHSS may also be minimised through mild stimulation protocols which administer FSH only in the mid to late follicular phase.<ref name="PMID20416867" />

'''Adjuvant Metformin Therapy'''

Adjuvant Metformin Therapy has been found to lower the risk of OHSS by 63%.<ref name="PMID25406011"><pubmed>25406011</pubmed></ref> It involves the administration of metformin at a daily dosage of 1000 to 2000mg, 2 months prior to Controlled Ovarian Stimulation <ref name="PMID26074966"/>. Metformin lowers the elevated insulin levels in PCOS which consequently reduce intraovarian androgen levels. This leads to a reduced sensitivity and expression of granulosa cell-follicle stimulating hormone receptors which result in a less exaggerated response to gonadotropins. Furthermore, it is suggested that Metformin prevents OHSS by controlling vascular permeability through the inhibition of various vasoactive molecules, including VEGF.

'''Avoiding hCG during Luteal Phase Support

Following Controlled Ovarian Stimulation, the steroid levels of E2 and P4 are reduced during the luteal phase due to the negative feedback on the pituitary. This leads to low endogenous LH levels, which consequently reduce endometrial receptivity as well as the luteal phase duration itself. As a result, implantation and pregnancy rates are reduced and early pregnancy loss rates are increased.<ref name="PMID20416867" /> Luteal Phase Support (LPS) serves to combat these adverse events with the use of hCG. However, hCG has been found to increase the risk of OHSS. Alternatively, the use of progesterone has been found to not only halve the risk of OHSS, but also induce similar improvements in pregnancy and miscarriage rates as hCG.<ref name="PMID26148507"><pubmed>26148507</pubmed></ref>

===Secondary Prevention===

Secondary Prevention aims to prevent progression to OHSS once COS has been initiated and the patient has been found to mount an exaggerated response. <ref name="PMID20416867" />

'''Coasting'''

Coasting is a first-line secondary preventative strategy. It consists of the withdrawal of gonadotrophins when a critical number of follicles and/or E2 concentration is reached. hCG is administered once the E2 concentration reduces to a safe level, before the process of oocyte retrieval commences. This preventative strategy is conducted for a period of less than 3 days in order to avoid compromising IVF outcomes.

'''Cryopreservation'''

Cryopreservation of embryos after oocyte retrieval is another avenue which may avert OHSS progression. The cryopreserved embryos are only reimplanted once the patient's hormone serum levels have normalised. Using oocyte vitrification, crystal formation within embryo tissue is avoided and so cryopreserved embryos have been found to produce better pregnancy rates with a 32% increase, than fresh embryo transfer. Recent studies suggest cryopreservation itself does not reduce OHSS rates, but must be followed by a GnRHa trigger to avert OHSS.

'''Cycle cancellation'''

Cycle cancellation is a guaranteed method to prevent early OHSS whereby hCG is withheld. This is a last resort strategy as it carries the risk of significant psychological distress and financial loss for the patient.

</div>

==Effect on the Newborn==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

</div>
Women who develop OHSS while undergoing Assisted Reproductive Technologies (ART) treatment are not only more likely to achieve a pregnancy, but have a live birth as the pregnancy outcome. This live birth is also more likely to be a multiple birth of two, three or more children. <ref name="PMID19591989"><pubmed>19591989</pubmed></ref> It has been postulated that a multifetal pregnancy leads to a more rapid increase in hCG levels, resulting in an increased risk of OHSS. However, the causal nature between multifetal pregnancy and OHSS development is disputed and further research is required to distinguish correlation from causation. <ref name="PMID19573292"><pubmed>19573292</pubmed></ref>

OHSS development is also associated with an increased risk of adverse outcomes including stillbirth, premature birth and low birthweight.<ref name="PMID19591989" /> Although the cause for the increased risk in adverse pregnancy outcomes is unknown, it is suggested that as the incidence of OHSS is reduced through various prevention strategies, the risk of such outcomes may be also be reduced.

==Genetics==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

Despite OHSS typically being of iatrogenic origin as a result of ovarian stimulation with gonadotropins, research has been conducted into the potential genetics behind OHSS as many sporadic and familial cases have been observed. '''Mutations''' in the receptor for hormones such as Follicle Simulating Hormone (FSH), Lutenizing Hormone (LH) and hCG have all been targets of OHSS genetics research. Interestingly, they too also arise from a common ancestral gene.

===Follicle Stimulating Hormome===

Dr. Botros Rizk, of the University of South Alabama College of Medicine <ref name="PMID19573286"><pubmed>19573286</pubmed></ref>, has written extensively regarding the genetics behind OHSS. In particular, he talks about '''FSH receptors''' (FSHR) and their role in the syndrome. He hypothesises that mutations in these receptors could be activating or inactivating, leading to an increased risk of developing OHSS or sterility respectively. Currently, 744 single nucleotide polymorphisms (a type of mutation) have been found in the gene encoding the FSHR, 8 of which are located in its exons (coding regions of the gene). How the ovary responds is resultant on the FSHR genotype. For example, Ser680Asn, a polymorphism in the FSHR gene has been shown to aid in predicting the severity of a woman's OHSS. Ordinarily FSH stimulates the growth of ovarian follicles, however, when mutated, it is stimulated by the hCG resulting in excessive follicle development.

Spontaneous OHSS, OHSS that arises and cannot be attributed to any form of ovarian stimulation or Assisted Reproductive Technology, has been linked to activating mutations in the FSHR <ref name="PMID23499866"><pubmed>23499866</pubmed></ref>. This familial disorder is an autosomal dominant one. In most cases the FSHR can be stimulated by the presence of Thyroid Stimulating Hormone (TSH) or hCG, in the absence of FSH (the ligand for FSHR).

===Lutenizing Hormome===

The '''Lutenizing Hormone Receptor''' (LHR) gene in humans is comprised of 11 exons. Animal studies have shown that many primates exhibit a similar gene which is comprised of only 10 exons, however a gene lacking the 10th exon has been identified and termed the type 2 LHR. Expression of the type 2 LHR has been seen in humans. The type 2 LHR, compared to the wild-type LHR appears to be repaired with regard to its function. Defects in the type 2 LHR include a decrease in efficiency of transport to the plasma membrane and irregularities in signal transduction. Inactivating mutations in the LHR have been seen to cause infertility in women as well as amenorrhoea. Activating LHR gene mutations are asymptomatic and are not associated with OHSS in women.

===Bone Morphogenic Protein===

An imporant growth factor, derived from oocytes called '''BMP-15''' (Bone Morphogenic Protein 15) is vital for female fertility. It belongs to the family of growth factors, Transforming Growth Factor β (TGF-β) and is heavily involved in folliculogenesis. It has been found that mutations in the BMP-15 gene caused infertility in female sheep. Conversely, it has also been indicated in enhanced fertility when BMP-15 is present is high amounts in follicular fluid <ref name="PMID19573286" />.

A case study done by Hanevik ''et. al.'' in 2013 <ref name="PMID21565556"><pubmed>21565556</pubmed></ref> found that a Single Nuclear Polymorphism (SNP) in the BMP-15 gene is responsible for a high response to ovarian hyper-stimulation. The aim of the study was to test the effect the SNP had on BMP-15 with regard to high and low responders buy taking blood from 53 high responders, 38 low responders and 100 non-responders (controls) and analysing 5 noted SNP's. Results from their study showed a correlation between a high response to ovarian hyper-stimulation and the BMP-15 9G allele. The article does state however, that further research is required into the molecular effects of SNP's on the function of BMP-15.

===Vascular Endothelial Growth Factor===

'''Vascular endothelial growth factor''' (VEGF) has been indicated as one of the key agents causing vascular permeability and subsequent ascites in OHSS. The gene, which is located on chromosome 12, is made up of 8 exons (coding regions), of which exons 6 and 7 do not always appear due to the exons being spliced out.The splicing of this gene allows for various isoforms of the gene to exist of which VEGF 121 and 165 appear to play a role in angiogenesis. There are two VEGF Receptors, VEGFR-1 and VEGFR-2 that belong to the tyrosine kinase family of receptors (for more information on VEGF see [[Pathophysiology]]). Because of its distinct role in OHSS, it has been targeted as an area for research for potential treatments. The idea is that if the genetic expression of VEGF and its receptors can be controlled, OHSS can be avoided or treated.<ref name="PMID19573286" />

A different study by Hanevik ''et. al.'' , <ref name="PMID22587628"><pubmed>22587628</pubmed></ref> done in 2012 involved analysing blood samples from 53 women with OHSS and 100 women without it (controls) and analysing 6 SNP's in the VEGFR2 gene to find any genetic variations. They found a correlation between women with the VEGF +405cc genotype and the development of OHSS indicating women that undergo controlled ovarian hyper-stimulation and posses his genotype, are at an increased risk of developing OHSS.

</div>

== Current Research on Animal Models==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">
{|
|-bgcolor="F8E0F1"
|
<span style="font-size:120%">'''Inhibition of Cyclooxygenase-2 (COX-2) by Meloxican decreasing the incidence of OHSS in Rat Model'''</span> <ref name="PMID18166186"><pubmed>18166186</pubmed></ref>

Reasearch was carried out to investigate the effects of selective inhibition of the enzyme COX-2 on the Ovarian Hyperstimulation Syndrome (OHSS) using Female Wistar rates as the subjects. The research aimed to find results by measuring the number of antral and luteinized follicles, ovarian weight, vascualr endothelial growth factors and COX-2 immunohistochemistry. The rats being tested were all 22 days old and were divided into four equal groups;

'''Group 1 (Control group)''' was subject to a 0.1 ml of Intraperitoneal Saline from days 22 ~ 26

'''Group 2 (Mildly-stimulated group)''' subject to 10IU of pregnant mare serum gonadotrophin (PMSG) on day 24 and then 10IU of Human Chorionic Gonadotrophin (hCG) on day 26

'''Group 3 (OHSS positive group)''' was subject to 10IU of PMSG from days 22 ~ 26 and then administered 30IU of hCG on day 26 to induce OHSS

'''Group 4 (OHSS positive variant group)''' received 15mg/ml of Meloxicam 2 hours prior to administration of 10IU PMSG from days 22 ~ 26

Results showed there was no difference in ovarian weight in samples from Group 1 and Group 2, however Group 3 showed signs of significant ovarian weight increase which in group 4 was suppressed by the introduction of Meloxicam. No differences were observed in the number of antral follicles amongst the four test groups. Results from Group 2 and Group 3 showed that the granulosa cells of preovulatory follicles and the stromal cells were highly VEGF immunoreactive, however the Meloxicam treated Group 4 showed less immunoreactivity than Group 2 and Group 3 which indicated the correlation between Meloxicam and the diminished VEGF expression. Group 3 presented an increased COS-2 immunoreactivity which was highly diminished than in Group 4.

The research concluded that in a rat model, the enzyme Meloxicam has a beneficial effect on OHSS by reducing the increase of ovarian weight and the expression of VEGF associated with OHSS, the effects of which may be mediated by the inhibitory capacity of COX-2 on Meloxicam
|}

{|
|-bgcolor="FF99FF"
|
<span style="font-size:120%">'''Inhibition of Ovarian VEGF secretion by activation of Dopamine Receptor 2'''</span> <ref name="PMID25217874"><pubmed>25217874</pubmed></ref>

This research was carried out to investigate a possibility in whether a Dopamine Receptor 2 agonist '''(D2-ag)''' can assist in the prevention of Ovarian Hyperstimulation Syndrome, using rat models, by decreasing the ovarian vascular endothelial growth factor '''(VEGF)''' production. Using Immature Wistar rats (22 days old) as their animal model, the rats were initially stimulated with Gonadotrophins to mimic the onset and effects of OHSS and then subjected to treatment with a D2-agonist and/or a D2-antagonist (D2-ant). The vascular permeability was measured at the endpoint after day 26 by measuring the peritoneal extravasion of a previously injected dye and ovaries from all subjects were collected to assess the effects of D2-ag and D2-ant on the production of Ovarian VEGF. The expression of VEGF mRNA was measured by quantitative real time PCR and the levels of VEGF proteins were measured by Western Blots.

Results showed that the D2-ag caused a large reduction in the vascular permeability which was in turn associated with the great decreased in VEGF protein production in the OHSS rat ovaries, whereas the introduction of D2-ant showed opposite results with a increase in the vascular permeability leading to the increase of VEGF protein production in the ovaries. Ovarian VEGF mRNA levels were found to be unaffected by the introduction of these drugs in OHSS rat subjects. Conclusions were drawn on the fact that Dopamine Receptor 2 agonists prevent the increase of vascular permeability in subjects with OHSS by decreasing the ovarian production of VEGF and also that due to the dose-dependent inhibitory effect of the D2-ag on ovarian VEGF, current OHSS therapies used in humans can benefit by increasing the intraovarian concentration of D2-ag.
|}
</div>

==Glossary==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

'''Ascites'''- An accumulation of fluid in the peritoneal cavity with resultant abdominal swelling

'''Cabergoline''' - A dopamine receptor agonist used to treat hormone imbalance.

'''GnRH antagonist''' - Gonadotropin Releasing Hormone - A class of compounds that are similar in terms of the structure of natural Gonadotropin Releasing Hormone but has a antagonistic effect.

'''hCG'''- Human Chorionic Gonadotropin

'''Hemoconcentration'''- An increase in the concentration of circulating red blood cells in response to a decrease in blood plasma volume

'''Hypovolemic'''- A decrease in circulating blood volume

'''Iatrogenic'''- Illness caused as a result of a medical examination or treatment

'''Intravenous fluids''' - Is the infusion of liquid substances directly into a vein.

'''IVF'''- In-vitro Fertilization

'''NSAID'''- Non-steroidal Anti-Inflammatory Drug e.g. Ibuprofen

'''OHSS'''- Ovarian Hyper-stimulation Syndrome

'''FSH''' - Follicle Stimulating Hormone

'''LH''' - Luteinizing Hormone

'''Oliguria'''- Decreased urine output/small amounts of urine produced

</div>

==References==

2015 Group Project 2

2015-10-22T21:04:53Z

Z3372824: /* Complications */

{{ANAT2341Project2015header}}

==<span style="font-size:120%">'''Ovarian Hyper-stimulation Syndrome (OHSS)'''</span>==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

Ovarian Hyper stimulation Syndrome (OHSS) is an iatrogenic complication of '''Assisted Reproduction Technology''' (ART), in which women take medications to stimulate oocyte growth. It is generally identified by cystic enlargements of the ovaries and fluid accumulation in the peritoneal cavity due to the increased capillary permeability and ovarian neoangiogenesis <ref name="PMID22065820"><pubmed>22065820</pubmed></ref>. It is an occurrence which is dependent on the controlled stimulation of the ovaries in preparation for IVF i.e. administration of human Chorionic Gonadotropin (hCG).

OHSS was first described in 1943 as ''“syndrome d’hyperluteinisation massive
des ovaries”''. It was during this time that gonadotropins were prepared from animals such as sheep to bring on ovulation in women. The first recorded death as a result of OHSS occurred in 1951 and was due to renal failure as a result of oligouria, a complication of the syndrome <ref name="OHSS"> Marie M. Budev, DO, MPH; Alejandro C. Arroliga, MD; Tommaso Falcone, MD, [ http://utilis.net/Morning%20Topics/REI/Ovarian%20Hyperstimulation.pdf ], 'Ovarian Hyperstimulation Syndrome'</ref> <ref name="PMID12638783"><pubmed>12638783</pubmed></ref>.

<span style="color:#FA58D0">This wikipage aims to provide clear information on various areas surrounding OHSS such as diagnosis, prevention and complications and will look into the genetics behind the disorder and the various animals models used to research it.</span>

<html5media height="350" width="450">https://www.youtube.com/watch?v=aXmjJw234a4</html5media>

'''Overview of the Ovarian Hyperstimulation Syndrome''' <ref> Howcast (2013, August 27) Ovarian Hyperstimulation Syndrome | Infertility. Retrieved from https://www.youtube.com/watch?v=aXmjJw234a4</ref>

</div>

==Epidemiology==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

Ovarian Hyper-Stimulation Syndrome (OHSS) rarely occurs sporadically, and if it does, it is usually the result of an underlying genetic problem. The majority of OHSS is due to the ovaries being stimulated to mature and release an abundance of oocytes, in response to hormones Human Chorionic Gonadotropin (hCG) and Follicle Stimulating hormone (FSH), during IVF. Rarely, Clomifene Citrate therapy can cause OHSS.<ref name="WikiOHSS"> Wikipedia, [ https://en.wikipedia.org/wiki/Ovarian_hyperstimulation_syndrome ], 'Ovarian Hyperstimulation Syndrome'</ref>

OHSS only affects '''0.5-5%''' of women undergoing Ovarian Hyper-stimulation, but despite its small prevalence, it is a potentially fatal outcome of a non-vital procedure and remains a prevalent problem for fertility specialists <ref name="PMID12498425"><pubmed>12498425</pubmed></ref> <ref name="PMID12638783"><pubmed>12638783</pubmed></ref>. Age has been cited as a factor affecting those with OHSS, with younger women more at risk. Additionally, women with allergies were seen to have a higher incidence of OHSS. It is important to note that at this point in time, there is no positive correlation between gonadotropin dose and OHSS.

Of the 0.5-5% of women affected with OHSS mentioned above, 2% of those women will require hospitalisation. As of 2011, it has been reported that the incidence of OHSS was '''increasing''', resulting in approximately 3 deaths per 100,000 women undergoing ovarian stimulation per year <ref name="PMID21828116"><pubmed>21828116</pubmed></ref>. This is particularly worrying as in 2008, in the United States alone, there were around 150,000 IVF cycles undertaken.

{|
|-bgcolor="F8E0F1"
|
'''With the field of Assisted Reproductive Technologies expanding and more women partaking in IVF treatments, the threat of women developing OHSS is an ongoing and increasing one''' <ref name="PMID21828116" />.
|}
{| class="wikitable mw-collapsible mw-collapsed"
! Characteristics of women by complication group <ref name="PMID19591989"><pubmed>19591989</pubmed></ref>
|-
! scope="col" width="100px" height="60px" style="text-align:center| '''Characteristic'''
! scope="col" width="100px" height="60px" style="text-align:center| '''No Complications
(N = 212,041)'''
! scope="col" width="100px" height="60px" style="text-align:center| '''Moderate OHSS
(N = 1,523)'''
! scope="col" width="100px" height="60px" style="text-align:center| '''Severe OHSS
(N = 655)'''
|-
|style="text-align:center; background: #FF99FF;"| '''Maternal Age (Mean ± SD)'''
|style="text-align:center; background: #F6CEEC;"| 35.6 ± 4.6
|style="text-align:center; background: #F6CEEC;"| 33.0 ± 4.3
|style="text-align:center; background: #F6CEEC;"| 33.1 ± 4.4
|-
|style="text-align:center; background: #FF99FF;"| '''Maternal Age (%)'''
|-
|style="text-align:left; background: #F6CEEC;"| <30 years
|style="text-align:center; background: #F6CEEC;"| 10 %
|style="text-align:center; background: #F6CEEC;"| 21.1 %
|style="text-align:center; background: #F6CEEC;"| 20.6 %
|-
|style="text-align:left; background: #F6CEEC;"| 30-34 years
|style="text-align:center; background: #F6CEEC;"| 30.4 %
|style="text-align:center; background: #F6CEEC;"| 43.2 %
|style="text-align:center; background: #F6CEEC;"| 40.5 %
|-
|style="text-align:left; background: #F6CEEC;"| 35-39 years
|style="text-align:center; background: #F6CEEC;"| 37.8 %
|style="text-align:center; background: #F6CEEC;"| 27.2 %
|style="text-align:center; background: #F6CEEC;"| 32.5 %
|-
|style="text-align:left; background: #F6CEEC;"| >40 years
|style="text-align:center; background: #F6CEEC;"| 21.8 %
|style="text-align:center; background: #F6CEEC;"| 8.4 %
|style="text-align:center; background: #F6CEEC;"| 6.4 %
|-
|style="text-align:center; background: #FF99FF;"| '''Nulligravida (%)'''
|style="text-align:center; background: #F6CEEC;"| 45.8 %
|style="text-align:center; background: #F6CEEC;"| 51.5 %
|style="text-align:center; background: #F6CEEC;"| 51.8 %
|-
|style="text-align:center; background: #FF99FF;"| '''Infertility Diagnosis (%)'''
|-
|style="text-align:left; background: #F6CEEC;"| Male factor
|style="text-align:center; background: #F6CEEC;"| 37.7 %
|style="text-align:center; background: #F6CEEC;"| 41.0 %
|style="text-align:center; background: #F6CEEC;"| 33.4 %
|-
|style="text-align:left; background: #F6CEEC;"| Endometriosis
|style="text-align:center; background: #F6CEEC;"| 13.5 %
|style="text-align:center; background: #F6CEEC;"| 13.5 %
|style="text-align:center; background: #F6CEEC;"| 10.7 %
|-
|style="text-align:left; background: #F6CEEC;"| Ovulation Disorders
|style="text-align:center; background: #F6CEEC;"| 14.0 %
|style="text-align:center; background: #F6CEEC;"| 29.5 %
|style="text-align:center; background: #F6CEEC;"| 22.4 %
|-
|style="text-align:left; background: #F6CEEC;"| Diminished ovarian reserve
|style="text-align:center; background: #F6CEEC;"| 16.9 %
|style="text-align:center; background: #F6CEEC;"| 3.2 %
|style="text-align:center; background: #F6CEEC;"| 2.4 %
|-
|style="text-align:left; background: #F6CEEC;"| Tubal factors
|style="text-align:center; background: #F6CEEC;"| 20.4 %
|style="text-align:center; background: #F6CEEC;"| 22.6 %
|style="text-align:center; background: #F6CEEC;"| 22.3 %
|-
|style="text-align:left; background: #F6CEEC;"| Uterine factors
|style="text-align:center; background: #F6CEEC;"| 5.1 %
|style="text-align:center; background: #F6CEEC;"| 4.3 %
|style="text-align:center; background: #F6CEEC;"| 3.1 %
|-
|style="text-align:left; background: #F6CEEC;"| Other factors
|style="text-align:center; background: #F6CEEC;"| 13.9 %
|style="text-align:center; background: #F6CEEC;"| 13.1 %
|style="text-align:center; background: #F6CEEC;"| 10.4 %
|-
|style="text-align:left; background: #F6CEEC;"| Unexplained factor
|style="text-align:center; background: #F6CEEC;"| 12.7 %
|style="text-align:center; background: #F6CEEC;"| 11.8 %
|style="text-align:center; background: #F6CEEC;"| 18.6 %
|-
|}
</div>

==Causative Agents==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

[[File:Follicular Development.jpeg|right|thumbnail|500px|Infertility treatments aim to facilitate follicular development and induce ovulation to improve chances of fertilisation <ref name="PMID24717179"><pubmed>24717179</pubmed></ref>]]

Normally a woman produces one egg per month from the ovaries, which travel down the Fallopian tube to be fertilized or be released from the body. In cases where women have difficulty falling pregnant, they are given medication which help them to produce and release eggs (as shown in the diagram to the right), further increasing their chances of fertilization and pregnancy <ref><pubmed>19573285</pubmed></ref>. Ovarian Hyper stimulation Syndrome generally occurs during infertility treatments when the ovaries are overstimulated by the fertility medication which causes the ovaries to swell and leak fluids into the belly and abdomen. The prevalence of OHSS onset is linked with excessive number of follicle development in response to the administration of injectable Follicle Stimulating Hormones (FSH) followed by the '''Human Chorionic Gonadotrophins''' (hCG) which triggers the release of the oocytes <ref><pubmed>26190539</pubmed></ref>.

'''Follicle Stimulating Hormones''' (FSH) <ref name="PMID9020850"><pubmed>9020850</pubmed></ref> are glycoprotein hormones that are produced and secreted from the Anterior Pituitary gland into the bloodstream, which regulate the developmental, growth, maturation and the reproductive processes within the body. In females, the Follicle Stimulating Hormones initiates the stages of growth and development of immature ovarian follicles within the ovaries before the release of an egg from a follicle at ovulation. When FSH is administered to a patient who is suffering from infertility, the increase FSH levels affect the rate of development and production, in turn increasing the amount of follicles which are ready to be released during ovulation.

</div>

==Symptoms==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

OHSS is classified based on a criteria from mild, moderate and severe <ref name="WikiOHSS" />:

'''Mild Symptoms'''- abdominal bloating, minimal weight gain, nausea, diarrhoea and a feeling of fullness.

'''Moderate Symptoms'''- Substantial weight gain (on average 2 or more pounds a day), increased abdominal girth, darkend urine and excessive thirst in addition to the mild symptoms.

'''Severe Symptoms'''- In addition to the symptoms associated with Mild and Moderate OHSS, in severe OHSS, you see shortness of breath, calf and chest pains and pleural effusion.

<span style="font-size:100%">'''Classifications of Ovarian Hyper-stimulation Syndrome:'''</span> <ref name="PMID22065820"><pubmed>22065820</pubmed></ref>
{| class="wikitable" style="text-align:center
|-
! scope="col" width="70px"| '''Classification'''
! scope="col" width="650px"| '''Symptoms'''
|-
|style="text-align:center; background: #F6CEEC;"| '''Mild'''
|style="height: 60px; background: #F6CEEC;"| '''Grade 1''' - Abdominal distention and discomfort
'''Grade 2''' - Abdominal distention, discomfort with nausea, vomiting and/or diarrhea and ovarian enlargement from 5~12cm
|-
|style="text-align:center; background: #F8E0F1;"| '''Moderate'''
|style="height: 60px; background: #F8E0F1;"| '''Grade 3''' - All features of Mild OHSS with ultrasonographic evidence of ascites
|-
|style="text-align:center; background: #F6CEEC;"| '''Severe'''
|style="height: 60px; background: #F6CEEC;"| '''Grade 4''' - All features of Moderate OHSS with the addition of clinical evidence of ascites and breathing difficulties present
'''Grade 5''' - All of the above symptoms along with a change in the blood volume, increased blood viscosity due to coagulation and diminished renal function
|}

</div>

==Diagnosis==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

Whilst symptoms of OHSS can occur as soon as 24 hours post hCG administration, they are usually seen in women 7-10 days post administration. Initially women with OHSS will present with abdominal bloating, as a result of fluid in the peritoneal cavity and an increase in ovary size. When women present with severe OHSS they are often dehydrated, due to increased vascular permeability, and have hemoconcentration. The above results in a decrease in intravascular volume, leading to oligouria <ref name="PMID22416285" />.

===History===

Initially a thorough history of the patient is taken during which the clinician looks for evidence of ovarian stimulation, followed by ovulation. During this history taking, the clinician will inquire into any weight gain noticed, urine output, and the woman's ability to maintain oral hydration. A key diagnostic tool for clinicians regarding women who are taking gonadotropins is to identify if they are at an increased risk of developing OHSS. Some risk factors include woman aged less than 30, women who have polycystic ovaries, woman with a previous history of OHSS and women who have had greater than 20 oocytes retrieved <ref name="PMID22416285" />.

===Physical Exam===
[[File:Vaginal_Ultrasonography_in_Sagittal_Plane.jpg|right|thumbnail|600px|Vaginal Ultrasonography in Sagittal plane <ref name="Wikiversity Journal of Medicine"> Häggström, Mikael. "Medical gallery of Mikael Häggström 2014". Wikiversity Journal of Medicine 1 (2). DOI:10.15347/wjm/2014.008. ISSN 20018762</ref>]]
After a history of the patient is taken, the next step is to perform a physical exam on the patient. Women who present with abdominal bloating will produce a shifting dullness upon abdominal percussion. Additionally the clinician will test the woman's vital signs, measure her abdominal girth, weight and will look for evidence of ascites or increase in calf size (usually unilateral)<ref name="PMID22416285" />.

===Investigations===

If the clinician further suspects a women of having OHSS, various investigations can be done such as an ultrasound.The intraperitoneal fluid is best imaged via vaginal ultrasound due to the enlarged ovaries making it difficult to image the pelvis using transabdominal ultrasound. The clinician can also order laboratory testing to look for urine specific gravity and and complete blood count to look for hemoconcentration with a hematocrit. Additionally, liver function tests can be ordered to look for elevated function. The clinician will also look for evidence of elevated D-dimers and fibrinogen and decreased levels of anti-thrombin 3 <ref name="SAHealth"> Government of South Australia Health [ http://www.sahealth.sa.gov.au/wps/wcm/connect/9b61ed004ee5348da663afd150ce4f37/Ovarian-hyperstimulation-syndrome-WCHN-PPG-17072012.pdf?MOD=AJPERES&CACHEID=9b61ed004ee5348da663afd150ce4f37 ], 'South Australian Paediatric Clinical Guidelines OHSS'</ref>.

====Ultrasound====

Typical appearances of the ultrasound include <ref name="Ultrasound"> Radiopaedia [ http://radiopaedia.org/articles/ovarian-hyperstimulation-syndrome-1 ], 'Ovarian Hyperstimulation Syndrome'</ref>:

*Bilaterally and symmetrically enlarged ovaries (>12cm)
* "Spoke-Wheel appearance" - presence of multiple cysts of varying size
*May also see ascites (fluid)

===Severity===

Once a clinician has deduced a women is suffering from OHSS, the severity of their condition needs to be established as either mild, moderate or severe. This is done by referring to the criteria under the sub-heading [[Symptoms]].The subsequent course of treatment for the woman will be based upon this evaluation.

{|
|-bgcolor="F6CEEC"
|
'''Further investigations''' can be done including a Chest X-ray to check for pleural effusions and oedema and USS with Doppler's to check for ascites or possible ovary torsion. <ref name="PMID22416285"><pubmed>22416285</pubmed></ref>
|}

===Differential Diagnosis===

Conditions presenting with similar symptoms or ultrasound images include <ref name="Ultrasound" />:

*Polycystic Ovaries (PO)
:: The difference is that with PO is that the cycts are typically smaller than OHSS cysts and there is no evidence of ascited or pleural effusion
*Mucinous Ovarian Malignancy
:: A type of Ovarian Epithelial tumour
*Ectopic Pregnancy <ref name="Casereport"> Australian Medical Student Journal [ http://www.amsj.org/wpcontent/uploads/files/articles/amsj_v2_i1/AMSJ_v2_i1_pg58-60.pdf ], 'Ovarian hyperstimulation syndrome'</ref>
::A pregnancy in which the foetus develops outside of the uterus e.g. in the fallopian tube

</div>

==Pathophysiology==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

[[File:Pathogenesis_of_OHSS.png|600px|thumb|Pathogenesis of OHSS <ref name="PMID20416867"><pubmed>20416867</pubmed></ref>]]

The definition of Ovarian Stimulation is enlarged ovaries with many luteinized cysts, that can present with secondary complications. What distinguishes Ovarian Stimulation from OHSS is the presence of vascular hyper-permeability that results in fluids being redirected elsewhere in the body.

The key process to OHSS appears to be caused by '''Vascular Endothelial Growth Factor''' (VEGF), that is released along with other cytokines, estrogen and progesterone, due to the ovary undergoing luteinization as a result of stimulation by hCG. VEGF increases vascular permeability and as a result the capillaries become more "leaky" to the fluids in them. These fluids can then escape the capillaries and accumulate in the pleural and abdominal cavities as ascites. The woman then becomes hypovolemic and is at an increased risk of circulatory, renal and respiratory issues such as arterial thromboembolism due to the thickening of the blood. Note, the blood is thickened as fluid is leaving the capillaries, leaving behind red blood cells and other cellular components of the blood <ref name="WikiOHSS" />.

The increase in expression of VEGF and VEGF Receptor 2 (VEGFR2) is attributed to the greatly increased amount of their mRNA present in the body after stimulation with hCG <ref name="PMID21082502"><pubmed>21082502</pubmed></ref>. VEGF interacts with VEGF2 and VEGF Receptor 1 (VEGFR1) to create a strong angiogenic effect. Both VEGFR2 and VEGFR1 belong to a family of receptors called tyrosine kinases. VEGF2 is involved in the regulation of angiogenesis and vascular permeability whilst VEGF1 has a slightly contradictory role in that is is involved in the maintenance of the tight junctions between endothelial cells in blood vessels. A study by Gómez ''et. al.'' <ref name="PMID21082502" /> showed that women experiencing OHSS had substantially higher plasma levels of VEGF and lower levels of VEGFR1.

</div>

==Complications==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

Ovarian torsion or rupture, renal insufficiency and thrombophlebitis can all complicate OHSS. If a pregnancy occurs, symptoms may persist longer than the usual 1 to 2 weeks and become more severe, however, even with severe OHSS, they do not extend past the first trimester <ref name="WikiOHSS" />.

<span style="color:#FA58D0"> '''1-2% of women who undergo ovarian stimulation develop a severe form of OHSS''' </span>. Complications from severe OHSS include:

*Fluid collection in the abdomen
*Electrolyte disturbances (sodium and potassium)
*Kidney failure
*Ovary twisting
*Rupture of a cyst in an ovary
*Breathing problems
*Blood clots in large vessels (most commonly the legs)
*Pregnancy loss from miscarriage or termination
*Rarely, death

A study by Nouri ''et. al.'' <ref name="PMID24996451"><pubmed>24996451</pubmed></ref> found that women with '''Polycystic Ovarian Syndrome''' (PCOS) and those that were induced with hCG experienced longer recovery times from severe OHSS than women who were not pregnant. They looked at a cohort of women hospitalised for the first time with severe OHSS and subject them to the same treatments. Based on a defined criteria, they established the recovery time of these women and compared the times between those that were pregnant to those that were not pregnant. They also found that whether a woman had PCOS or ovulation induction did not affect her risk of developing OHSS if she was not pregnant. It is only a risk factor for pregnant women.

===Thromboembolic events===

A frequent and deadly complication of OHSS are thromboembolic events due to increased blood clotting. This increase in blood clotting has been attributed to a variety of complications such as hemoconcentration (which thickens the blood), hypolvolemia and an increase in the permeability of blood vessels as a result of increased vasoactive substances in the body of ovarian origin. Thromboembolic events include venous thromboses often in the upper extremities and arterial thromboses such as those in the cerebrovascular region. These events can lead to amputations of extremities, brain damage, miscarriage and death. To avoid this, anti-coagulants are given to pateitns with OHSS and they are fitted with compression stockings (see [[Treatment]]) <ref name="PMID23378404"><pubmed>23378404</pubmed></ref>.

{|
|-bgcolor="F8E0F1"
|
The risk of a woman developing OHSS is higher if she is having a '''twin pregnancy''', as she is exposed to higher concentration of hCG. <ref name="PMID9756273"><pubmed>9756273</pubmed></ref>
|}

</div>

==Treatment==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

'''General treatment
'''
*''Acetaminophen'' with or without a narcotic agent- used to treat abdominal discomfort
*Women are encouraged to drink 2-3 litres of water a day to prevent hemoconcentration
*Women are advised to avoid sexual intercourse and vigorous exercise at the risk of torsion or rupture of the ovaries
*NSAID's with anti-platelet properties should NOT be used as they may effect renal function in a women with OHSS
*Patients with significantly painful ascites or breathing problems may undergo ''Paracentesis'' (drainage of the ascites)
*''Culdocentesis'' (extraction of fluid from recto-uterine pouch) can be done to decrease the likelihood of a woman with moderate OHSS progressing to severe OHSS.<ref name="PMID22416285" />

===Mild to Moderate OHSS===

Mild OHSS can often resolve on its own, however, moderate OHSS may include treatments such as<ref name="WikiOHSS" />:

*Anti-nausea medication and prescription painkillers
*Regular physical examinations and ultrasounds
*Daily weigh-ins and waist measurements
*Measuring the amount of urine produced each day
*Frequent blood tests for monitoring dehydration and electrolyte imbalance
*Maintaining a high balance of fluids
*Drainage of excess abdominal fluid by inserting a needle in the abdominal cavity
*Wearing support stockings which help prevent blood clots/thrombosis

===Severe OHSS===

Severe OHSS requires hospital care in order for constant monitoring and treatment such as <ref name="WikiOHSS" />:

*Intravenous fluids with a crystalloid solution (100-150mL/hr)
*Intravenous Albumin is administered is IV fluids are insufficient (15-20mL/hr of 25% albumin for 4 hrs)
*In addition to Acetaminophen, ''Opioid analgesics'' can be administered for pain relief
*''Antiemetics'' can be used to subside nauseas and/or vomiting
*Woman administered to hospital of OHSS are considered at high risk of thromboembolic complications and are given low molecular weight ''heparin'', an anti-coagulant
*''Cabergoline''- lessens OHSS symptoms
*''GnRH agonist''- suppresses ovarian activity
**If at risk of OHSS, alternates include using a GnRH agonist instead of hCG however its effects on pregnancy rates are questionable. Using a GnRH agonist to replace the use of hCG for final oocyte stimulation will see a 6% decrease in delivery rate.

*Daily monitoring of creatine, urea, creatine clearance C-reactive protein (to rule out infection) are all required in combination with weekly tests such as liver and renal function tests and chest x-rays (to check for pleural effusion) <ref name="PMID12638783" />.

If there are serious complications then additional treatments are required:

*Surgery for a ruptured ovarian cyst
*Intensive care for the liver or lung complications

====Paracentesis====

For women with severe/grade 3 OHSS, paracentesis, the removal of fluid from the body using an aspiration needle, can be undertaken. It is a diagnostic and a therapeutic method that can be done trans-abdominally and trans-vaginally. It is used to relieve symptoms, improve haemodynamics e.g. Urinary output, and shorten the women's hospital stay. Complications of paracentesis include bleeding, infection and organ injury, however are note common <ref name="Paracentesis"> S. Monica Soni, HMS 3, Gillian Lieberman, MD [ http://eradiology.bidmc.harvard.edu/LearningLab/genito/Soni.pdf ], 'Ovarian Hyperstimulation Syndrome'</ref>.

{|
|-bgcolor="F8E0F1"
|
The most important aspect of treatment for any women with OHSS is close and constant '''monitoring''' with her healthcare professional. Counselling may also be provided to women and their partners or families in order to provide them with the best possible knowledge base to manage and treat their OHSS. It is important to note that there is '''no one cure or treatment''' for OHSS. Treatment involves managing and eliminating the symptoms until such time as the syndrome resolves itself <ref name="WikiOHSS" />.
|}

</div>

==Prevention==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

There are three key avenues through which the incidence of OHSS may be prevented. These include identifying risk factors to predict OHSS development, modifying treatment regimes on the basis of the identified risk factors and intervention to prevent progression to OHSS once the patient has undergone Controlled Ovarian Stimulation.

=== Risk factors===

'''Primary risk factors'''

Pre-existing factors likely to exacerbate the ovarian stimulation response. Primary risk factors include <ref name="PMID26074966"><pubmed>26074966</pubmed></ref>:

*Young age
*Low body weight
*History of elevated response to gonadotropins
*Polycystic Ovary Syndrome (PCOS)
*Isolated PCOS characteristic
*A previous history of OHSS.
*Hormonal markers (e.g. Anti-Mullerian Hormone markers)
*Ultrasonographic markers (e.g. Antral Follicle Count)

'''Secondary risk factors'''

Secondary risk factors involve the monitoring of ovarian response parameters once COS has been initiated. These parameters are monitored for <ref name="PMID19007627"><pubmed>19007627</pubmed></ref>:

*rapidly rising E2 levels
*E2 concentration larger than 2500 pg/mL
*large number of developing follicles (10-14mm) on the day hCG is administered
*large number of oocytes retrieved

These factors in combination, act as a predictive tool to assess the likelihood of severe OHSS development, with a 83% sensitivity and 84% specificity. <ref name="PMID19007627"/>

=== Primary Prevention===

Primary Prevention involves the modification of treatment regimens on the basis of OHSS risk classifications, in order to prevent OHSS occurrence.

'''Ovulation Induction'''

Unifollicular Ovulation Induction through Ovulation Induction (OI) is a primary means of avoiding OHSS in women with Polycystic Ovarian Syndrome, who are at an increased risk. In order to promote unifollicular development, the ovaries are stimulated with a low starting dose of FSH (75 IU).<ref name="PMID20416867"><pubmed>20416867</pubmed></ref> Studies suggests that a minimum gonadotropin dose lowers OHSS risk and thus a step-up regimen is utilised to achieve an ovarian response, whereby the FSH dosage is increased every 7 days until follicular development of greater than 10mm is noted <ref name="PMID26074966" />. Alternatively, a step-down regimen may be followed, whereby a high initial FSH dosage is lowered according to the ovarian response. Another method to increase FSH levels during OI, is through Aromatase Inhibitors which promote folliculogenesis by increasing pituitary secretion of FSH, and downregulate oestrogen production through a negative feedback loop. However, Aromatase Inhibitors have not been shown to reduce OHSS incidence in comparison to other methods of OI. During OI, a key objective is to prevent early cycle cancellation due to premature luteinisation from pituitary secretion of LH. In order to downregulate LH secretion, Gonadotropin-releasing hormone agonists (GnRHa) are administered in addition to gonadotropins. The duration of exposure to gonadotropins and subsequent risk of OHSS may also be minimised through mild stimulation protocols which administer FSH only in the mid to late follicular phase.<ref name="PMID20416867" />

'''Adjuvant Metformin Therapy'''

Adjuvant Metformin Therapy has been found to lower the risk of OHSS by 63% <ref name="PMID25406011"><pubmed>25406011</pubmed></ref>. It involves the administration of metformin at a daily dosage of 1000 to 2000mg, 2 months prior to Controlled Ovarian Stimulation <ref name="PMID26074966"/>. Metformin lowers the elevated insulin levels in PCOS which consequently reduce intraovarian androgen levels. This leads to a reduced sensitivity and expression of granulosa cell-follicle stimulating hormone receptors which result in a less exaggerated response to gonadotropins. Furthermore, it is suggested that Metformin prevents OHSS by controlling vascular permeability through the inhibition of various vasoactive molecules, including VEGF.

'''Avoiding hCG during Luteal Phase Support

Following Controlled Ovarian Stimulation, the steroid levels of E2 and P4 are reduced during the luteal phase due to the negative feedback on the pituitary. This leads to low endogenous LH levels, which consequently reduce endometrial receptivity as well as the luteal phase duration itself. As a result, implantation and pregnancy rates are reduced and early pregnancy loss rates are increased.<ref name="PMID20416867" /> Luteal Phase Support (LPS) serves to combat these adverse events with the use of hCG. However, hCG has been found to increase the risk of OHSS. Alternatively, the use of progesterone has been found to not only halve the risk of OHSS, but also induce similar improvements in pregnancy and miscarriage rates as hCG.<ref name="PMID26148507"><pubmed>26148507</pubmed></ref>

===Secondary Prevention===

Secondary Prevention aims to prevent progression to OHSS once COS has been initiated and the patient has been found to mount an exaggerated response. <ref name="PMID20416867" />

'''Coasting'''

Coasting is a first-line secondary preventative strategy. It consists of the withdrawal of gonadotrophins when a critical number of follicles and/or E2 concentration is reached. hCG is administered once the E2 concentration reduces to a safe level, before the process of oocyte retrieval commences. This preventative strategy is conducted for a period of less than 3 days in order to avoid compromising IVF outcomes.

'''Cryopreservation'''

Cryopreservation of embryos after oocyte retrieval is another avenue which may avert OHSS progression. The cryopreserved embryos are only reimplanted once the patient's hormone serum levels have normalised. Using oocyte vitrification, crystal formation within embryo tissue is avoided and so cryopreserved embryos have been found to produce better pregnancy rates with a 32% increase, than fresh embryo transfer. Recent studies suggest cryopreservation itself does not reduce OHSS rates, but must be followed by a GnRHa trigger to avert OHSS.

'''Cycle cancellation'''

Cycle cancellation is a guaranteed method to prevent early OHSS whereby hCG is withheld. This is a last resort strategy as it carries the risk of significant psychological distress and financial loss for the patient.

</div>

==Effect on the Newborn==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

</div>
Women who develop OHSS while undergoing Assisted Reproductive Technologies (ART) treatment are not only more likely to achieve a pregnancy, but have a live birth as the pregnancy outcome. This live birth is also more likely to be a multiple birth of two, three or more children. <ref name="PMID19591989"><pubmed>19591989</pubmed></ref> It has been postulated that a multifetal pregnancy leads to a more rapid increase in hCG levels, resulting in an increased risk of OHSS. However, the causal nature between multifetal pregnancy and OHSS development is disputed and further research is required to distinguish correlation from causation. <ref name="PMID19573292"><pubmed>19573292</pubmed></ref>

OHSS development is also associated with an increased risk of adverse outcomes including stillbirth, premature birth and low birthweight.<ref name="PMID19591989" /> Although the cause for the increased risk in adverse pregnancy outcomes is unknown, it is suggested that as the incidence of OHSS is reduced through various prevention strategies, the risk of such outcomes may be also be reduced.

==Genetics==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

Despite OHSS typically being of iatrogenic origin as a result of ovarian stimulation with gonadotropins, research has been conducted into the potential genetics behind OHSS as many sporadic and familial cases have been observed. '''Mutations''' in the receptor for hormones such as Follicle Simulating Hormone (FSH), Lutenizing Hormone (LH) and hCG have all been targets of OHSS genetics research. Interestingly, they too also arise from a common ancestral gene.

===Follicle Stimulating Hormome===

Dr. Botros Rizk, of the University of South Alabama College of Medicine <ref name="PMID19573286"><pubmed>19573286</pubmed></ref>, has written extensively regarding the genetics behind OHSS. In particular, he talks about '''FSH receptors''' (FSHR) and their role in the syndrome. He hypothesises that mutations in these receptors could be activating or inactivating, leading to an increased risk of developing OHSS or sterility respectively. Currently, 744 single nucleotide polymorphisms (a type of mutation) have been found in the gene encoding the FSHR, 8 of which are located in its exons (coding regions of the gene). How the ovary responds is resultant on the FSHR genotype. For example, Ser680Asn, a polymorphism in the FSHR gene has been shown to aid in predicting the severity of a woman's OHSS. Ordinarily FSH stimulates the growth of ovarian follicles, however, when mutated, it is stimulated by the hCG resulting in excessive follicle development.

Spontaneous OHSS, OHSS that arises and cannot be attributed to any form of ovarian stimulation or Assisted Reproductive Technology, has been linked to activating mutations in the FSHR <ref name="PMID23499866"><pubmed>23499866</pubmed></ref>. This familial disorder is an autosomal dominant one. In most cases the FSHR can be stimulated by the presence of Thyroid Stimulating Hormone (TSH) or hCG, in the absence of FSH (the ligand for FSHR).

===Lutenizing Hormome===

The '''Lutenizing Hormone Receptor''' (LHR) gene in humans is comprised of 11 exons. Animal studies have shown that many primates exhibit a similar gene which is comprised of only 10 exons, however a gene lacking the 10th exon has been identified and termed the type 2 LHR. Expression of the type 2 LHR has been seen in humans. The type 2 LHR, compared to the wild-type LHR appears to be repaired with regard to its function. Defects in the type 2 LHR include a decrease in efficiency of transport to the plasma membrane and irregularities in signal transduction. Inactivating mutations in the LHR have been seen to cause infertility in women as well as amenorrhoea. Activating LHR gene mutations are asymptomatic and are not associated with OHSS in women.

===Bone Morphogenic Protein===

An imporant growth factor, derived from oocytes called '''BMP-15''' (Bone Morphogenic Protein 15) is vital for female fertility. It belongs to the family of growth factors, Transforming Growth Factor β (TGF-β) and is heavily involved in folliculogenesis. It has been found that mutations in the BMP-15 gene caused infertility in female sheep. Conversely, it has also been indicated in enhanced fertility when BMP-15 is present is high amounts in follicular fluid <ref name="PMID19573286" />.

A case study done by Hanevik ''et. al.'' in 2013 <ref name="PMID21565556"><pubmed>21565556</pubmed></ref> found that a Single Nuclear Polymorphism (SNP) in the BMP-15 gene is responsible for a high response to ovarian hyper-stimulation. The aim of the study was to test the effect the SNP had on BMP-15 with regard to high and low responders buy taking blood from 53 high responders, 38 low responders and 100 non-responders (controls) and analysing 5 noted SNP's. Results from their study showed a correlation between a high response to ovarian hyper-stimulation and the BMP-15 9G allele. The article does state however, that further research is required into the molecular effects of SNP's on the function of BMP-15.

===Vascular Endothelial Growth Factor===

'''Vascular endothelial growth factor''' (VEGF) has been indicated as one of the key agents causing vascular permeability and subsequent ascites in OHSS. The gene, which is located on chromosome 12, is made up of 8 exons (coding regions), of which exons 6 and 7 do not always appear due to the exons being spliced out.The splicing of this gene allows for various isoforms of the gene to exist of which VEGF 121 and 165 appear to play a role in angiogenesis. There are two VEGF Receptors, VEGFR-1 and VEGFR-2 that belong to the tyrosine kinase family of receptors (for more information on VEGF see [[Pathophysiology]]). Because of its distinct role in OHSS, it has been targeted as an area for research for potential treatments. The idea is that if the genetic expression of VEGF and its receptors can be controlled, OHSS can be avoided or treated.<ref name="PMID19573286" />

A different study by Hanevik ''et. al.'' , <ref name="PMID22587628"><pubmed>22587628</pubmed></ref> done in 2012 involved analysing blood samples from 53 women with OHSS and 100 women without it (controls) and analysing 6 SNP's in the VEGFR2 gene to find any genetic variations. They found a correlation between women with the VEGF +405cc genotype and the development of OHSS indicating women that undergo controlled ovarian hyper-stimulation and posses his genotype, are at an increased risk of developing OHSS.

</div>

== Current Research on Animal Models==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">
{|
|-bgcolor="F8E0F1"
|
<span style="font-size:120%">'''Inhibition of Cyclooxygenase-2 (COX-2) by Meloxican decreasing the incidence of OHSS in Rat Model'''</span> <ref name="PMID18166186"><pubmed>18166186</pubmed></ref>

Reasearch was carried out to investigate the effects of selective inhibition of the enzyme COX-2 on the Ovarian Hyperstimulation Syndrome (OHSS) using Female Wistar rates as the subjects. The research aimed to find results by measuring the number of antral and luteinized follicles, ovarian weight, vascualr endothelial growth factors and COX-2 immunohistochemistry. The rats being tested were all 22 days old and were divided into four equal groups;

'''Group 1 (Control group)''' was subject to a 0.1 ml of Intraperitoneal Saline from days 22 ~ 26

'''Group 2 (Mildly-stimulated group)''' subject to 10IU of pregnant mare serum gonadotrophin (PMSG) on day 24 and then 10IU of Human Chorionic Gonadotrophin (hCG) on day 26

'''Group 3 (OHSS positive group)''' was subject to 10IU of PMSG from days 22 ~ 26 and then administered 30IU of hCG on day 26 to induce OHSS

'''Group 4 (OHSS positive variant group)''' received 15mg/ml of Meloxicam 2 hours prior to administration of 10IU PMSG from days 22 ~ 26

Results showed there was no difference in ovarian weight in samples from Group 1 and Group 2, however Group 3 showed signs of significant ovarian weight increase which in group 4 was suppressed by the introduction of Meloxicam. No differences were observed in the number of antral follicles amongst the four test groups. Results from Group 2 and Group 3 showed that the granulosa cells of preovulatory follicles and the stromal cells were highly VEGF immunoreactive, however the Meloxicam treated Group 4 showed less immunoreactivity than Group 2 and Group 3 which indicated the correlation between Meloxicam and the diminished VEGF expression. Group 3 presented an increased COS-2 immunoreactivity which was highly diminished than in Group 4.

The research concluded that in a rat model, the enzyme Meloxicam has a beneficial effect on OHSS by reducing the increase of ovarian weight and the expression of VEGF associated with OHSS, the effects of which may be mediated by the inhibitory capacity of COX-2 on Meloxicam
|}

{|
|-bgcolor="FF99FF"
|
<span style="font-size:120%">'''Inhibition of Ovarian VEGF secretion by activation of Dopamine Receptor 2'''</span> <ref name="PMID25217874"><pubmed>25217874</pubmed></ref>

This research was carried out to investigate a possibility in whether a Dopamine Receptor 2 agonist '''(D2-ag)''' can assist in the prevention of Ovarian Hyperstimulation Syndrome, using rat models, by decreasing the ovarian vascular endothelial growth factor '''(VEGF)''' production. Using Immature Wistar rats (22 days old) as their animal model, the rats were initially stimulated with Gonadotrophins to mimic the onset and effects of OHSS and then subjected to treatment with a D2-agonist and/or a D2-antagonist (D2-ant). The vascular permeability was measured at the endpoint after day 26 by measuring the peritoneal extravasion of a previously injected dye and ovaries from all subjects were collected to assess the effects of D2-ag and D2-ant on the production of Ovarian VEGF. The expression of VEGF mRNA was measured by quantitative real time PCR and the levels of VEGF proteins were measured by Western Blots.

Results showed that the D2-ag caused a large reduction in the vascular permeability which was in turn associated with the great decreased in VEGF protein production in the OHSS rat ovaries, whereas the introduction of D2-ant showed opposite results with a increase in the vascular permeability leading to the increase of VEGF protein production in the ovaries. Ovarian VEGF mRNA levels were found to be unaffected by the introduction of these drugs in OHSS rat subjects. Conclusions were drawn on the fact that Dopamine Receptor 2 agonists prevent the increase of vascular permeability in subjects with OHSS by decreasing the ovarian production of VEGF and also that due to the dose-dependent inhibitory effect of the D2-ag on ovarian VEGF, current OHSS therapies used in humans can benefit by increasing the intraovarian concentration of D2-ag.
|}
</div>

==Glossary==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

'''Ascites'''- An accumulation of fluid in the peritoneal cavity with resultant abdominal swelling

'''Cabergoline''' - A dopamine receptor agonist used to treat hormone imbalance.

'''GnRH antagonist''' - Gonadotropin Releasing Hormone - A class of compounds that are similar in terms of the structure of natural Gonadotropin Releasing Hormone but has a antagonistic effect.

'''hCG'''- Human Chorionic Gonadotropin

'''Hemoconcentration'''- An increase in the concentration of circulating red blood cells in response to a decrease in blood plasma volume

'''Hypovolemic'''- A decrease in circulating blood volume

'''Iatrogenic'''- Illness caused as a result of a medical examination or treatment

'''Intravenous fluids''' - Is the infusion of liquid substances directly into a vein.

'''IVF'''- In-vitro Fertilization

'''NSAID'''- Non-steroidal Anti-Inflammatory Drug e.g. Ibuprofen

'''OHSS'''- Ovarian Hyper-stimulation Syndrome

'''FSH''' - Follicle Stimulating Hormone

'''LH''' - Luteinizing Hormone

'''Oliguria'''- Decreased urine output/small amounts of urine produced

</div>

==References==

File:Follicular Development.jpeg

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==Follicular Development==

Infertility treatments such as the Controlled Ovarian Stimulation medical protocol, primarily aim to facilitate follicular development and induce ovulation, in order to increase chances of fertilisation.

===Reference===

<pubmed>24717179</pubmed>| [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4271669/]

====Copyright====

© 2014 The Authors. Animal Science Journal published by Wiley Publishing Asia Pty Ltd on behalf of Japanese Society of Animal Science.
This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes. (https://creativecommons.org/licenses/by-nc/2.0/au/)

Figure 1: asj0085-0627-f1.jpeg

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2015 Group Project 2

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{{ANAT2341Project2015header}}

==<span style="font-size:120%">'''Ovarian Hyper-stimulation Syndrome (OHSS)'''</span>==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

Ovarian Hyper stimulation Syndrome (OHSS) is an iatrogenic complication of '''Assisted Reproduction Technology''' (ART), in which women take medications to stimulate oocyte growth. It is generally identified by cystic enlargements of the ovaries and fluid accumulation in the peritoneal cavity due to the increased capillary permeability and ovarian neoangiogenesis <ref name="PMID22065820"><pubmed>22065820</pubmed></ref>. It is an occurrence which is dependent on the controlled stimulation of the ovaries in preparation for IVF i.e. administration of human Chorionic Gonadotropin (hCG).

OHSS was first described in 1943 as ''“syndrome d’hyperluteinisation massive
des ovaries”''. It was during this time that gonadotropins were prepared from animals such as sheep to bring on ovulation in women. The first recorded death as a result of OHSS occurred in 1951 and was due to renal failure as a result of oligouria, a complication of the syndrome <ref name="OHSS"> Marie M. Budev, DO, MPH; Alejandro C. Arroliga, MD; Tommaso Falcone, MD, [ http://utilis.net/Morning%20Topics/REI/Ovarian%20Hyperstimulation.pdf ], 'Ovarian Hyperstimulation Syndrome'</ref> <ref name="PMID12638783"><pubmed>12638783</pubmed></ref>.

<span style="color:#FA58D0">This wikipage aims to provide clear information on various areas surrounding OHSS such as diagnosis, prevention and complications and will look into the genetics behind the disorder and the various animals models used to research it.</span>

<html5media height="350" width="450">https://www.youtube.com/watch?v=aXmjJw234a4</html5media>

'''Overview of the Ovarian Hyperstimulation Syndrome''' <ref> Howcast (2013, August 27) Ovarian Hyperstimulation Syndrome | Infertility. Retrieved from https://www.youtube.com/watch?v=aXmjJw234a4</ref>

</div>

==Epidemiology==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

Ovarian Hyper-Stimulation Syndrome (OHSS) rarely occurs sporadically, and if it does, it is usually the result of an underlying genetic problem. The majority of OHSS is due to the ovaries being stimulated to mature and release an abundance of oocytes, in response to hormones Human Chorionic Gonadotropin (hCG) and Follicle Stimulating hormone (FSH), during IVF. Rarely, Clomifene Citrate therapy can cause OHSS.<ref name="WikiOHSS"> Wikipedia, [ https://en.wikipedia.org/wiki/Ovarian_hyperstimulation_syndrome ], 'Ovarian Hyperstimulation Syndrome'</ref>

OHSS only affects '''0.5-5%''' of women undergoing Ovarian Hyper-stimulation, but despite its small prevalence, it is a potentially fatal outcome of a non-vital procedure and remains a prevalent problem for fertility specialists <ref name="PMID12498425"><pubmed>12498425</pubmed></ref> <ref name="PMID12638783"><pubmed>12638783</pubmed></ref>. Age has been cited as a factor affecting those with OHSS, with younger women more at risk. Additionally, women with allergies were seen to have a higher incidence of OHSS. It is important to note that at this point in time, there is no positive correlation between gonadotropin dose and OHSS.

Of the 0.5-5% of women affected with OHSS mentioned above, 2% of those women will require hospitalisation. As of 2011, it has been reported that the incidence of OHSS was '''increasing''', resulting in approximately 3 deaths per 100,000 women undergoing ovarian stimulation per year <ref name="PMID21828116"><pubmed>21828116</pubmed></ref>. This is particularly worrying as in 2008, in the United States alone, there were around 150,000 IVF cycles undertaken.

{|
|-bgcolor="F8E0F1"
|
'''With the field of Assisted Reproductive Technologies expanding and more women partaking in IVF treatments, the threat of women developing OHSS is an ongoing and increasing one''' <ref name="PMID21828116" />.
|}
{| class="wikitable mw-collapsible mw-collapsed"
! Characteristics of women by complication group <ref name="PMID19591989"><pubmed>19591989</pubmed></ref>
|-
! scope="col" width="100px" height="60px" style="text-align:center| '''Characteristic'''
! scope="col" width="100px" height="60px" style="text-align:center| '''No Complications
(N = 212,041)'''
! scope="col" width="100px" height="60px" style="text-align:center| '''Moderate OHSS
(N = 1,523)'''
! scope="col" width="100px" height="60px" style="text-align:center| '''Severe OHSS
(N = 655)'''
|-
|style="text-align:center; background: #FF99FF;"| '''Maternal Age (Mean ± SD)'''
|style="text-align:center; background: #F6CEEC;"| 35.6 ± 4.6
|style="text-align:center; background: #F6CEEC;"| 33.0 ± 4.3
|style="text-align:center; background: #F6CEEC;"| 33.1 ± 4.4
|-
|style="text-align:center; background: #FF99FF;"| '''Maternal Age (%)'''
|-
|style="text-align:left; background: #F6CEEC;"| <30 years
|style="text-align:center; background: #F6CEEC;"| 10 %
|style="text-align:center; background: #F6CEEC;"| 21.1 %
|style="text-align:center; background: #F6CEEC;"| 20.6 %
|-
|style="text-align:left; background: #F6CEEC;"| 30-34 years
|style="text-align:center; background: #F6CEEC;"| 30.4 %
|style="text-align:center; background: #F6CEEC;"| 43.2 %
|style="text-align:center; background: #F6CEEC;"| 40.5 %
|-
|style="text-align:left; background: #F6CEEC;"| 35-39 years
|style="text-align:center; background: #F6CEEC;"| 37.8 %
|style="text-align:center; background: #F6CEEC;"| 27.2 %
|style="text-align:center; background: #F6CEEC;"| 32.5 %
|-
|style="text-align:left; background: #F6CEEC;"| >40 years
|style="text-align:center; background: #F6CEEC;"| 21.8 %
|style="text-align:center; background: #F6CEEC;"| 8.4 %
|style="text-align:center; background: #F6CEEC;"| 6.4 %
|-
|style="text-align:center; background: #FF99FF;"| '''Nulligravida (%)'''
|style="text-align:center; background: #F6CEEC;"| 45.8 %
|style="text-align:center; background: #F6CEEC;"| 51.5 %
|style="text-align:center; background: #F6CEEC;"| 51.8 %
|-
|style="text-align:center; background: #FF99FF;"| '''Infertility Diagnosis (%)'''
|-
|style="text-align:left; background: #F6CEEC;"| Male factor
|style="text-align:center; background: #F6CEEC;"| 37.7 %
|style="text-align:center; background: #F6CEEC;"| 41.0 %
|style="text-align:center; background: #F6CEEC;"| 33.4 %
|-
|style="text-align:left; background: #F6CEEC;"| Endometriosis
|style="text-align:center; background: #F6CEEC;"| 13.5 %
|style="text-align:center; background: #F6CEEC;"| 13.5 %
|style="text-align:center; background: #F6CEEC;"| 10.7 %
|-
|style="text-align:left; background: #F6CEEC;"| Ovulation Disorders
|style="text-align:center; background: #F6CEEC;"| 14.0 %
|style="text-align:center; background: #F6CEEC;"| 29.5 %
|style="text-align:center; background: #F6CEEC;"| 22.4 %
|-
|style="text-align:left; background: #F6CEEC;"| Diminished ovarian reserve
|style="text-align:center; background: #F6CEEC;"| 16.9 %
|style="text-align:center; background: #F6CEEC;"| 3.2 %
|style="text-align:center; background: #F6CEEC;"| 2.4 %
|-
|style="text-align:left; background: #F6CEEC;"| Tubal factors
|style="text-align:center; background: #F6CEEC;"| 20.4 %
|style="text-align:center; background: #F6CEEC;"| 22.6 %
|style="text-align:center; background: #F6CEEC;"| 22.3 %
|-
|style="text-align:left; background: #F6CEEC;"| Uterine factors
|style="text-align:center; background: #F6CEEC;"| 5.1 %
|style="text-align:center; background: #F6CEEC;"| 4.3 %
|style="text-align:center; background: #F6CEEC;"| 3.1 %
|-
|style="text-align:left; background: #F6CEEC;"| Other factors
|style="text-align:center; background: #F6CEEC;"| 13.9 %
|style="text-align:center; background: #F6CEEC;"| 13.1 %
|style="text-align:center; background: #F6CEEC;"| 10.4 %
|-
|style="text-align:left; background: #F6CEEC;"| Unexplained factor
|style="text-align:center; background: #F6CEEC;"| 12.7 %
|style="text-align:center; background: #F6CEEC;"| 11.8 %
|style="text-align:center; background: #F6CEEC;"| 18.6 %
|-
|}
</div>

==Causative Agents==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

[[File:Follicular Development.jpeg|right|thumbnail|500px|Infertility treatments aim to facilitate follicular development and induce ovulation to improve chances of fertilisation <ref name="PMID24717179"><pubmed>24717179</pubmed></ref>]]

Normally a woman produces one egg per month from the ovaries, which travel down the Fallopian tube to be fertilized or be released from the body. In cases where women have difficulty falling pregnant, they are given medication which help them to produce and release eggs (as shown in the diagram to the right), further increasing their chances of fertilization and pregnancy <ref><pubmed>19573285</pubmed></ref>. Ovarian Hyper stimulation Syndrome generally occurs during infertility treatments when the ovaries are overstimulated by the fertility medication which causes the ovaries to swell and leak fluids into the belly and abdomen. The prevalence of OHSS onset is linked with excessive number of follicle development in response to the administration of injectable Follicle Stimulating Hormones (FSH) followed by the '''Human Chorionic Gonadotrophins''' (hCG) which triggers the release of the oocytes <ref><pubmed>26190539</pubmed></ref>.

'''Follicle Stimulating Hormones''' (FSH) <ref name="PMID9020850"><pubmed>9020850</pubmed></ref> are glycoprotein hormones that are produced and secreted from the Anterior Pituitary gland into the bloodstream, which regulate the developmental, growth, maturation and the reproductive processes within the body. In females, the Follicle Stimulating Hormones initiates the stages of growth and development of immature ovarian follicles within the ovaries before the release of an egg from a follicle at ovulation. When FSH is administered to a patient who is suffering from infertility, the increase FSH levels affect the rate of development and production, in turn increasing the amount of follicles which are ready to be released during ovulation.

</div>

==Symptoms==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

OHSS is classified based on a criteria from mild, moderate and severe <ref name="WikiOHSS" />:

'''Mild Symptoms'''- abdominal bloating, minimal weight gain, nausea, diarrhoea and a feeling of fullness.

'''Moderate Symptoms'''- Substantial weight gain (on average 2 or more pounds a day), increased abdominal girth, darkend urine and excessive thirst in addition to the mild symptoms.

'''Severe Symptoms'''- In addition to the symptoms associated with Mild and Moderate OHSS, in severe OHSS, you see shortness of breath, calf and chest pains and pleural effusion.

<span style="font-size:100%">'''Classifications of Ovarian Hyper-stimulation Syndrome:'''</span> <ref name="PMID22065820"><pubmed>22065820</pubmed></ref>
{| class="wikitable" style="text-align:center
|-
! scope="col" width="70px"| '''Classification'''
! scope="col" width="650px"| '''Symptoms'''
|-
|style="text-align:center; background: #F6CEEC;"| '''Mild'''
|style="height: 60px; background: #F6CEEC;"| '''Grade 1''' - Abdominal distention and discomfort
'''Grade 2''' - Abdominal distention, discomfort with nausea, vomiting and/or diarrhea and ovarian enlargement from 5~12cm
|-
|style="text-align:center; background: #F8E0F1;"| '''Moderate'''
|style="height: 60px; background: #F8E0F1;"| '''Grade 3''' - All features of Mild OHSS with ultrasonographic evidence of ascites
|-
|style="text-align:center; background: #F6CEEC;"| '''Severe'''
|style="height: 60px; background: #F6CEEC;"| '''Grade 4''' - All features of Moderate OHSS with the addition of clinical evidence of ascites and breathing difficulties present
'''Grade 5''' - All of the above symptoms along with a change in the blood volume, increased blood viscosity due to coagulation and diminished renal function
|}

</div>

==Diagnosis==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

Whilst symptoms of OHSS can occur as soon as 24 hours post hCG administration, they are usually seen in women 7-10 days post administration. Initially women with OHSS will present with abdominal bloating, as a result of fluid in the peritoneal cavity and an increase in ovary size. When women present with severe OHSS they are often dehydrated, due to increased vascular permeability, and have hemoconcentration. The above results in a decrease in intravascular volume, leading to oligouria <ref name="PMID22416285" />.

===History===

Initially a thorough history of the patient is taken during which the clinician looks for evidence of ovarian stimulation, followed by ovulation. During this history taking, the clinician will inquire into any weight gain noticed, urine output, and the woman's ability to maintain oral hydration. A key diagnostic tool for clinicians regarding women who are taking gonadotropins is to identify if they are at an increased risk of developing OHSS. Some risk factors include woman aged less than 30, women who have polycystic ovaries, woman with a previous history of OHSS and women who have had greater than 20 oocytes retrieved <ref name="PMID22416285" />.

===Physical Exam===
[[File:Vaginal_Ultrasonography_in_Sagittal_Plane.jpg|right|thumbnail|600px|Vaginal Ultrasonography in Sagittal plane <ref name="Wikiversity Journal of Medicine"> Häggström, Mikael. "Medical gallery of Mikael Häggström 2014". Wikiversity Journal of Medicine 1 (2). DOI:10.15347/wjm/2014.008. ISSN 20018762</ref>]]
After a history of the patient is taken, the next step is to perform a physical exam on the patient. Women who present with abdominal bloating will produce a shifting dullness upon abdominal percussion. Additionally the clinician will test the woman's vital signs, measure her abdominal girth, weight and will look for evidence of ascites or increase in calf size (usually unilateral)<ref name="PMID22416285" />.

===Investigations===

If the clinician further suspects a women of having OHSS, various investigations can be done such as an ultrasound.The intraperitoneal fluid is best imaged via vaginal ultrasound due to the enlarged ovaries making it difficult to image the pelvis using transabdominal ultrasound. The clinician can also order laboratory testing to look for urine specific gravity and and complete blood count to look for hemoconcentration with a hematocrit. Additionally, liver function tests can be ordered to look for elevated function. The clinician will also look for evidence of elevated D-dimers and fibrinogen and decreased levels of anti-thrombin 3 <ref name="SAHealth"> Government of South Australia Health [ http://www.sahealth.sa.gov.au/wps/wcm/connect/9b61ed004ee5348da663afd150ce4f37/Ovarian-hyperstimulation-syndrome-WCHN-PPG-17072012.pdf?MOD=AJPERES&CACHEID=9b61ed004ee5348da663afd150ce4f37 ], 'South Australian Paediatric Clinical Guidelines OHSS'</ref>.

====Ultrasound====

Typical appearances of the ultrasound include <ref name="Ultrasound"> Radiopaedia [ http://radiopaedia.org/articles/ovarian-hyperstimulation-syndrome-1 ], 'Ovarian Hyperstimulation Syndrome'</ref>:

*Bilaterally and symmetrically enlarged ovaries (>12cm)
* "Spoke-Wheel appearance" - presence of multiple cysts of varying size
*May also see ascites (fluid)

===Severity===

Once a clinician has deduced a women is suffering from OHSS, the severity of their condition needs to be established as either mild, moderate or severe. This is done by referring to the criteria under the sub-heading [[Symptoms]].The subsequent course of treatment for the woman will be based upon this evaluation.

{|
|-bgcolor="F6CEEC"
|
'''Further investigations''' can be done including a Chest X-ray to check for pleural effusions and oedema and USS with Doppler's to check for ascites or possible ovary torsion. <ref name="PMID22416285"><pubmed>22416285</pubmed></ref>
|}

===Differential Diagnosis===

Conditions presenting with similar symptoms or ultrasound images include <ref name="Ultrasound" />:

*Polycystic Ovaries (PO)
:: The difference is that with PO is that the cycts are typically smaller than OHSS cysts and there is no evidence of ascited or pleural effusion
*Mucinous Ovarian Malignancy
:: A type of Ovarian Epithelial tumour
*Ectopic Pregnancy <ref name="Casereport"> Australian Medical Student Journal [ http://www.amsj.org/wpcontent/uploads/files/articles/amsj_v2_i1/AMSJ_v2_i1_pg58-60.pdf ], 'Ovarian hyperstimulation syndrome'</ref>
::A pregnancy in which the foetus develops outside of the uterus e.g. in the fallopian tube

</div>

==Pathophysiology==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

[[File:Pathogenesis_of_OHSS.png|600px|thumb|Pathogenesis of OHSS <ref name="PMID20416867"><pubmed>20416867</pubmed></ref>]]

The definition of Ovarian Stimulation is enlarged ovaries with many luteinized cysts, that can present with secondary complications. What distinguishes Ovarian Stimulation from OHSS is the presence of vascular hyper-permeability that results in fluids being redirected elsewhere in the body.

The key process to OHSS appears to be caused by '''Vascular Endothelial Growth Factor''' (VEGF), that is released along with other cytokines, estrogen and progesterone, due to the ovary undergoing luteinization as a result of stimulation by hCG. VEGF increases vascular permeability and as a result the capillaries become more "leaky" to the fluids in them. These fluids can then escape the capillaries and accumulate in the pleural and abdominal cavities as ascites. The woman then becomes hypovolemic and is at an increased risk of circulatory, renal and respiratory issues such as arterial thromboembolism due to the thickening of the blood. Note, the blood is thickened as fluid is leaving the capillaries, leaving behind red blood cells and other cellular components of the blood <ref name="WikiOHSS" />.

The increase in expression of VEGF and VEGF Receptor 2 (VEGFR2) is attributed to the greatly increased amount of their mRNA present in the body after stimulation with hCG <ref name="PMID21082502"><pubmed>21082502</pubmed></ref>. VEGF interacts with VEGF2 and VEGF Receptor 1 (VEGFR1) to create a strong angiogenic effect. Both VEGFR2 and VEGFR1 belong to a family of receptors called tyrosine kinases. VEGF2 is involved in the regulation of angiogenesis and vascular permeability whilst VEGF1 has a slightly contradictory role in that is is involved in the maintenance of the tight junctions between endothelial cells in blood vessels. A study by Gómez ''et. al.'' <ref name="PMID21082502" /> showed that women experiencing OHSS had substantially higher plasma levels of VEGF and lower levels of VEGFR1.

</div>

==Complications==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

Ovarian torsion or rupture, renal insufficiency and thrombophlebitis can all complicate OHSS. If a pregnancy occurs, symptoms may persist longer than the usual 1 to 2 weeks and become more severe, however, even with severe OHSS, they do not extend past the first trimester <ref name="WikiOHSS" />.

<span style="color:#FA58D0"> '''1-2% of women who suffer from ovarian stimulation develop a severe form of OHSS''' </span>. Complications from severe OHSS include:

*Fluid collection in the abdomen
*Electrolyte disturbances (sodium and potassium)
*Kidney failure
*Ovary twisting
*Rupture of a cyst in an ovary
*Breathing problems
*Blood clots in large vessels (most commonly the legs)
*Pregnancy loss from miscarriage or termination
*Rarely, death

A study by Nouri ''et. al.'' <ref name="PMID24996451"><pubmed>24996451</pubmed></ref> found that women with '''Polycystic Ovarian Syndrome''' (PCOS) and those that were induced with hCG experienced longer recovery times from severe OHSS than women who were not pregnant. They looked at a cohort of women hospitalised for the first time with severe OHSS and subject them to the same treatments. Based on a defined criteria, they established the recovery time of these women and compared the times between those that were pregnant to those that were not pregnant. They also found that whether a woman had PCOS or ovulation induction did not affect her risk of developing OHSS if she was not pregnant. It is only a risk factor for pregnant women.

===Thromboembolic events===

A frequent and deadly complication of OHSS are thromboembolic events due to increased blood clotting. This increase in blood clotting has been attributed to a variety of complications such as hemoconcentration (which thickens the blood), hypolvolemia and an increase in the permeability of blood vessels as a result of increased vasoactive substances in the body of ovarian origin. Thromboembolic events include venous thromboses often in the upper extremities and arterial thromboses such as those in the cerebrovascular region. These events can lead to amputations of extremities, brain damage, miscarriage and death. To avoid this, anti-coagulants are given to pateitns with OHSS and they are fitted with compression stockings (see [[Treatment]]) <ref name="PMID23378404"><pubmed>23378404</pubmed></ref>.

{|
|-bgcolor="F8E0F1"
|
The risk of a woman developing OHSS is higher if she is having a '''twin pregnancy''', as she is exposed to higher concentration of hCG. <ref name="PMID9756273"><pubmed>9756273</pubmed></ref>
|}

</div>

==Treatment==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

'''General treatment
'''
*''Acetaminophen'' with or without a narcotic agent- used to treat abdominal discomfort
*Women are encouraged to drink 2-3 litres of water a day to prevent hemoconcentration
*Women are advised to avoid sexual intercourse and vigorous exercise at the risk of torsion or rupture of the ovaries
*NSAID's with anti-platelet properties should NOT be used as they may effect renal function in a women with OHSS
*Patients with significantly painful ascites or breathing problems may undergo ''Paracentesis'' (drainage of the ascites)
*''Culdocentesis'' (extraction of fluid from recto-uterine pouch) can be done to decrease the likelihood of a woman with moderate OHSS progressing to severe OHSS.<ref name="PMID22416285" />

===Mild to Moderate OHSS===

Mild OHSS can often resolve on its own, however, moderate OHSS may include treatments such as<ref name="WikiOHSS" />:

*Anti-nausea medication and prescription painkillers
*Regular physical examinations and ultrasounds
*Daily weigh-ins and waist measurements
*Measuring the amount of urine produced each day
*Frequent blood tests for monitoring dehydration and electrolyte imbalance
*Maintaining a high balance of fluids
*Drainage of excess abdominal fluid by inserting a needle in the abdominal cavity
*Wearing support stockings which help prevent blood clots/thrombosis

===Severe OHSS===

Severe OHSS requires hospital care in order for constant monitoring and treatment such as <ref name="WikiOHSS" />:

*Intravenous fluids with a crystalloid solution (100-150mL/hr)
*Intravenous Albumin is administered is IV fluids are insufficient (15-20mL/hr of 25% albumin for 4 hrs)
*In addition to Acetaminophen, ''Opioid analgesics'' can be administered for pain relief
*''Antiemetics'' can be used to subside nauseas and/or vomiting
*Woman administered to hospital of OHSS are considered at high risk of thromboembolic complications and are given low molecular weight ''heparin'', an anti-coagulant
*''Cabergoline''- lessens OHSS symptoms
*''GnRH agonist''- suppresses ovarian activity
**If at risk of OHSS, alternates include using a GnRH agonist instead of hCG however its effects on pregnancy rates are questionable. Using a GnRH agonist to replace the use of hCG for final oocyte stimulation will see a 6% decrease in delivery rate.

*Daily monitoring of creatine, urea, creatine clearance C-reactive protein (to rule out infection) are all required in combination with weekly tests such as liver and renal function tests and chest x-rays (to check for pleural effusion) <ref name="PMID12638783" />.

If there are serious complications then additional treatments are required:

*Surgery for a ruptured ovarian cyst
*Intensive care for the liver or lung complications

====Paracentesis====

For women with severe/grade 3 OHSS, paracentesis, the removal of fluid from the body using an aspiration needle, can be undertaken. It is a diagnostic and a therapeutic method that can be done trans-abdominally and trans-vaginally. It is used to relieve symptoms, improve haemodynamics e.g. Urinary output, and shorten the women's hospital stay. Complications of paracentesis include bleeding, infection and organ injury, however are note common <ref name="Paracentesis"> S. Monica Soni, HMS 3, Gillian Lieberman, MD [ http://eradiology.bidmc.harvard.edu/LearningLab/genito/Soni.pdf ], 'Ovarian Hyperstimulation Syndrome'</ref>.

{|
|-bgcolor="F8E0F1"
|
The most important aspect of treatment for any women with OHSS is close and constant '''monitoring''' with her healthcare professional. Counselling may also be provided to women and their partners or families in order to provide them with the best possible knowledge base to manage and treat their OHSS. It is important to note that there is '''no one cure or treatment''' for OHSS. Treatment involves managing and eliminating the symptoms until such time as the syndrome resolves itself <ref name="WikiOHSS" />.
|}

</div>

==Prevention==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

There are three key avenues through which the incidence of OHSS may be prevented. These include identifying risk factors to predict OHSS development, modifying treatment regimes on the basis of the identified risk factors and intervention to prevent progression to OHSS once the patient has undergone Controlled Ovarian Stimulation.

=== Risk factors===

'''Primary risk factors'''

Pre-existing factors likely to exacerbate the ovarian stimulation response. Primary risk factors include <ref name="PMID26074966"><pubmed>26074966</pubmed></ref>:

*Young age
*Low body weight
*History of elevated response to gonadotropins
*Polycystic Ovary Syndrome (PCOS)
*Isolated PCOS characteristic
*A previous history of OHSS.
*Hormonal markers (e.g. Anti-Mullerian Hormone markers)
*Ultrasonographic markers (e.g. Antral Follicle Count)

'''Secondary risk factors'''

Secondary risk factors involve the monitoring of ovarian response parameters once COS has been initiated. These parameters are monitored for <ref name="PMID19007627"><pubmed>19007627</pubmed></ref>:

*rapidly rising E2 levels
*E2 concentration larger than 2500 pg/mL
*large number of developing follicles (10-14mm) on the day hCG is administered
*large number of oocytes retrieved

These factors in combination, act as a predictive tool to assess the likelihood of severe OHSS development, with a 83% sensitivity and 84% specificity. <ref name="PMID19007627"/>

=== Primary Prevention===

Primary Prevention involves the modification of treatment regimens on the basis of OHSS risk classifications, in order to prevent OHSS occurrence.

'''Ovulation Induction'''

Unifollicular Ovulation Induction through Ovulation Induction (OI) is a primary means of avoiding OHSS in women with Polycystic Ovarian Syndrome, who are at an increased risk. In order to promote unifollicular development, the ovaries are stimulated with a low starting dose of FSH (75 IU).<ref name="PMID20416867"><pubmed>20416867</pubmed></ref> Studies suggests that a minimum gonadotropin dose lowers OHSS risk and thus a step-up regimen is utilised to achieve an ovarian response, whereby the FSH dosage is increased every 7 days until follicular development of greater than 10mm is noted <ref name="PMID26074966" />. Alternatively, a step-down regimen may be followed, whereby a high initial FSH dosage is lowered according to the ovarian response. Another method to increase FSH levels during OI, is through Aromatase Inhibitors which promote folliculogenesis by increasing pituitary secretion of FSH, and downregulate oestrogen production through a negative feedback loop. However, Aromatase Inhibitors have not been shown to reduce OHSS incidence in comparison to other methods of OI. During OI, a key objective is to prevent early cycle cancellation due to premature luteinisation from pituitary secretion of LH. In order to downregulate LH secretion, Gonadotropin-releasing hormone agonists (GnRHa) are administered in addition to gonadotropins. The duration of exposure to gonadotropins and subsequent risk of OHSS may also be minimised through mild stimulation protocols which administer FSH only in the mid to late follicular phase.<ref name="PMID20416867" />

'''Adjuvant Metformin Therapy'''

Adjuvant Metformin Therapy has been found to lower the risk of OHSS by 63% <ref name="PMID25406011"><pubmed>25406011</pubmed></ref>. It involves the administration of metformin at a daily dosage of 1000 to 2000mg, 2 months prior to Controlled Ovarian Stimulation <ref name="PMID26074966"/>. Metformin lowers the elevated insulin levels in PCOS which consequently reduce intraovarian androgen levels. This leads to a reduced sensitivity and expression of granulosa cell-follicle stimulating hormone receptors which result in a less exaggerated response to gonadotropins. Furthermore, it is suggested that Metformin prevents OHSS by controlling vascular permeability through the inhibition of various vasoactive molecules, including VEGF.

'''Avoiding hCG during Luteal Phase Support

Following Controlled Ovarian Stimulation, the steroid levels of E2 and P4 are reduced during the luteal phase due to the negative feedback on the pituitary. This leads to low endogenous LH levels, which consequently reduce endometrial receptivity as well as the luteal phase duration itself. As a result, implantation and pregnancy rates are reduced and early pregnancy loss rates are increased.<ref name="PMID20416867" /> Luteal Phase Support (LPS) serves to combat these adverse events with the use of hCG. However, hCG has been found to increase the risk of OHSS. Alternatively, the use of progesterone has been found to not only halve the risk of OHSS, but also induce similar improvements in pregnancy and miscarriage rates as hCG.<ref name="PMID26148507"><pubmed>26148507</pubmed></ref>

===Secondary Prevention===

Secondary Prevention aims to prevent progression to OHSS once COS has been initiated and the patient has been found to mount an exaggerated response. <ref name="PMID20416867" />

'''Coasting'''

Coasting is a first-line secondary preventative strategy. It consists of the withdrawal of gonadotrophins when a critical number of follicles and/or E2 concentration is reached. hCG is administered once the E2 concentration reduces to a safe level, before the process of oocyte retrieval commences. This preventative strategy is conducted for a period of less than 3 days in order to avoid compromising IVF outcomes.

'''Cryopreservation'''

Cryopreservation of embryos after oocyte retrieval is another avenue which may avert OHSS progression. The cryopreserved embryos are only reimplanted once the patient's hormone serum levels have normalised. Using oocyte vitrification, crystal formation within embryo tissue is avoided and so cryopreserved embryos have been found to produce better pregnancy rates with a 32% increase, than fresh embryo transfer. Recent studies suggest cryopreservation itself does not reduce OHSS rates, but must be followed by a GnRHa trigger to avert OHSS.

'''Cycle cancellation'''

Cycle cancellation is a guaranteed method to prevent early OHSS whereby hCG is withheld. This is a last resort strategy as it carries the risk of significant psychological distress and financial loss for the patient.

</div>

==Effect on the Newborn==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

</div>
Women who develop OHSS while undergoing Assisted Reproductive Technologies (ART) treatment are not only more likely to achieve a pregnancy, but have a live birth as the pregnancy outcome. This live birth is also more likely to be a multiple birth of two, three or more children. <ref name="PMID19591989"><pubmed>19591989</pubmed></ref> It has been postulated that a multifetal pregnancy leads to a more rapid increase in hCG levels, resulting in an increased risk of OHSS. However, the causal nature between multifetal pregnancy and OHSS development is disputed and further research is required to distinguish correlation from causation. <ref name="PMID19573292"><pubmed>19573292</pubmed></ref>

OHSS development is also associated with an increased risk of adverse outcomes including stillbirth, premature birth and low birthweight.<ref name="PMID19591989" /> Although the cause for the increased risk in adverse pregnancy outcomes is unknown, it is suggested that as the incidence of OHSS is reduced through various prevention strategies, the risk of such outcomes may be also be reduced.

==Genetics==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

Despite OHSS typically being of iatrogenic origin as a result of ovarian stimulation with gonadotropins, research has been conducted into the potential genetics behind OHSS as many sporadic and familial cases have been observed. '''Mutations''' in the receptor for hormones such as Follicle Simulating Hormone (FSH), Lutenizing Hormone (LH) and hCG have all been targets of OHSS genetics research. Interestingly, they too also arise from a common ancestral gene.

===Follicle Stimulating Hormome===

Dr. Botros Rizk, of the University of South Alabama College of Medicine <ref name="PMID19573286"><pubmed>19573286</pubmed></ref>, has written extensively regarding the genetics behind OHSS. In particular, he talks about '''FSH receptors''' (FSHR) and their role in the syndrome. He hypothesises that mutations in these receptors could be activating or inactivating, leading to an increased risk of developing OHSS or sterility respectively. Currently, 744 single nucleotide polymorphisms (a type of mutation) have been found in the gene encoding the FSHR, 8 of which are located in its exons (coding regions of the gene). How the ovary responds is resultant on the FSHR genotype. For example, Ser680Asn, a polymorphism in the FSHR gene has been shown to aid in predicting the severity of a woman's OHSS. Ordinarily FSH stimulates the growth of ovarian follicles, however, when mutated, it is stimulated by the hCG resulting in excessive follicle development.

Spontaneous OHSS, OHSS that arises and cannot be attributed to any form of ovarian stimulation or Assisted Reproductive Technology, has been linked to activating mutations in the FSHR <ref name="PMID23499866"><pubmed>23499866</pubmed></ref>. This familial disorder is an autosomal dominant one. In most cases the FSHR can be stimulated by the presence of Thyroid Stimulating Hormone (TSH) or hCG, in the absence of FSH (the ligand for FSHR).

===Lutenizing Hormome===

The '''Lutenizing Hormone Receptor''' (LHR) gene in humans is comprised of 11 exons. Animal studies have shown that many primates exhibit a similar gene which is comprised of only 10 exons, however a gene lacking the 10th exon has been identified and termed the type 2 LHR. Expression of the type 2 LHR has been seen in humans. The type 2 LHR, compared to the wild-type LHR appears to be repaired with regard to its function. Defects in the type 2 LHR include a decrease in efficiency of transport to the plasma membrane and irregularities in signal transduction. Inactivating mutations in the LHR have been seen to cause infertility in women as well as amenorrhoea. Activating LHR gene mutations are asymptomatic and are not associated with OHSS in women.

===Bone Morphogenic Protein===

An imporant growth factor, derived from oocytes called '''BMP-15''' (Bone Morphogenic Protein 15) is vital for female fertility. It belongs to the family of growth factors, Transforming Growth Factor β (TGF-β) and is heavily involved in folliculogenesis. It has been found that mutations in the BMP-15 gene caused infertility in female sheep. Conversely, it has also been indicated in enhanced fertility when BMP-15 is present is high amounts in follicular fluid <ref name="PMID19573286" />.

A case study done by Hanevik ''et. al.'' in 2013 <ref name="PMID21565556"><pubmed>21565556</pubmed></ref> found that a Single Nuclear Polymorphism (SNP) in the BMP-15 gene is responsible for a high response to ovarian hyper-stimulation. The aim of the study was to test the effect the SNP had on BMP-15 with regard to high and low responders buy taking blood from 53 high responders, 38 low responders and 100 non-responders (controls) and analysing 5 noted SNP's. Results from their study showed a correlation between a high response to ovarian hyper-stimulation and the BMP-15 9G allele. The article does state however, that further research is required into the molecular effects of SNP's on the function of BMP-15.

===Vascular Endothelial Growth Factor===

'''Vascular endothelial growth factor''' (VEGF) has been indicated as one of the key agents causing vascular permeability and subsequent ascites in OHSS. The gene, which is located on chromosome 12, is made up of 8 exons (coding regions), of which exons 6 and 7 do not always appear due to the exons being spliced out.The splicing of this gene allows for various isoforms of the gene to exist of which VEGF 121 and 165 appear to play a role in angiogenesis. There are two VEGF Receptors, VEGFR-1 and VEGFR-2 that belong to the tyrosine kinase family of receptors (for more information on VEGF see [[Pathophysiology]]). Because of its distinct role in OHSS, it has been targeted as an area for research for potential treatments. The idea is that if the genetic expression of VEGF and its receptors can be controlled, OHSS can be avoided or treated.<ref name="PMID19573286" />

A different study by Hanevik ''et. al.'' , <ref name="PMID22587628"><pubmed>22587628</pubmed></ref> done in 2012 involved analysing blood samples from 53 women with OHSS and 100 women without it (controls) and analysing 6 SNP's in the VEGFR2 gene to find any genetic variations. They found a correlation between women with the VEGF +405cc genotype and the development of OHSS indicating women that undergo controlled ovarian hyper-stimulation and posses his genotype, are at an increased risk of developing OHSS.

</div>

== Current Research on Animal Models==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">
{|
|-bgcolor="F8E0F1"
|
<span style="font-size:120%">'''Inhibition of Cyclooxygenase-2 (COX-2) by Meloxican decreasing the incidence of OHSS in Rat Model'''</span> <ref name="PMID18166186"><pubmed>18166186</pubmed></ref>

Reasearch was carried out to investigate the effects of selective inhibition of the enzyme COX-2 on the Ovarian Hyperstimulation Syndrome (OHSS) using Female Wistar rates as the subjects. The research aimed to find results by measuring the number of antral and luteinized follicles, ovarian weight, vascualr endothelial growth factors and COX-2 immunohistochemistry. The rats being tested were all 22 days old and were divided into four equal groups;

'''Group 1 (Control group)''' was subject to a 0.1 ml of Intraperitoneal Saline from days 22 ~ 26

'''Group 2 (Mildly-stimulated group)''' subject to 10IU of pregnant mare serum gonadotrophin (PMSG) on day 24 and then 10IU of Human Chorionic Gonadotrophin (hCG) on day 26

'''Group 3 (OHSS positive group)''' was subject to 10IU of PMSG from days 22 ~ 26 and then administered 30IU of hCG on day 26 to induce OHSS

'''Group 4 (OHSS positive variant group)''' received 15mg/ml of Meloxicam 2 hours prior to administration of 10IU PMSG from days 22 ~ 26

Results showed there was no difference in ovarian weight in samples from Group 1 and Group 2, however Group 3 showed signs of significant ovarian weight increase which in group 4 was suppressed by the introduction of Meloxicam. No differences were observed in the number of antral follicles amongst the four test groups. Results from Group 2 and Group 3 showed that the granulosa cells of preovulatory follicles and the stromal cells were highly VEGF immunoreactive, however the Meloxicam treated Group 4 showed less immunoreactivity than Group 2 and Group 3 which indicated the correlation between Meloxicam and the diminished VEGF expression. Group 3 presented an increased COS-2 immunoreactivity which was highly diminished than in Group 4.

The research concluded that in a rat model, the enzyme Meloxicam has a beneficial effect on OHSS by reducing the increase of ovarian weight and the expression of VEGF associated with OHSS, the effects of which may be mediated by the inhibitory capacity of COX-2 on Meloxicam
|}

{|
|-bgcolor="FF99FF"
|
<span style="font-size:120%">'''Inhibition of Ovarian VEGF secretion by activation of Dopamine Receptor 2'''</span> <ref name="PMID25217874"><pubmed>25217874</pubmed></ref>

This research was carried out to investigate a possibility in whether a Dopamine Receptor 2 agonist '''(D2-ag)''' can assist in the prevention of Ovarian Hyperstimulation Syndrome, using rat models, by decreasing the ovarian vascular endothelial growth factor '''(VEGF)''' production. Using Immature Wistar rats (22 days old) as their animal model, the rats were initially stimulated with Gonadotrophins to mimic the onset and effects of OHSS and then subjected to treatment with a D2-agonist and/or a D2-antagonist (D2-ant). The vascular permeability was measured at the endpoint after day 26 by measuring the peritoneal extravasion of a previously injected dye and ovaries from all subjects were collected to assess the effects of D2-ag and D2-ant on the production of Ovarian VEGF. The expression of VEGF mRNA was measured by quantitative real time PCR and the levels of VEGF proteins were measured by Western Blots.

Results showed that the D2-ag caused a large reduction in the vascular permeability which was in turn associated with the great decreased in VEGF protein production in the OHSS rat ovaries, whereas the introduction of D2-ant showed opposite results with a increase in the vascular permeability leading to the increase of VEGF protein production in the ovaries. Ovarian VEGF mRNA levels were found to be unaffected by the introduction of these drugs in OHSS rat subjects. Conclusions were drawn on the fact that Dopamine Receptor 2 agonists prevent the increase of vascular permeability in subjects with OHSS by decreasing the ovarian production of VEGF and also that due to the dose-dependent inhibitory effect of the D2-ag on ovarian VEGF, current OHSS therapies used in humans can benefit by increasing the intraovarian concentration of D2-ag.
|}
</div>

==Glossary==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

'''Ascites'''- An accumulation of fluid in the peritoneal cavity with resultant abdominal swelling

'''Cabergoline''' - A dopamine receptor agonist used to treat hormone imbalance.

'''GnRH antagonist''' - Gonadotropin Releasing Hormone - A class of compounds that are similar in terms of the structure of natural Gonadotropin Releasing Hormone but has a antagonistic effect.

'''hCG'''- Human Chorionic Gonadotropin

'''Hemoconcentration'''- An increase in the concentration of circulating red blood cells in response to a decrease in blood plasma volume

'''Hypovolemic'''- A decrease in circulating blood volume

'''Iatrogenic'''- Illness caused as a result of a medical examination or treatment

'''Intravenous fluids''' - Is the infusion of liquid substances directly into a vein.

'''IVF'''- In-vitro Fertilization

'''NSAID'''- Non-steroidal Anti-Inflammatory Drug e.g. Ibuprofen

'''OHSS'''- Ovarian Hyper-stimulation Syndrome

'''FSH''' - Follicle Stimulating Hormone

'''LH''' - Luteinizing Hormone

'''Oliguria'''- Decreased urine output/small amounts of urine produced

</div>

==References==

2015 Group Project 2

2015-10-22T20:59:22Z

Z3372824: /* Causative Agents */

{{ANAT2341Project2015header}}

==<span style="font-size:120%">'''Ovarian Hyper-stimulation Syndrome (OHSS)'''</span>==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

Ovarian Hyper stimulation Syndrome (OHSS) is an iatrogenic complication of '''Assisted Reproduction Technology''' (ART), in which women take medications to stimulate oocyte growth. It is generally identified by cystic enlargements of the ovaries and fluid accumulation in the peritoneal cavity due to the increased capillary permeability and ovarian neoangiogenesis <ref name="PMID22065820"><pubmed>22065820</pubmed></ref>. It is an occurrence which is dependent on the controlled stimulation of the ovaries in preparation for IVF i.e. administration of human Chorionic Gonadotropin (hCG).

OHSS was first described in 1943 as ''“syndrome d’hyperluteinisation massive
des ovaries”''. It was during this time that gonadotropins were prepared from animals such as sheep to bring on ovulation in women. The first recorded death as a result of OHSS occurred in 1951 and was due to renal failure as a result of oligouria, a complication of the syndrome <ref name="OHSS"> Marie M. Budev, DO, MPH; Alejandro C. Arroliga, MD; Tommaso Falcone, MD, [ http://utilis.net/Morning%20Topics/REI/Ovarian%20Hyperstimulation.pdf ], 'Ovarian Hyperstimulation Syndrome'</ref> <ref name="PMID12638783"><pubmed>12638783</pubmed></ref>.

<span style="color:#FA58D0">This wikipage aims to provide clear information on various areas surrounding OHSS such as diagnosis, prevention and complications and will look into the genetics behind the disorder and the various animals models used to research it.</span>

<html5media height="350" width="450">https://www.youtube.com/watch?v=aXmjJw234a4</html5media>

'''Overview of the Ovarian Hyperstimulation Syndrome''' <ref> Howcast (2013, August 27) Ovarian Hyperstimulation Syndrome | Infertility. Retrieved from https://www.youtube.com/watch?v=aXmjJw234a4</ref>

</div>

==Epidemiology==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

Ovarian Hyper-Stimulation Syndrome (OHSS) rarely occurs sporadically, and if it does, it is usually the result of an underlying genetic problem. The majority of OHSS is due to the ovaries being stimulated to mature and release an abundance of oocytes, in response to hormones Human Chorionic Gonadotropin (hCG) and Follicle Stimulating hormone (FSH), during IVF. Rarely, Clomifene Citrate therapy can cause OHSS.<ref name="WikiOHSS"> Wikipedia, [ https://en.wikipedia.org/wiki/Ovarian_hyperstimulation_syndrome ], 'Ovarian Hyperstimulation Syndrome'</ref>

OHSS only affects '''0.5-5%''' of women undergoing Ovarian Hyper-stimulation, but despite its small prevalence, it is a potentially fatal outcome of a non-vital procedure and remains a prevalent problem for fertility specialists <ref name="PMID12498425"><pubmed>12498425</pubmed></ref> <ref name="PMID12638783"><pubmed>12638783</pubmed></ref>. Age has been cited as a factor affecting those with OHSS, with younger women more at risk. Additionally, women with allergies were seen to have a higher incidence of OHSS. It is important to note that at this point in time, there is no positive correlation between gonadotropin dose and OHSS.

Of the 0.5-5% of women affected with OHSS mentioned above, 2% of those women will require hospitalisation. As of 2011, it has been reported that the incidence of OHSS was '''increasing''', resulting in approximately 3 deaths per 100,000 women undergoing ovarian stimulation per year <ref name="PMID21828116"><pubmed>21828116</pubmed></ref>. This is particularly worrying as in 2008, in the United States alone, there were around 150,000 IVF cycles undertaken.

{|
|-bgcolor="F8E0F1"
|
'''With the field of Assisted Reproductive Technologies expanding and more women partaking in IVF treatments, the threat of women developing OHSS is an ongoing and increasing one''' <ref name="PMID21828116" />.
|}
{| class="wikitable mw-collapsible mw-collapsed"
! Characteristics of women by complication group <ref name="PMID19591989"><pubmed>19591989</pubmed></ref>
|-
! scope="col" width="100px" height="60px" style="text-align:center| '''Characteristic'''
! scope="col" width="100px" height="60px" style="text-align:center| '''No Complications
(N = 212,041)'''
! scope="col" width="100px" height="60px" style="text-align:center| '''Moderate OHSS
(N = 1,523)'''
! scope="col" width="100px" height="60px" style="text-align:center| '''Severe OHSS
(N = 655)'''
|-
|style="text-align:center; background: #FF99FF;"| '''Maternal Age (Mean ± SD)'''
|style="text-align:center; background: #F6CEEC;"| 35.6 ± 4.6
|style="text-align:center; background: #F6CEEC;"| 33.0 ± 4.3
|style="text-align:center; background: #F6CEEC;"| 33.1 ± 4.4
|-
|style="text-align:center; background: #FF99FF;"| '''Maternal Age (%)'''
|-
|style="text-align:left; background: #F6CEEC;"| <30 years
|style="text-align:center; background: #F6CEEC;"| 10 %
|style="text-align:center; background: #F6CEEC;"| 21.1 %
|style="text-align:center; background: #F6CEEC;"| 20.6 %
|-
|style="text-align:left; background: #F6CEEC;"| 30-34 years
|style="text-align:center; background: #F6CEEC;"| 30.4 %
|style="text-align:center; background: #F6CEEC;"| 43.2 %
|style="text-align:center; background: #F6CEEC;"| 40.5 %
|-
|style="text-align:left; background: #F6CEEC;"| 35-39 years
|style="text-align:center; background: #F6CEEC;"| 37.8 %
|style="text-align:center; background: #F6CEEC;"| 27.2 %
|style="text-align:center; background: #F6CEEC;"| 32.5 %
|-
|style="text-align:left; background: #F6CEEC;"| >40 years
|style="text-align:center; background: #F6CEEC;"| 21.8 %
|style="text-align:center; background: #F6CEEC;"| 8.4 %
|style="text-align:center; background: #F6CEEC;"| 6.4 %
|-
|style="text-align:center; background: #FF99FF;"| '''Nulligravida (%)'''
|style="text-align:center; background: #F6CEEC;"| 45.8 %
|style="text-align:center; background: #F6CEEC;"| 51.5 %
|style="text-align:center; background: #F6CEEC;"| 51.8 %
|-
|style="text-align:center; background: #FF99FF;"| '''Infertility Diagnosis (%)'''
|-
|style="text-align:left; background: #F6CEEC;"| Male factor
|style="text-align:center; background: #F6CEEC;"| 37.7 %
|style="text-align:center; background: #F6CEEC;"| 41.0 %
|style="text-align:center; background: #F6CEEC;"| 33.4 %
|-
|style="text-align:left; background: #F6CEEC;"| Endometriosis
|style="text-align:center; background: #F6CEEC;"| 13.5 %
|style="text-align:center; background: #F6CEEC;"| 13.5 %
|style="text-align:center; background: #F6CEEC;"| 10.7 %
|-
|style="text-align:left; background: #F6CEEC;"| Ovulation Disorders
|style="text-align:center; background: #F6CEEC;"| 14.0 %
|style="text-align:center; background: #F6CEEC;"| 29.5 %
|style="text-align:center; background: #F6CEEC;"| 22.4 %
|-
|style="text-align:left; background: #F6CEEC;"| Diminished ovarian reserve
|style="text-align:center; background: #F6CEEC;"| 16.9 %
|style="text-align:center; background: #F6CEEC;"| 3.2 %
|style="text-align:center; background: #F6CEEC;"| 2.4 %
|-
|style="text-align:left; background: #F6CEEC;"| Tubal factors
|style="text-align:center; background: #F6CEEC;"| 20.4 %
|style="text-align:center; background: #F6CEEC;"| 22.6 %
|style="text-align:center; background: #F6CEEC;"| 22.3 %
|-
|style="text-align:left; background: #F6CEEC;"| Uterine factors
|style="text-align:center; background: #F6CEEC;"| 5.1 %
|style="text-align:center; background: #F6CEEC;"| 4.3 %
|style="text-align:center; background: #F6CEEC;"| 3.1 %
|-
|style="text-align:left; background: #F6CEEC;"| Other factors
|style="text-align:center; background: #F6CEEC;"| 13.9 %
|style="text-align:center; background: #F6CEEC;"| 13.1 %
|style="text-align:center; background: #F6CEEC;"| 10.4 %
|-
|style="text-align:left; background: #F6CEEC;"| Unexplained factor
|style="text-align:center; background: #F6CEEC;"| 12.7 %
|style="text-align:center; background: #F6CEEC;"| 11.8 %
|style="text-align:center; background: #F6CEEC;"| 18.6 %
|-
|}
</div>

==Causative Agents==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

[[File:Follicular Development.jpeg|right|thumbnail|500px|Infertility treatments aim to facilitate follicular development and induce ovulation to improve chances of fertilisation <ref name="PMID24717179"><pubmed>24717179</pubmed></ref>]]

Normally a woman produces one egg per month from the ovaries, which travel down the Fallopian tube to be fertilized or be released from the body. In cases where women have difficulty falling pregnant, they are given medication which help them to produce and release eggs (as shown in the diagram to the right), further increasing their chances of fertilization and pregnancy <ref><pubmed>19573285</pubmed></ref>. Ovarian Hyper stimulation Syndrome generally occurs during infertility treatments when the ovaries are overstimulated by the fertility medication which causes the ovaries to swell and leak fluids into the belly and abdomen. The prevalence of OHSS onset is linked with excessive number of follicle development in response to the administration of injectable Follicle Stimulating Hormones (FSH) followed by the '''Human Chorionic Gonadotrophins''' (hCG) which triggers the release of the oocytes <ref><pubmed>26190539</pubmed></ref>.

'''Follicle Stimulating Hormones''' (FSH) <ref name="PMID9020850"><pubmed>9020850</pubmed></ref> are glycoprotein hormones that are produced and secreted from the Anterior Pituitary gland into the bloodstream, which regulate the developmental, growth, maturation and the reproductive processes within the body. In females, the Follicle Stimulating Hormones initiates the stages of growth and development of immature ovarian follicles within the ovaries before the release of an egg from a follicle at ovulation. When FSH is administered to a patient who is suffering from infertility, the increase FSH levels affect the rate of development and production, in turn increasing the amount of follicles which are ready to be released during ovulation.

</div>

==Symptoms==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

OHSS is classified based on a criteria from mild, moderate and severe <ref name="WikiOHSS" />:

'''Mild Symptoms'''- abdominal bloating, minimal weight gain, nausea, diarrhoea and a feeling of fullness.

'''Moderate Symptoms'''- Substantial weight gain (on average 2 or more pounds a day), increased abdominal girth, darkend urine and excessive thirst in addition to the mild symptoms.

'''Severe Symptoms'''- In addition to the symptoms associated with Mild and Moderate OHSS, in severe OHSS, you see shortness of breath, calf and chest pains and pleural effusion.

<span style="font-size:100%">'''Classifications of Ovarian Hyper-stimulation Syndrome:'''</span> <ref name="PMID22065820"><pubmed>22065820</pubmed></ref>
{| class="wikitable" style="text-align:center
|-
! scope="col" width="70px"| '''Classification'''
! scope="col" width="650px"| '''Symptoms'''
|-
|style="text-align:center; background: #F6CEEC;"| '''Mild'''
|style="height: 60px; background: #F6CEEC;"| '''Grade 1''' - Abdominal distention and discomfort
'''Grade 2''' - Abdominal distention, discomfort with nausea, vomiting and/or diarrhea and ovarian enlargement from 5~12cm
|-
|style="text-align:center; background: #F8E0F1;"| '''Moderate'''
|style="height: 60px; background: #F8E0F1;"| '''Grade 3''' - All features of Mild OHSS with ultrasonographic evidence of ascites
|-
|style="text-align:center; background: #F6CEEC;"| '''Severe'''
|style="height: 60px; background: #F6CEEC;"| '''Grade 4''' - All features of Moderate OHSS with the addition of clinical evidence of ascites and breathing difficulties present
'''Grade 5''' - All of the above symptoms along with a change in the blood volume, increased blood viscosity due to coagulation and diminished renal function
|}

</div>

==Diagnosis==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

Whilst symptoms of OHSS can occur as soon as 24 hours post hCG administration, they are usually seen in women 7-10 days post administration. Initially women with OHSS will present with abdominal bloating, as a result of fluid in the peritoneal cavity and an increase in ovary size. When women present with severe OHSS they are often dehydrated, due to increased vascular permeability, and have hemoconcentration. The above results in a decrease in intravascular volume, leading to oligouria <ref name="PMID22416285" />.

===History===

Initially a thorough history of the patient is taken during which the clinician looks for evidence of ovarian stimulation, followed by ovulation. During this history taking, the clinician will inquire into any weight gain noticed, urine output, and the woman's ability to maintain oral hydration. A key diagnostic tool for clinicians regarding women who are taking gonadotropins is to identify if they are at an increased risk of developing OHSS. Some risk factors include woman aged less than 30, women who have polycystic ovaries, woman with a previous history of OHSS and women who have had greater than 20 oocytes retrieved <ref name="PMID22416285" />.

===Physical Exam===
[[File:Vaginal_Ultrasonography_in_Sagittal_Plane.jpg|right|thumbnail|600px|Vaginal Ultrasonography in Sagittal plane <ref name="Wikiversity Journal of Medicine"> Häggström, Mikael. "Medical gallery of Mikael Häggström 2014". Wikiversity Journal of Medicine 1 (2). DOI:10.15347/wjm/2014.008. ISSN 20018762</ref>]]
After a history of the patient is taken, the next step is to perform a physical exam on the patient. Women who present with abdominal bloating will produce a shifting dullness upon abdominal percussion. Additionally the clinician will test the woman's vital signs, measure her abdominal girth, weight and will look for evidence of ascites or increase in calf size (usually unilateral)<ref name="PMID22416285" />.

===Investigations===

If the clinician further suspects a women of having OHSS, various investigations can be done such as an ultrasound.The intraperitoneal fluid is best imaged via vaginal ultrasound due to the enlarged ovaries making it difficult to image the pelvis using transabdominal ultrasound. The clinician can also order laboratory testing to look for urine specific gravity and and complete blood count to look for hemoconcentration with a hematocrit. Additionally, liver function tests can be ordered to look for elevated function. The clinician will also look for evidence of elevated D-dimers and fibrinogen and decreased levels of anti-thrombin 3 <ref name="SAHealth"> Government of South Australia Health [ http://www.sahealth.sa.gov.au/wps/wcm/connect/9b61ed004ee5348da663afd150ce4f37/Ovarian-hyperstimulation-syndrome-WCHN-PPG-17072012.pdf?MOD=AJPERES&CACHEID=9b61ed004ee5348da663afd150ce4f37 ], 'South Australian Paediatric Clinical Guidelines OHSS'</ref>.

====Ultrasound====

Typical appearances of the ultrasound include <ref name="Ultrasound"> Radiopaedia [ http://radiopaedia.org/articles/ovarian-hyperstimulation-syndrome-1 ], 'Ovarian Hyperstimulation Syndrome'</ref>:

*Bilaterally and symmetrically enlarged ovaries (>12cm)
* "Spoke-Wheel appearance" - presence of multiple cysts of varying size
*May also see ascites (fluid)

===Severity===

Once a clinician has deduced a women is suffering from OHSS, the severity of their condition needs to be established as either mild, moderate or severe. This is done by referring to the criteria under the sub-heading [[Symptoms]].The subsequent course of treatment for the woman will be based upon this evaluation.

{|
|-bgcolor="F6CEEC"
|
'''Further investigations''' can be done including a Chest X-ray to check for pleural effusions and oedema and USS with Doppler's to check for ascites or possible ovary torsion. <ref name="PMID22416285"><pubmed>22416285</pubmed></ref>
|}

===Differential Diagnosis===

Conditions presenting with similar symptoms or ultrasound images include <ref name="Ultrasound" />:

*Polycystic Ovaries (PO)
:: The difference is that with PO is that the cycts are typically smaller than OHSS cysts and there is no evidence of ascited or pleural effusion
*Mucinous Ovarian Malignancy
:: A type of Ovarian Epithelial tumour
*Ectopic Pregnancy <ref name="Casereport"> Australian Medical Student Journal [ http://www.amsj.org/wpcontent/uploads/files/articles/amsj_v2_i1/AMSJ_v2_i1_pg58-60.pdf ], 'Ovarian hyperstimulation syndrome'</ref>
::A pregnancy in which the foetus develops outside of the uterus e.g. in the fallopian tube

</div>

==Pathophysiology==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

[[File:Pathogenesis_of_OHSS.png|600px|thumb|Pathogenesis of OHSS <ref name="PMID20416867"><pubmed>20416867</pubmed></ref>]]

The definition of Ovarian Stimulation is enlarged ovaries with many luteinized cysts, that can present with secondary complications. What distinguishes Ovarian Stimulation from OHSS is the presence of vascular hyper-permeability that results in fluids being redirected elsewhere in the body.

The key process to OHSS appears to be caused by '''Vascular Endothelial Growth Factor''' (VEGF), that is released along with other cytokines, estrogen and progesterone, due to the ovary undergoing luteinization as a result of stimulation by hCG. VEGF increases vascular permeability and as a result the capillaries become more "leaky" to the fluids in them. These fluids can then escape the capillaries and accumulate in the pleural and abdominal cavities as ascites. The woman then becomes hypovolemic and is at an increased risk of circulatory, renal and respiratory issues such as arterial thromboembolism due to the thickening of the blood. Note, the blood is thickened as fluid is leaving the capillaries, leaving behind red blood cells and other cellular components of the blood <ref name="WikiOHSS" />.

The increase in expression of VEGF and VEGF Receptor 2 (VEGFR2) is attributed to the greatly increased amount of their mRNA present in the body after stimulation with hCG <ref name="PMID21082502"><pubmed>21082502</pubmed></ref>. VEGF interacts with VEGF2 and VEGF Receptor 1 (VEGFR1) to create a strong angiogenic effect. Both VEGFR2 and VEGFR1 belong to a family of receptors called tyrosine kinases. VEGF2 is involved in the regulation of angiogenesis and vascular permeability whilst VEGF1 has a slightly contradictory role in that is is involved in the maintenance of the tight junctions between endothelial cells in blood vessels. A study by Gómez ''et. al.'' <ref name="PMID21082502" /> showed that women experiencing OHSS had substantially higher plasma levels of VEGF and lower levels of VEGFR1.

</div>

==Complications==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

Ovarian torsion or rupture, renal insufficiency and thrombophlebitis can all complicate OHSS. If a pregnancy occurs, symptoms may persist longer than the usual 1 to 2 weeks and become more severe, however, even with severe OHSS, they do not extend past the first trimester <ref name="WikiOHSS" />.

<span style="color:#FA58D0"> '''1-2% of women who suffer from ovarian stimulation develop a severe form of OHSS''' </span>. Complications from severe OHSS include:

*Fluid collection in the abdomen
*Electrolyte disturbances (sodium and potassium)
*Kidney failure
*Ovary twisting
*Rupture of a cyst in an ovary
*Breathing problems
*Blood clots in large vessels (most commonly the legs)
*Pregnancy loss from miscarriage or termination
*Rarely, death

A study by Nouri ''et. al.'' <ref name="PMID24996451"><pubmed>24996451</pubmed></ref> found that women with '''Polycystic Ovarian Syndrome''' (PCOS) and those that were induced with hCG experienced longer recovery times from severe OHSS than women who were not pregnant. They looked at a cohort of women hospitalised for the first time with severe OHSS and subject them to the same treatments. Based on a defined criteria, they established the recovery time of these women and compared the times between those that were pregnant to those that were not pregnant. They also found that whether a woman had PCOS or ovulation induction did not affect her risk of developing OHSS if she was not pregnant. It is only a risk factor for pregnant women.

===Thromboembolic events===

A frequent and deadly complication of OHSS are thromboembolic events due to increased blood clotting. This increase in blood clotting has been attributed to a variety of complications such as hemoconcentration (which thickens the blood), hypolvolemia and an increase in the permeability of blood vessels as a result of increased vasoactive substances in the body of ovarian origin. Thromboembolic events include venous thromboses often in the upper extremities and arterial thromboses such as those in the cerebrovascular region. These events can lead to amputations of extremities, brain damage, miscarriage and death. To avoid this, anti-coagulants are given to pateitns with OHSS and they are fitted with compression stockings (see [[Treatment]]) <ref name="PMID23378404"><pubmed>23378404</pubmed></ref>.

{|
|-bgcolor="F8E0F1"
|
The risk of a woman developing OHSS is higher if she is having a '''twin pregnancy''', as she is exposed to higher concentration of hCG. <ref name="PMID9756273"><pubmed>9756273</pubmed></ref>
|}

</div>

==Treatment==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

'''General treatment
'''
*''Acetaminophen'' with or without a narcotic agent- used to treat abdominal discomfort
*Women are encouraged to drink 2-3 litres of water a day to prevent hemoconcentration
*Women are advised to avoid sexual intercourse and vigorous exercise at the risk of torsion or rupture of the ovaries
*NSAID's with anti-platelet properties should NOT be used as they may effect renal function in a women with OHSS
*Patients with significantly painful ascites or breathing problems may undergo ''Paracentesis'' (drainage of the ascites)
*''Culdocentesis'' (extraction of fluid from recto-uterine pouch) can be done to decrease the likelihood of a woman with moderate OHSS progressing to severe OHSS.<ref name="PMID22416285" />

===Mild to Moderate OHSS===

Mild OHSS can often resolve on its own, however, moderate OHSS may include treatments such as<ref name="WikiOHSS" />:

*Anti-nausea medication and prescription painkillers
*Regular physical examinations and ultrasounds
*Daily weigh-ins and waist measurements
*Measuring the amount of urine produced each day
*Frequent blood tests for monitoring dehydration and electrolyte imbalance
*Maintaining a high balance of fluids
*Drainage of excess abdominal fluid by inserting a needle in the abdominal cavity
*Wearing support stockings which help prevent blood clots/thrombosis

===Severe OHSS===

Severe OHSS requires hospital care in order for constant monitoring and treatment such as <ref name="WikiOHSS" />:

*Intravenous fluids with a crystalloid solution (100-150mL/hr)
*Intravenous Albumin is administered is IV fluids are insufficient (15-20mL/hr of 25% albumin for 4 hrs)
*In addition to Acetaminophen, ''Opioid analgesics'' can be administered for pain relief
*''Antiemetics'' can be used to subside nauseas and/or vomiting
*Woman administered to hospital of OHSS are considered at high risk of thromboembolic complications and are given low molecular weight ''heparin'', an anti-coagulant
*''Cabergoline''- lessens OHSS symptoms
*''GnRH agonist''- suppresses ovarian activity
**If at risk of OHSS, alternates include using a GnRH agonist instead of hCG however its effects on pregnancy rates are questionable. Using a GnRH agonist to replace the use of hCG for final oocyte stimulation will see a 6% decrease in delivery rate.

*Daily monitoring of creatine, urea, creatine clearance C-reactive protein (to rule out infection) are all required in combination with weekly tests such as liver and renal function tests and chest x-rays (to check for pleural effusion) <ref name="PMID12638783" />.

If there are serious complications then additional treatments are required:

*Surgery for a ruptured ovarian cyst
*Intensive care for the liver or lung complications

====Paracentesis====

For women with severe/grade 3 OHSS, paracentesis, the removal of fluid from the body using an aspiration needle, can be undertaken. It is a diagnostic and a therapeutic method that can be done trans-abdominally and trans-vaginally. It is used to relieve symptoms, improve haemodynamics e.g. Urinary output, and shorten the women's hospital stay. Complications of paracentesis include bleeding, infection and organ injury, however are note common <ref name="Paracentesis"> S. Monica Soni, HMS 3, Gillian Lieberman, MD [ http://eradiology.bidmc.harvard.edu/LearningLab/genito/Soni.pdf ], 'Ovarian Hyperstimulation Syndrome'</ref>.

{|
|-bgcolor="F8E0F1"
|
The most important aspect of treatment for any women with OHSS is close and constant '''monitoring''' with her healthcare professional. Counselling may also be provided to women and their partners or families in order to provide them with the best possible knowledge base to manage and treat their OHSS. It is important to note that there is '''no one cure or treatment''' for OHSS. Treatment involves managing and eliminating the symptoms until such time as the syndrome resolves itself <ref name="WikiOHSS" />.
|}

</div>

==Prevention==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

There are three key avenues through which the incidence of OHSS may be prevented. These include identifying risk factors to predict OHSS development, modifying treatment regimes on the basis of the identified risk factors and intervention to prevent progression to OHSS once the patient has undergone Controlled Ovarian Stimulation.

=== Risk factors===

'''Primary risk factors'''

Pre-existing factors likely to exacerbate the ovarian stimulation response. Primary risk factors include <ref name="PMID26074966"><pubmed>26074966</pubmed></ref>:

*Young age
*Low body weight
*History of elevated response to gonadotropins
*Polycystic Ovary Syndrome (PCOS)
*Isolated PCOS characteristic
*A previous history of OHSS.
*Hormonal markers (e.g. Anti-Mullerian Hormone markers)
*Ultrasonographic markers (e.g. Antral Follicle Count)

'''Secondary risk factors'''

Secondary risk factors involve the monitoring of ovarian response parameters once COS has been initiated. These parameters are monitored for <ref name="PMID19007627"><pubmed>19007627</pubmed></ref>:

*rapidly rising E2 levels
*E2 concentration larger than 2500 pg/mL
*large number of developing follicles (10-14mm) on the day hCG is administered
*large number of oocytes retrieved

These factors in combination, act as a predictive tool to assess the likelihood of severe OHSS development, with a 83% sensitivity and 84% specificity. <ref name="PMID19007627"/>

=== Primary Prevention===

Primary Prevention involves the modification of treatment regimens on the basis of OHSS risk classifications, in order to prevent OHSS occurrence.

'''Ovulation Induction'''

Unifollicular Ovulation Induction through Ovulation Induction (OI) is a primary means of avoiding OHSS in women with Polycystic Ovarian Syndrome, who are at an increased risk. In order to promote unifollicular development, the ovaries are stimulated with a low starting dose of FSH (75 IU).<ref name="PMID20416867"><pubmed>20416867</pubmed></ref> Studies suggests that a minimum gonadotropin dose lowers OHSS risk and thus a step-up regimen is utilised to achieve an ovarian response, whereby the FSH dosage is increased every 7 days until follicular development of greater than 10mm is noted <ref name="PMID26074966" />. Alternatively, a step-down regimen may be followed, whereby a high initial FSH dosage is lowered according to the ovarian response. Another method to increase FSH levels during OI, is through Aromatase Inhibitors which promote folliculogenesis by increasing pituitary secretion of FSH, and downregulate oestrogen production through a negative feedback loop. However, Aromatase Inhibitors have not been shown to reduce OHSS incidence in comparison to other methods of OI. During OI, a key objective is to prevent early cycle cancellation due to premature luteinisation from pituitary secretion of LH. In order to downregulate LH secretion, Gonadotropin-releasing hormone agonists (GnRHa) are administered in addition to gonadotropins. The duration of exposure to gonadotropins and subsequent risk of OHSS may also be minimised through mild stimulation protocols which administer FSH only in the mid to late follicular phase.<ref name="PMID20416867" />

'''Adjuvant Metformin Therapy'''

Adjuvant Metformin Therapy has been found to lower the risk of OHSS by 63% <ref name="PMID25406011"><pubmed>25406011</pubmed></ref>. It involves the administration of metformin at a daily dosage of 1000 to 2000mg, 2 months prior to Controlled Ovarian Stimulation <ref name="PMID26074966"/>. Metformin lowers the elevated insulin levels in PCOS which consequently reduce intraovarian androgen levels. This leads to a reduced sensitivity and expression of granulosa cell-follicle stimulating hormone receptors which result in a less exaggerated response to gonadotropins. Furthermore, it is suggested that Metformin prevents OHSS by controlling vascular permeability through the inhibition of various vasoactive molecules, including VEGF.

'''Avoiding hCG during Luteal Phase Support

Following Controlled Ovarian Stimulation, the steroid levels of E2 and P4 are reduced during the luteal phase due to the negative feedback on the pituitary. This leads to low endogenous LH levels, which consequently reduce endometrial receptivity as well as the luteal phase duration itself. As a result, implantation and pregnancy rates are reduced and early pregnancy loss rates are increased.<ref name="PMID20416867" /> Luteal Phase Support (LPS) serves to combat these adverse events with the use of hCG. However, hCG has been found to increase the risk of OHSS. Alternatively, the use of progesterone has been found to not only halve the risk of OHSS, but also induce similar improvements in pregnancy and miscarriage rates as hCG.<ref name="PMID26148507"><pubmed>26148507</pubmed></ref>

===Secondary Prevention===

Secondary Prevention aims to prevent progression to OHSS once COS has been initiated and the patient has been found to mount an exaggerated response. <ref name="PMID20416867" />

'''Coasting'''

Coasting is a first-line secondary preventative strategy. It consists of the withdrawal of gonadotrophins when a critical number of follicles and/or E2 concentration is reached. hCG is administered once the E2 concentration reduces to a safe level, before the process of oocyte retrieval commences. This preventative strategy is conducted for a period of less than 3 days in order to avoid compromising IVF outcomes.

'''Cryopreservation'''

Cryopreservation of embryos after oocyte retrieval is another avenue which may avert OHSS progression. The cryopreserved embryos are only reimplanted once the patient's hormone serum levels have normalised. Using oocyte vitrification, crystal formation within embryo tissue is avoided and so cryopreserved embryos have been found to produce better pregnancy rates with a 32% increase, than fresh embryo transfer. Recent studies suggest cryopreservation itself does not reduce OHSS rates, but must be followed by a GnRHa trigger to avert OHSS.

'''Cycle cancellation'''

Cycle cancellation is a guaranteed method to prevent early OHSS whereby hCG is withheld. This is a last resort strategy as it carries the risk of significant psychological distress and financial loss for the patient.

</div>

==Effect on the Newborn==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

</div>
Women who develop OHSS while undergoing Assisted Reproductive Technologies (ART) treatment are not only more likely to achieve a pregnancy, but have a live birth as the pregnancy outcome. This live birth is also more likely to be a multiple birth of two, three or more children. <ref name="PMID19591989"><pubmed>19591989</pubmed></ref> It has been postulated that a multifetal pregnancy leads to a more rapid increase in hCG levels, resulting in an increased risk of OHSS. However, the causal nature between multifetal pregnancy and OHSS development is disputed and further research is required to distinguish correlation from causation. <ref name="PMID19573292"><pubmed>19573292</pubmed></ref>

OHSS development is also associated with an increased risk of adverse outcomes including stillbirth, premature birth and low birthweight.<ref name="PMID19591989" /> Although the cause for the increased risk in adverse pregnancy outcomes is unknown, it is suggested that as the incidence of OHSS is reduced through various prevention strategies, the risk of such outcomes may be also be reduced.

==Genetics==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

Despite OHSS typically being of iatrogenic origin as a result of ovarian stimulation with gonadotropins, research has been conducted into the potential genetics behind OHSS as many sporadic and familial cases have been observed. '''Mutations''' in the receptor for hormones such as Follicle Simulating Hormone (FSH), Lutenizing Hormone (LH) and hCG have all been targets of OHSS genetics research. Interestingly, they too also arise from a common ancestral gene.

===Follicle Stimulating Hormome===

Dr. Botros Rizk, of the University of South Alabama College of Medicine <ref name="PMID19573286"><pubmed>19573286</pubmed></ref>, has written extensively regarding the genetics behind OHSS. In particular, he talks about '''FSH receptors''' (FSHR) and their role in the syndrome. He hypothesises that mutations in these receptors could be activating or inactivating, leading to an increased risk of developing OHSS or sterility respectively. Currently, 744 single nucleotide polymorphisms (a type of mutation) have been found in the gene encoding the FSHR, 8 of which are located in its exons (coding regions of the gene). How the ovary responds is resultant on the FSHR genotype. For example, Ser680Asn, a polymorphism in the FSHR gene has been shown to aid in predicting the severity of a woman's OHSS. Ordinarily FSH stimulates the growth of ovarian follicles, however, when mutated, it is stimulated by the hCG resulting in excessive follicle development.

Spontaneous OHSS, OHSS that arises and cannot be attributed to any form of ovarian stimulation or Assisted Reproductive Technology, has been linked to activating mutations in the FSHR <ref name="PMID23499866"><pubmed>23499866</pubmed></ref>. This familial disorder is an autosomal dominant one. In most cases the FSHR can be stimulated by the presence of Thyroid Stimulating Hormone (TSH) or hCG, in the absence of FSH (the ligand for FSHR).

===Lutenizing Hormome===

The '''Lutenizing Hormone Receptor''' (LHR) gene in humans is comprised of 11 exons. Animal studies have shown that many primates exhibit a similar gene which is comprised of only 10 exons, however a gene lacking the 10th exon has been identified and termed the type 2 LHR. Expression of the type 2 LHR has been seen in humans. The type 2 LHR, compared to the wild-type LHR appears to be repaired with regard to its function. Defects in the type 2 LHR include a decrease in efficiency of transport to the plasma membrane and irregularities in signal transduction. Inactivating mutations in the LHR have been seen to cause infertility in women as well as amenorrhoea. Activating LHR gene mutations are asymptomatic and are not associated with OHSS in women.

===Bone Morphogenic Protein===

An imporant growth factor, derived from oocytes called '''BMP-15''' (Bone Morphogenic Protein 15) is vital for female fertility. It belongs to the family of growth factors, Transforming Growth Factor β (TGF-β) and is heavily involved in folliculogenesis. It has been found that mutations in the BMP-15 gene caused infertility in female sheep. Conversely, it has also been indicated in enhanced fertility when BMP-15 is present is high amounts in follicular fluid <ref name="PMID19573286" />.

A case study done by Hanevik ''et. al.'' in 2013 <ref name="PMID21565556"><pubmed>21565556</pubmed></ref> found that a Single Nuclear Polymorphism (SNP) in the BMP-15 gene is responsible for a high response to ovarian hyper-stimulation. The aim of the study was to test the effect the SNP had on BMP-15 with regard to high and low responders buy taking blood from 53 high responders, 38 low responders and 100 non-responders (controls) and analysing 5 noted SNP's. Results from their study showed a correlation between a high response to ovarian hyper-stimulation and the BMP-15 9G allele. The article does state however, that further research is required into the molecular effects of SNP's on the function of BMP-15.

===Vascular Endothelial Growth Factor===

'''Vascular endothelial growth factor''' (VEGF) has been indicated as one of the key agents causing vascular permeability and subsequent ascites in OHSS. The gene, which is located on chromosome 12, is made up of 8 exons (coding regions), of which exons 6 and 7 do not always appear due to the exons being spliced out.The splicing of this gene allows for various isoforms of the gene to exist of which VEGF 121 and 165 appear to play a role in angiogenesis. There are two VEGF Receptors, VEGFR-1 and VEGFR-2 that belong to the tyrosine kinase family of receptors (for more information on VEGF see [[Pathophysiology]]). Because of its distinct role in OHSS, it has been targeted as an area for research for potential treatments. The idea is that if the genetic expression of VEGF and its receptors can be controlled, OHSS can be avoided or treated.<ref name="PMID19573286" />

A different study by Hanevik ''et. al.'' , <ref name="PMID22587628"><pubmed>22587628</pubmed></ref> done in 2012 involved analysing blood samples from 53 women with OHSS and 100 women without it (controls) and analysing 6 SNP's in the VEGFR2 gene to find any genetic variations. They found a correlation between women with the VEGF +405cc genotype and the development of OHSS indicating women that undergo controlled ovarian hyper-stimulation and posses his genotype, are at an increased risk of developing OHSS.

</div>

== Current Research on Animal Models==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">
{|
|-bgcolor="F8E0F1"
|
<span style="font-size:120%">'''Inhibition of Cyclooxygenase-2 (COX-2) by Meloxican decreasing the incidence of OHSS in Rat Model'''</span> <ref name="PMID18166186"><pubmed>18166186</pubmed></ref>

Reasearch was carried out to investigate the effects of selective inhibition of the enzyme COX-2 on the Ovarian Hyperstimulation Syndrome (OHSS) using Female Wistar rates as the subjects. The research aimed to find results by measuring the number of antral and luteinized follicles, ovarian weight, vascualr endothelial growth factors and COX-2 immunohistochemistry. The rats being tested were all 22 days old and were divided into four equal groups;

'''Group 1 (Control group)''' was subject to a 0.1 ml of Intraperitoneal Saline from days 22 ~ 26

'''Group 2 (Mildly-stimulated group)''' subject to 10IU of pregnant mare serum gonadotrophin (PMSG) on day 24 and then 10IU of Human Chorionic Gonadotrophin (hCG) on day 26

'''Group 3 (OHSS positive group)''' was subject to 10IU of PMSG from days 22 ~ 26 and then administered 30IU of hCG on day 26 to induce OHSS

'''Group 4 (OHSS positive variant group)''' received 15mg/ml of Meloxicam 2 hours prior to administration of 10IU PMSG from days 22 ~ 26

Results showed there was no difference in ovarian weight in samples from Group 1 and Group 2, however Group 3 showed signs of significant ovarian weight increase which in group 4 was suppressed by the introduction of Meloxicam. No differences were observed in the number of antral follicles amongst the four test groups. Results from Group 2 and Group 3 showed that the granulosa cells of preovulatory follicles and the stromal cells were highly VEGF immunoreactive, however the Meloxicam treated Group 4 showed less immunoreactivity than Group 2 and Group 3 which indicated the correlation between Meloxicam and the diminished VEGF expression. Group 3 presented an increased COS-2 immunoreactivity which was highly diminished than in Group 4.

The research concluded that in a rat model, the enzyme Meloxicam has a beneficial effect on OHSS by reducing the increase of ovarian weight and the expression of VEGF associated with OHSS, the effects of which may be mediated by the inhibitory capacity of COX-2 on Meloxicam
|}

{|
|-bgcolor="FF99FF"
|
<span style="font-size:120%">'''Inhibition of Ovarian VEGF secretion by activation of Dopamine Receptor 2'''</span> <ref name="PMID25217874"><pubmed>25217874</pubmed></ref>

This research was carried out to investigate a possibility in whether a Dopamine Receptor 2 agonist '''(D2-ag)''' can assist in the prevention of Ovarian Hyperstimulation Syndrome, using rat models, by decreasing the ovarian vascular endothelial growth factor '''(VEGF)''' production. Using Immature Wistar rats (22 days old) as their animal model, the rats were initially stimulated with Gonadotrophins to mimic the onset and effects of OHSS and then subjected to treatment with a D2-agonist and/or a D2-antagonist (D2-ant). The vascular permeability was measured at the endpoint after day 26 by measuring the peritoneal extravasion of a previously injected dye and ovaries from all subjects were collected to assess the effects of D2-ag and D2-ant on the production of Ovarian VEGF. The expression of VEGF mRNA was measured by quantitative real time PCR and the levels of VEGF proteins were measured by Western Blots.

Results showed that the D2-ag caused a large reduction in the vascular permeability which was in turn associated with the great decreased in VEGF protein production in the OHSS rat ovaries, whereas the introduction of D2-ant showed opposite results with a increase in the vascular permeability leading to the increase of VEGF protein production in the ovaries. Ovarian VEGF mRNA levels were found to be unaffected by the introduction of these drugs in OHSS rat subjects. Conclusions were drawn on the fact that Dopamine Receptor 2 agonists prevent the increase of vascular permeability in subjects with OHSS by decreasing the ovarian production of VEGF and also that due to the dose-dependent inhibitory effect of the D2-ag on ovarian VEGF, current OHSS therapies used in humans can benefit by increasing the intraovarian concentration of D2-ag.
|}
</div>

==Glossary==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

'''Ascites'''- An accumulation of fluid in the peritoneal cavity with resultant abdominal swelling

'''Cabergoline''' - A dopamine receptor agonist used to treat hormone imbalance.

'''GnRH antagonist''' - Gonadotropin Releasing Hormone - A class of compounds that are similar in terms of the structure of natural Gonadotropin Releasing Hormone but has a antagonistic effect.

'''hCG'''- Human Chorionic Gonadotropin

'''Hemoconcentration'''- An increase in the concentration of circulating red blood cells in response to a decrease in blood plasma volume

'''Hypovolemic'''- A decrease in circulating blood volume

'''Iatrogenic'''- Illness caused as a result of a medical examination or treatment

'''Intravenous fluids''' - Is the infusion of liquid substances directly into a vein.

'''IVF'''- In-vitro Fertilization

'''NSAID'''- Non-steroidal Anti-Inflammatory Drug e.g. Ibuprofen

'''OHSS'''- Ovarian Hyper-stimulation Syndrome

'''FSH''' - Follicle Stimulating Hormone

'''LH''' - Luteinizing Hormone

'''Oliguria'''- Decreased urine output/small amounts of urine produced

</div>

==References==

2015 Group Project 2

2015-10-22T20:55:41Z

Z3372824: /* Causative Agents */

{{ANAT2341Project2015header}}

==<span style="font-size:120%">'''Ovarian Hyper-stimulation Syndrome (OHSS)'''</span>==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

Ovarian Hyper stimulation Syndrome (OHSS) is an iatrogenic complication of '''Assisted Reproduction Technology''' (ART), in which women take medications to stimulate oocyte growth. It is generally identified by cystic enlargements of the ovaries and fluid accumulation in the peritoneal cavity due to the increased capillary permeability and ovarian neoangiogenesis <ref name="PMID22065820"><pubmed>22065820</pubmed></ref>. It is an occurrence which is dependent on the controlled stimulation of the ovaries in preparation for IVF i.e. administration of human Chorionic Gonadotropin (hCG).

OHSS was first described in 1943 as ''“syndrome d’hyperluteinisation massive
des ovaries”''. It was during this time that gonadotropins were prepared from animals such as sheep to bring on ovulation in women. The first recorded death as a result of OHSS occurred in 1951 and was due to renal failure as a result of oligouria, a complication of the syndrome <ref name="OHSS"> Marie M. Budev, DO, MPH; Alejandro C. Arroliga, MD; Tommaso Falcone, MD, [ http://utilis.net/Morning%20Topics/REI/Ovarian%20Hyperstimulation.pdf ], 'Ovarian Hyperstimulation Syndrome'</ref> <ref name="PMID12638783"><pubmed>12638783</pubmed></ref>.

<span style="color:#FA58D0">This wikipage aims to provide clear information on various areas surrounding OHSS such as diagnosis, prevention and complications and will look into the genetics behind the disorder and the various animals models used to research it.</span>

<html5media height="350" width="450">https://www.youtube.com/watch?v=aXmjJw234a4</html5media>

'''Overview of the Ovarian Hyperstimulation Syndrome''' <ref> Howcast (2013, August 27) Ovarian Hyperstimulation Syndrome | Infertility. Retrieved from https://www.youtube.com/watch?v=aXmjJw234a4</ref>

</div>

==Epidemiology==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

Ovarian Hyper-Stimulation Syndrome (OHSS) rarely occurs sporadically, and if it does, it is usually the result of an underlying genetic problem. The majority of OHSS is due to the ovaries being stimulated to mature and release an abundance of oocytes, in response to hormones Human Chorionic Gonadotropin (hCG) and Follicle Stimulating hormone (FSH), during IVF. Rarely, Clomifene Citrate therapy can cause OHSS.<ref name="WikiOHSS"> Wikipedia, [ https://en.wikipedia.org/wiki/Ovarian_hyperstimulation_syndrome ], 'Ovarian Hyperstimulation Syndrome'</ref>

OHSS only affects '''0.5-5%''' of women undergoing Ovarian Hyper-stimulation, but despite its small prevalence, it is a potentially fatal outcome of a non-vital procedure and remains a prevalent problem for fertility specialists <ref name="PMID12498425"><pubmed>12498425</pubmed></ref> <ref name="PMID12638783"><pubmed>12638783</pubmed></ref>. Age has been cited as a factor affecting those with OHSS, with younger women more at risk. Additionally, women with allergies were seen to have a higher incidence of OHSS. It is important to note that at this point in time, there is no positive correlation between gonadotropin dose and OHSS.

Of the 0.5-5% of women affected with OHSS mentioned above, 2% of those women will require hospitalisation. As of 2011, it has been reported that the incidence of OHSS was '''increasing''', resulting in approximately 3 deaths per 100,000 women undergoing ovarian stimulation per year <ref name="PMID21828116"><pubmed>21828116</pubmed></ref>. This is particularly worrying as in 2008, in the United States alone, there were around 150,000 IVF cycles undertaken.

{|
|-bgcolor="F8E0F1"
|
'''With the field of Assisted Reproductive Technologies expanding and more women partaking in IVF treatments, the threat of women developing OHSS is an ongoing and increasing one''' <ref name="PMID21828116" />.
|}
{| class="wikitable mw-collapsible mw-collapsed"
! Characteristics of women by complication group <ref name="PMID19591989"><pubmed>19591989</pubmed></ref>
|-
! scope="col" width="100px" height="60px" style="text-align:center| '''Characteristic'''
! scope="col" width="100px" height="60px" style="text-align:center| '''No Complications
(N = 212,041)'''
! scope="col" width="100px" height="60px" style="text-align:center| '''Moderate OHSS
(N = 1,523)'''
! scope="col" width="100px" height="60px" style="text-align:center| '''Severe OHSS
(N = 655)'''
|-
|style="text-align:center; background: #FF99FF;"| '''Maternal Age (Mean ± SD)'''
|style="text-align:center; background: #F6CEEC;"| 35.6 ± 4.6
|style="text-align:center; background: #F6CEEC;"| 33.0 ± 4.3
|style="text-align:center; background: #F6CEEC;"| 33.1 ± 4.4
|-
|style="text-align:center; background: #FF99FF;"| '''Maternal Age (%)'''
|-
|style="text-align:left; background: #F6CEEC;"| <30 years
|style="text-align:center; background: #F6CEEC;"| 10 %
|style="text-align:center; background: #F6CEEC;"| 21.1 %
|style="text-align:center; background: #F6CEEC;"| 20.6 %
|-
|style="text-align:left; background: #F6CEEC;"| 30-34 years
|style="text-align:center; background: #F6CEEC;"| 30.4 %
|style="text-align:center; background: #F6CEEC;"| 43.2 %
|style="text-align:center; background: #F6CEEC;"| 40.5 %
|-
|style="text-align:left; background: #F6CEEC;"| 35-39 years
|style="text-align:center; background: #F6CEEC;"| 37.8 %
|style="text-align:center; background: #F6CEEC;"| 27.2 %
|style="text-align:center; background: #F6CEEC;"| 32.5 %
|-
|style="text-align:left; background: #F6CEEC;"| >40 years
|style="text-align:center; background: #F6CEEC;"| 21.8 %
|style="text-align:center; background: #F6CEEC;"| 8.4 %
|style="text-align:center; background: #F6CEEC;"| 6.4 %
|-
|style="text-align:center; background: #FF99FF;"| '''Nulligravida (%)'''
|style="text-align:center; background: #F6CEEC;"| 45.8 %
|style="text-align:center; background: #F6CEEC;"| 51.5 %
|style="text-align:center; background: #F6CEEC;"| 51.8 %
|-
|style="text-align:center; background: #FF99FF;"| '''Infertility Diagnosis (%)'''
|-
|style="text-align:left; background: #F6CEEC;"| Male factor
|style="text-align:center; background: #F6CEEC;"| 37.7 %
|style="text-align:center; background: #F6CEEC;"| 41.0 %
|style="text-align:center; background: #F6CEEC;"| 33.4 %
|-
|style="text-align:left; background: #F6CEEC;"| Endometriosis
|style="text-align:center; background: #F6CEEC;"| 13.5 %
|style="text-align:center; background: #F6CEEC;"| 13.5 %
|style="text-align:center; background: #F6CEEC;"| 10.7 %
|-
|style="text-align:left; background: #F6CEEC;"| Ovulation Disorders
|style="text-align:center; background: #F6CEEC;"| 14.0 %
|style="text-align:center; background: #F6CEEC;"| 29.5 %
|style="text-align:center; background: #F6CEEC;"| 22.4 %
|-
|style="text-align:left; background: #F6CEEC;"| Diminished ovarian reserve
|style="text-align:center; background: #F6CEEC;"| 16.9 %
|style="text-align:center; background: #F6CEEC;"| 3.2 %
|style="text-align:center; background: #F6CEEC;"| 2.4 %
|-
|style="text-align:left; background: #F6CEEC;"| Tubal factors
|style="text-align:center; background: #F6CEEC;"| 20.4 %
|style="text-align:center; background: #F6CEEC;"| 22.6 %
|style="text-align:center; background: #F6CEEC;"| 22.3 %
|-
|style="text-align:left; background: #F6CEEC;"| Uterine factors
|style="text-align:center; background: #F6CEEC;"| 5.1 %
|style="text-align:center; background: #F6CEEC;"| 4.3 %
|style="text-align:center; background: #F6CEEC;"| 3.1 %
|-
|style="text-align:left; background: #F6CEEC;"| Other factors
|style="text-align:center; background: #F6CEEC;"| 13.9 %
|style="text-align:center; background: #F6CEEC;"| 13.1 %
|style="text-align:center; background: #F6CEEC;"| 10.4 %
|-
|style="text-align:left; background: #F6CEEC;"| Unexplained factor
|style="text-align:center; background: #F6CEEC;"| 12.7 %
|style="text-align:center; background: #F6CEEC;"| 11.8 %
|style="text-align:center; background: #F6CEEC;"| 18.6 %
|-
|}
</div>

==Causative Agents==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

[[File:Follicular Development.jpeg|right|thumbnail|500px|Infertility treatments aim to facilitate follicular development to improve chances of fertilisation <ref name="PMID24717179"><pubmed>24717179</pubmed></ref>]]

Normally a woman produces one egg per month from the ovaries, which travel down the Fallopian tube to be fertilized or be released from the body. In cases where women have difficulty falling pregnant, they are given medication which help them to produce and release eggs (as shown in the diagram to the right), further increasing their chances of fertilization and pregnancy <ref><pubmed>19573285</pubmed></ref>. Ovarian Hyper stimulation Syndrome generally occurs during infertility treatments when the ovaries are overstimulated by the fertility medication which causes the ovaries to swell and leak fluids into the belly and abdomen. The prevalence of OHSS onset is linked with excessive number of follicle development in response to the administration of injectable Follicle Stimulating Hormones (FSH) followed by the '''Human Chorionic Gonadotrophins''' (hCG) which triggers the release of the oocytes <ref><pubmed>26190539</pubmed></ref>.

'''Follicle Stimulating Hormones''' (FSH) <ref name="PMID9020850"><pubmed>9020850</pubmed></ref> are glycoprotein hormones that are produced and secreted from the Anterior Pituitary gland into the bloodstream, which regulate the developmental, growth, maturation and the reproductive processes within the body. In females, the Follicle Stimulating Hormones initiates the stages of growth and development of immature ovarian follicles within the ovaries before the release of an egg from a follicle at ovulation. When FSH is administered to a patient who is suffering from infertility, the increase FSH levels affect the rate of development and production, in turn increasing the amount of follicles which are ready to be released during ovulation.

</div>

==Symptoms==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

OHSS is classified based on a criteria from mild, moderate and severe <ref name="WikiOHSS" />:

'''Mild Symptoms'''- abdominal bloating, minimal weight gain, nausea, diarrhoea and a feeling of fullness.

'''Moderate Symptoms'''- Substantial weight gain (on average 2 or more pounds a day), increased abdominal girth, darkend urine and excessive thirst in addition to the mild symptoms.

'''Severe Symptoms'''- In addition to the symptoms associated with Mild and Moderate OHSS, in severe OHSS, you see shortness of breath, calf and chest pains and pleural effusion.

<span style="font-size:100%">'''Classifications of Ovarian Hyper-stimulation Syndrome:'''</span> <ref name="PMID22065820"><pubmed>22065820</pubmed></ref>
{| class="wikitable" style="text-align:center
|-
! scope="col" width="70px"| '''Classification'''
! scope="col" width="650px"| '''Symptoms'''
|-
|style="text-align:center; background: #F6CEEC;"| '''Mild'''
|style="height: 60px; background: #F6CEEC;"| '''Grade 1''' - Abdominal distention and discomfort
'''Grade 2''' - Abdominal distention, discomfort with nausea, vomiting and/or diarrhea and ovarian enlargement from 5~12cm
|-
|style="text-align:center; background: #F8E0F1;"| '''Moderate'''
|style="height: 60px; background: #F8E0F1;"| '''Grade 3''' - All features of Mild OHSS with ultrasonographic evidence of ascites
|-
|style="text-align:center; background: #F6CEEC;"| '''Severe'''
|style="height: 60px; background: #F6CEEC;"| '''Grade 4''' - All features of Moderate OHSS with the addition of clinical evidence of ascites and breathing difficulties present
'''Grade 5''' - All of the above symptoms along with a change in the blood volume, increased blood viscosity due to coagulation and diminished renal function
|}

</div>

==Diagnosis==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

Whilst symptoms of OHSS can occur as soon as 24 hours post hCG administration, they are usually seen in women 7-10 days post administration. Initially women with OHSS will present with abdominal bloating, as a result of fluid in the peritoneal cavity and an increase in ovary size. When women present with severe OHSS they are often dehydrated, due to increased vascular permeability, and have hemoconcentration. The above results in a decrease in intravascular volume, leading to oligouria <ref name="PMID22416285" />.

===History===

Initially a thorough history of the patient is taken during which the clinician looks for evidence of ovarian stimulation, followed by ovulation. During this history taking, the clinician will inquire into any weight gain noticed, urine output, and the woman's ability to maintain oral hydration. A key diagnostic tool for clinicians regarding women who are taking gonadotropins is to identify if they are at an increased risk of developing OHSS. Some risk factors include woman aged less than 30, women who have polycystic ovaries, woman with a previous history of OHSS and women who have had greater than 20 oocytes retrieved <ref name="PMID22416285" />.

===Physical Exam===
[[File:Vaginal_Ultrasonography_in_Sagittal_Plane.jpg|right|thumbnail|600px|Vaginal Ultrasonography in Sagittal plane <ref name="Wikiversity Journal of Medicine"> Häggström, Mikael. "Medical gallery of Mikael Häggström 2014". Wikiversity Journal of Medicine 1 (2). DOI:10.15347/wjm/2014.008. ISSN 20018762</ref>]]
After a history of the patient is taken, the next step is to perform a physical exam on the patient. Women who present with abdominal bloating will produce a shifting dullness upon abdominal percussion. Additionally the clinician will test the woman's vital signs, measure her abdominal girth, weight and will look for evidence of ascites or increase in calf size (usually unilateral)<ref name="PMID22416285" />.

===Investigations===

If the clinician further suspects a women of having OHSS, various investigations can be done such as an ultrasound.The intraperitoneal fluid is best imaged via vaginal ultrasound due to the enlarged ovaries making it difficult to image the pelvis using transabdominal ultrasound. The clinician can also order laboratory testing to look for urine specific gravity and and complete blood count to look for hemoconcentration with a hematocrit. Additionally, liver function tests can be ordered to look for elevated function. The clinician will also look for evidence of elevated D-dimers and fibrinogen and decreased levels of anti-thrombin 3 <ref name="SAHealth"> Government of South Australia Health [ http://www.sahealth.sa.gov.au/wps/wcm/connect/9b61ed004ee5348da663afd150ce4f37/Ovarian-hyperstimulation-syndrome-WCHN-PPG-17072012.pdf?MOD=AJPERES&CACHEID=9b61ed004ee5348da663afd150ce4f37 ], 'South Australian Paediatric Clinical Guidelines OHSS'</ref>.

====Ultrasound====

Typical appearances of the ultrasound include <ref name="Ultrasound"> Radiopaedia [ http://radiopaedia.org/articles/ovarian-hyperstimulation-syndrome-1 ], 'Ovarian Hyperstimulation Syndrome'</ref>:

*Bilaterally and symmetrically enlarged ovaries (>12cm)
* "Spoke-Wheel appearance" - presence of multiple cysts of varying size
*May also see ascites (fluid)

===Severity===

Once a clinician has deduced a women is suffering from OHSS, the severity of their condition needs to be established as either mild, moderate or severe. This is done by referring to the criteria under the sub-heading [[Symptoms]].The subsequent course of treatment for the woman will be based upon this evaluation.

{|
|-bgcolor="F6CEEC"
|
'''Further investigations''' can be done including a Chest X-ray to check for pleural effusions and oedema and USS with Doppler's to check for ascites or possible ovary torsion. <ref name="PMID22416285"><pubmed>22416285</pubmed></ref>
|}

===Differential Diagnosis===

Conditions presenting with similar symptoms or ultrasound images include <ref name="Ultrasound" />:

*Polycystic Ovaries (PO)
:: The difference is that with PO is that the cycts are typically smaller than OHSS cysts and there is no evidence of ascited or pleural effusion
*Mucinous Ovarian Malignancy
:: A type of Ovarian Epithelial tumour
*Ectopic Pregnancy <ref name="Casereport"> Australian Medical Student Journal [ http://www.amsj.org/wpcontent/uploads/files/articles/amsj_v2_i1/AMSJ_v2_i1_pg58-60.pdf ], 'Ovarian hyperstimulation syndrome'</ref>
::A pregnancy in which the foetus develops outside of the uterus e.g. in the fallopian tube

</div>

==Pathophysiology==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

[[File:Pathogenesis_of_OHSS.png|600px|thumb|Pathogenesis of OHSS <ref name="PMID20416867"><pubmed>20416867</pubmed></ref>]]

The definition of Ovarian Stimulation is enlarged ovaries with many luteinized cysts, that can present with secondary complications. What distinguishes Ovarian Stimulation from OHSS is the presence of vascular hyper-permeability that results in fluids being redirected elsewhere in the body.

The key process to OHSS appears to be caused by '''Vascular Endothelial Growth Factor''' (VEGF), that is released along with other cytokines, estrogen and progesterone, due to the ovary undergoing luteinization as a result of stimulation by hCG. VEGF increases vascular permeability and as a result the capillaries become more "leaky" to the fluids in them. These fluids can then escape the capillaries and accumulate in the pleural and abdominal cavities as ascites. The woman then becomes hypovolemic and is at an increased risk of circulatory, renal and respiratory issues such as arterial thromboembolism due to the thickening of the blood. Note, the blood is thickened as fluid is leaving the capillaries, leaving behind red blood cells and other cellular components of the blood <ref name="WikiOHSS" />.

The increase in expression of VEGF and VEGF Receptor 2 (VEGFR2) is attributed to the greatly increased amount of their mRNA present in the body after stimulation with hCG <ref name="PMID21082502"><pubmed>21082502</pubmed></ref>. VEGF interacts with VEGF2 and VEGF Receptor 1 (VEGFR1) to create a strong angiogenic effect. Both VEGFR2 and VEGFR1 belong to a family of receptors called tyrosine kinases. VEGF2 is involved in the regulation of angiogenesis and vascular permeability whilst VEGF1 has a slightly contradictory role in that is is involved in the maintenance of the tight junctions between endothelial cells in blood vessels. A study by Gómez ''et. al.'' <ref name="PMID21082502" /> showed that women experiencing OHSS had substantially higher plasma levels of VEGF and lower levels of VEGFR1.

</div>

==Complications==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

Ovarian torsion or rupture, renal insufficiency and thrombophlebitis can all complicate OHSS. If a pregnancy occurs, symptoms may persist longer than the usual 1 to 2 weeks and become more severe, however, even with severe OHSS, they do not extend past the first trimester <ref name="WikiOHSS" />.

<span style="color:#FA58D0"> '''1-2% of women who suffer from ovarian stimulation develop a severe form of OHSS''' </span>. Complications from severe OHSS include:

*Fluid collection in the abdomen
*Electrolyte disturbances (sodium and potassium)
*Kidney failure
*Ovary twisting
*Rupture of a cyst in an ovary
*Breathing problems
*Blood clots in large vessels (most commonly the legs)
*Pregnancy loss from miscarriage or termination
*Rarely, death

A study by Nouri ''et. al.'' <ref name="PMID24996451"><pubmed>24996451</pubmed></ref> found that women with '''Polycystic Ovarian Syndrome''' (PCOS) and those that were induced with hCG experienced longer recovery times from severe OHSS than women who were not pregnant. They looked at a cohort of women hospitalised for the first time with severe OHSS and subject them to the same treatments. Based on a defined criteria, they established the recovery time of these women and compared the times between those that were pregnant to those that were not pregnant. They also found that whether a woman had PCOS or ovulation induction did not affect her risk of developing OHSS if she was not pregnant. It is only a risk factor for pregnant women.

===Thromboembolic events===

A frequent and deadly complication of OHSS are thromboembolic events due to increased blood clotting. This increase in blood clotting has been attributed to a variety of complications such as hemoconcentration (which thickens the blood), hypolvolemia and an increase in the permeability of blood vessels as a result of increased vasoactive substances in the body of ovarian origin. Thromboembolic events include venous thromboses often in the upper extremities and arterial thromboses such as those in the cerebrovascular region. These events can lead to amputations of extremities, brain damage, miscarriage and death. To avoid this, anti-coagulants are given to pateitns with OHSS and they are fitted with compression stockings (see [[Treatment]]) <ref name="PMID23378404"><pubmed>23378404</pubmed></ref>.

{|
|-bgcolor="F8E0F1"
|
The risk of a woman developing OHSS is higher if she is having a '''twin pregnancy''', as she is exposed to higher concentration of hCG. <ref name="PMID9756273"><pubmed>9756273</pubmed></ref>
|}

</div>

==Treatment==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

'''General treatment
'''
*''Acetaminophen'' with or without a narcotic agent- used to treat abdominal discomfort
*Women are encouraged to drink 2-3 litres of water a day to prevent hemoconcentration
*Women are advised to avoid sexual intercourse and vigorous exercise at the risk of torsion or rupture of the ovaries
*NSAID's with anti-platelet properties should NOT be used as they may effect renal function in a women with OHSS
*Patients with significantly painful ascites or breathing problems may undergo ''Paracentesis'' (drainage of the ascites)
*''Culdocentesis'' (extraction of fluid from recto-uterine pouch) can be done to decrease the likelihood of a woman with moderate OHSS progressing to severe OHSS.<ref name="PMID22416285" />

===Mild to Moderate OHSS===

Mild OHSS can often resolve on its own, however, moderate OHSS may include treatments such as<ref name="WikiOHSS" />:

*Anti-nausea medication and prescription painkillers
*Regular physical examinations and ultrasounds
*Daily weigh-ins and waist measurements
*Measuring the amount of urine produced each day
*Frequent blood tests for monitoring dehydration and electrolyte imbalance
*Maintaining a high balance of fluids
*Drainage of excess abdominal fluid by inserting a needle in the abdominal cavity
*Wearing support stockings which help prevent blood clots/thrombosis

===Severe OHSS===

Severe OHSS requires hospital care in order for constant monitoring and treatment such as <ref name="WikiOHSS" />:

*Intravenous fluids with a crystalloid solution (100-150mL/hr)
*Intravenous Albumin is administered is IV fluids are insufficient (15-20mL/hr of 25% albumin for 4 hrs)
*In addition to Acetaminophen, ''Opioid analgesics'' can be administered for pain relief
*''Antiemetics'' can be used to subside nauseas and/or vomiting
*Woman administered to hospital of OHSS are considered at high risk of thromboembolic complications and are given low molecular weight ''heparin'', an anti-coagulant
*''Cabergoline''- lessens OHSS symptoms
*''GnRH agonist''- suppresses ovarian activity
**If at risk of OHSS, alternates include using a GnRH agonist instead of hCG however its effects on pregnancy rates are questionable. Using a GnRH agonist to replace the use of hCG for final oocyte stimulation will see a 6% decrease in delivery rate.

*Daily monitoring of creatine, urea, creatine clearance C-reactive protein (to rule out infection) are all required in combination with weekly tests such as liver and renal function tests and chest x-rays (to check for pleural effusion) <ref name="PMID12638783" />.

If there are serious complications then additional treatments are required:

*Surgery for a ruptured ovarian cyst
*Intensive care for the liver or lung complications

====Paracentesis====

For women with severe/grade 3 OHSS, paracentesis, the removal of fluid from the body using an aspiration needle, can be undertaken. It is a diagnostic and a therapeutic method that can be done trans-abdominally and trans-vaginally. It is used to relieve symptoms, improve haemodynamics e.g. Urinary output, and shorten the women's hospital stay. Complications of paracentesis include bleeding, infection and organ injury, however are note common <ref name="Paracentesis"> S. Monica Soni, HMS 3, Gillian Lieberman, MD [ http://eradiology.bidmc.harvard.edu/LearningLab/genito/Soni.pdf ], 'Ovarian Hyperstimulation Syndrome'</ref>.

{|
|-bgcolor="F8E0F1"
|
The most important aspect of treatment for any women with OHSS is close and constant '''monitoring''' with her healthcare professional. Counselling may also be provided to women and their partners or families in order to provide them with the best possible knowledge base to manage and treat their OHSS. It is important to note that there is '''no one cure or treatment''' for OHSS. Treatment involves managing and eliminating the symptoms until such time as the syndrome resolves itself <ref name="WikiOHSS" />.
|}

</div>

==Prevention==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

There are three key avenues through which the incidence of OHSS may be prevented. These include identifying risk factors to predict OHSS development, modifying treatment regimes on the basis of the identified risk factors and intervention to prevent progression to OHSS once the patient has undergone Controlled Ovarian Stimulation.

=== Risk factors===

'''Primary risk factors'''

Pre-existing factors likely to exacerbate the ovarian stimulation response. Primary risk factors include <ref name="PMID26074966"><pubmed>26074966</pubmed></ref>:

*Young age
*Low body weight
*History of elevated response to gonadotropins
*Polycystic Ovary Syndrome (PCOS)
*Isolated PCOS characteristic
*A previous history of OHSS.
*Hormonal markers (e.g. Anti-Mullerian Hormone markers)
*Ultrasonographic markers (e.g. Antral Follicle Count)

'''Secondary risk factors'''

Secondary risk factors involve the monitoring of ovarian response parameters once COS has been initiated. These parameters are monitored for <ref name="PMID19007627"><pubmed>19007627</pubmed></ref>:

*rapidly rising E2 levels
*E2 concentration larger than 2500 pg/mL
*large number of developing follicles (10-14mm) on the day hCG is administered
*large number of oocytes retrieved

These factors in combination, act as a predictive tool to assess the likelihood of severe OHSS development, with a 83% sensitivity and 84% specificity. <ref name="PMID19007627"/>

=== Primary Prevention===

Primary Prevention involves the modification of treatment regimens on the basis of OHSS risk classifications, in order to prevent OHSS occurrence.

'''Ovulation Induction'''

Unifollicular Ovulation Induction through Ovulation Induction (OI) is a primary means of avoiding OHSS in women with Polycystic Ovarian Syndrome, who are at an increased risk. In order to promote unifollicular development, the ovaries are stimulated with a low starting dose of FSH (75 IU).<ref name="PMID20416867"><pubmed>20416867</pubmed></ref> Studies suggests that a minimum gonadotropin dose lowers OHSS risk and thus a step-up regimen is utilised to achieve an ovarian response, whereby the FSH dosage is increased every 7 days until follicular development of greater than 10mm is noted <ref name="PMID26074966" />. Alternatively, a step-down regimen may be followed, whereby a high initial FSH dosage is lowered according to the ovarian response. Another method to increase FSH levels during OI, is through Aromatase Inhibitors which promote folliculogenesis by increasing pituitary secretion of FSH, and downregulate oestrogen production through a negative feedback loop. However, Aromatase Inhibitors have not been shown to reduce OHSS incidence in comparison to other methods of OI. During OI, a key objective is to prevent early cycle cancellation due to premature luteinisation from pituitary secretion of LH. In order to downregulate LH secretion, Gonadotropin-releasing hormone agonists (GnRHa) are administered in addition to gonadotropins. The duration of exposure to gonadotropins and subsequent risk of OHSS may also be minimised through mild stimulation protocols which administer FSH only in the mid to late follicular phase.<ref name="PMID20416867" />

'''Adjuvant Metformin Therapy'''

Adjuvant Metformin Therapy has been found to lower the risk of OHSS by 63% <ref name="PMID25406011"><pubmed>25406011</pubmed></ref>. It involves the administration of metformin at a daily dosage of 1000 to 2000mg, 2 months prior to Controlled Ovarian Stimulation <ref name="PMID26074966"/>. Metformin lowers the elevated insulin levels in PCOS which consequently reduce intraovarian androgen levels. This leads to a reduced sensitivity and expression of granulosa cell-follicle stimulating hormone receptors which result in a less exaggerated response to gonadotropins. Furthermore, it is suggested that Metformin prevents OHSS by controlling vascular permeability through the inhibition of various vasoactive molecules, including VEGF.

'''Avoiding hCG during Luteal Phase Support

Following Controlled Ovarian Stimulation, the steroid levels of E2 and P4 are reduced during the luteal phase due to the negative feedback on the pituitary. This leads to low endogenous LH levels, which consequently reduce endometrial receptivity as well as the luteal phase duration itself. As a result, implantation and pregnancy rates are reduced and early pregnancy loss rates are increased.<ref name="PMID20416867" /> Luteal Phase Support (LPS) serves to combat these adverse events with the use of hCG. However, hCG has been found to increase the risk of OHSS. Alternatively, the use of progesterone has been found to not only halve the risk of OHSS, but also induce similar improvements in pregnancy and miscarriage rates as hCG.<ref name="PMID26148507"><pubmed>26148507</pubmed></ref>

===Secondary Prevention===

Secondary Prevention aims to prevent progression to OHSS once COS has been initiated and the patient has been found to mount an exaggerated response. <ref name="PMID20416867" />

'''Coasting'''

Coasting is a first-line secondary preventative strategy. It consists of the withdrawal of gonadotrophins when a critical number of follicles and/or E2 concentration is reached. hCG is administered once the E2 concentration reduces to a safe level, before the process of oocyte retrieval commences. This preventative strategy is conducted for a period of less than 3 days in order to avoid compromising IVF outcomes.

'''Cryopreservation'''

Cryopreservation of embryos after oocyte retrieval is another avenue which may avert OHSS progression. The cryopreserved embryos are only reimplanted once the patient's hormone serum levels have normalised. Using oocyte vitrification, crystal formation within embryo tissue is avoided and so cryopreserved embryos have been found to produce better pregnancy rates with a 32% increase, than fresh embryo transfer. Recent studies suggest cryopreservation itself does not reduce OHSS rates, but must be followed by a GnRHa trigger to avert OHSS.

'''Cycle cancellation'''

Cycle cancellation is a guaranteed method to prevent early OHSS whereby hCG is withheld. This is a last resort strategy as it carries the risk of significant psychological distress and financial loss for the patient.

</div>

==Effect on the Newborn==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

</div>
Women who develop OHSS while undergoing Assisted Reproductive Technologies (ART) treatment are not only more likely to achieve a pregnancy, but have a live birth as the pregnancy outcome. This live birth is also more likely to be a multiple birth of two, three or more children. <ref name="PMID19591989"><pubmed>19591989</pubmed></ref> It has been postulated that a multifetal pregnancy leads to a more rapid increase in hCG levels, resulting in an increased risk of OHSS. However, the causal nature between multifetal pregnancy and OHSS development is disputed and further research is required to distinguish correlation from causation. <ref name="PMID19573292"><pubmed>19573292</pubmed></ref>

OHSS development is also associated with an increased risk of adverse outcomes including stillbirth, premature birth and low birthweight.<ref name="PMID19591989" /> Although the cause for the increased risk in adverse pregnancy outcomes is unknown, it is suggested that as the incidence of OHSS is reduced through various prevention strategies, the risk of such outcomes may be also be reduced.

==Genetics==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

Despite OHSS typically being of iatrogenic origin as a result of ovarian stimulation with gonadotropins, research has been conducted into the potential genetics behind OHSS as many sporadic and familial cases have been observed. '''Mutations''' in the receptor for hormones such as Follicle Simulating Hormone (FSH), Lutenizing Hormone (LH) and hCG have all been targets of OHSS genetics research. Interestingly, they too also arise from a common ancestral gene.

===Follicle Stimulating Hormome===

Dr. Botros Rizk, of the University of South Alabama College of Medicine <ref name="PMID19573286"><pubmed>19573286</pubmed></ref>, has written extensively regarding the genetics behind OHSS. In particular, he talks about '''FSH receptors''' (FSHR) and their role in the syndrome. He hypothesises that mutations in these receptors could be activating or inactivating, leading to an increased risk of developing OHSS or sterility respectively. Currently, 744 single nucleotide polymorphisms (a type of mutation) have been found in the gene encoding the FSHR, 8 of which are located in its exons (coding regions of the gene). How the ovary responds is resultant on the FSHR genotype. For example, Ser680Asn, a polymorphism in the FSHR gene has been shown to aid in predicting the severity of a woman's OHSS. Ordinarily FSH stimulates the growth of ovarian follicles, however, when mutated, it is stimulated by the hCG resulting in excessive follicle development.

Spontaneous OHSS, OHSS that arises and cannot be attributed to any form of ovarian stimulation or Assisted Reproductive Technology, has been linked to activating mutations in the FSHR <ref name="PMID23499866"><pubmed>23499866</pubmed></ref>. This familial disorder is an autosomal dominant one. In most cases the FSHR can be stimulated by the presence of Thyroid Stimulating Hormone (TSH) or hCG, in the absence of FSH (the ligand for FSHR).

===Lutenizing Hormome===

The '''Lutenizing Hormone Receptor''' (LHR) gene in humans is comprised of 11 exons. Animal studies have shown that many primates exhibit a similar gene which is comprised of only 10 exons, however a gene lacking the 10th exon has been identified and termed the type 2 LHR. Expression of the type 2 LHR has been seen in humans. The type 2 LHR, compared to the wild-type LHR appears to be repaired with regard to its function. Defects in the type 2 LHR include a decrease in efficiency of transport to the plasma membrane and irregularities in signal transduction. Inactivating mutations in the LHR have been seen to cause infertility in women as well as amenorrhoea. Activating LHR gene mutations are asymptomatic and are not associated with OHSS in women.

===Bone Morphogenic Protein===

An imporant growth factor, derived from oocytes called '''BMP-15''' (Bone Morphogenic Protein 15) is vital for female fertility. It belongs to the family of growth factors, Transforming Growth Factor β (TGF-β) and is heavily involved in folliculogenesis. It has been found that mutations in the BMP-15 gene caused infertility in female sheep. Conversely, it has also been indicated in enhanced fertility when BMP-15 is present is high amounts in follicular fluid <ref name="PMID19573286" />.

A case study done by Hanevik ''et. al.'' in 2013 <ref name="PMID21565556"><pubmed>21565556</pubmed></ref> found that a Single Nuclear Polymorphism (SNP) in the BMP-15 gene is responsible for a high response to ovarian hyper-stimulation. The aim of the study was to test the effect the SNP had on BMP-15 with regard to high and low responders buy taking blood from 53 high responders, 38 low responders and 100 non-responders (controls) and analysing 5 noted SNP's. Results from their study showed a correlation between a high response to ovarian hyper-stimulation and the BMP-15 9G allele. The article does state however, that further research is required into the molecular effects of SNP's on the function of BMP-15.

===Vascular Endothelial Growth Factor===

'''Vascular endothelial growth factor''' (VEGF) has been indicated as one of the key agents causing vascular permeability and subsequent ascites in OHSS. The gene, which is located on chromosome 12, is made up of 8 exons (coding regions), of which exons 6 and 7 do not always appear due to the exons being spliced out.The splicing of this gene allows for various isoforms of the gene to exist of which VEGF 121 and 165 appear to play a role in angiogenesis. There are two VEGF Receptors, VEGFR-1 and VEGFR-2 that belong to the tyrosine kinase family of receptors (for more information on VEGF see [[Pathophysiology]]). Because of its distinct role in OHSS, it has been targeted as an area for research for potential treatments. The idea is that if the genetic expression of VEGF and its receptors can be controlled, OHSS can be avoided or treated.<ref name="PMID19573286" />

A different study by Hanevik ''et. al.'' , <ref name="PMID22587628"><pubmed>22587628</pubmed></ref> done in 2012 involved analysing blood samples from 53 women with OHSS and 100 women without it (controls) and analysing 6 SNP's in the VEGFR2 gene to find any genetic variations. They found a correlation between women with the VEGF +405cc genotype and the development of OHSS indicating women that undergo controlled ovarian hyper-stimulation and posses his genotype, are at an increased risk of developing OHSS.

</div>

== Current Research on Animal Models==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">
{|
|-bgcolor="F8E0F1"
|
<span style="font-size:120%">'''Inhibition of Cyclooxygenase-2 (COX-2) by Meloxican decreasing the incidence of OHSS in Rat Model'''</span> <ref name="PMID18166186"><pubmed>18166186</pubmed></ref>

Reasearch was carried out to investigate the effects of selective inhibition of the enzyme COX-2 on the Ovarian Hyperstimulation Syndrome (OHSS) using Female Wistar rates as the subjects. The research aimed to find results by measuring the number of antral and luteinized follicles, ovarian weight, vascualr endothelial growth factors and COX-2 immunohistochemistry. The rats being tested were all 22 days old and were divided into four equal groups;

'''Group 1 (Control group)''' was subject to a 0.1 ml of Intraperitoneal Saline from days 22 ~ 26

'''Group 2 (Mildly-stimulated group)''' subject to 10IU of pregnant mare serum gonadotrophin (PMSG) on day 24 and then 10IU of Human Chorionic Gonadotrophin (hCG) on day 26

'''Group 3 (OHSS positive group)''' was subject to 10IU of PMSG from days 22 ~ 26 and then administered 30IU of hCG on day 26 to induce OHSS

'''Group 4 (OHSS positive variant group)''' received 15mg/ml of Meloxicam 2 hours prior to administration of 10IU PMSG from days 22 ~ 26

Results showed there was no difference in ovarian weight in samples from Group 1 and Group 2, however Group 3 showed signs of significant ovarian weight increase which in group 4 was suppressed by the introduction of Meloxicam. No differences were observed in the number of antral follicles amongst the four test groups. Results from Group 2 and Group 3 showed that the granulosa cells of preovulatory follicles and the stromal cells were highly VEGF immunoreactive, however the Meloxicam treated Group 4 showed less immunoreactivity than Group 2 and Group 3 which indicated the correlation between Meloxicam and the diminished VEGF expression. Group 3 presented an increased COS-2 immunoreactivity which was highly diminished than in Group 4.

The research concluded that in a rat model, the enzyme Meloxicam has a beneficial effect on OHSS by reducing the increase of ovarian weight and the expression of VEGF associated with OHSS, the effects of which may be mediated by the inhibitory capacity of COX-2 on Meloxicam
|}

{|
|-bgcolor="FF99FF"
|
<span style="font-size:120%">'''Inhibition of Ovarian VEGF secretion by activation of Dopamine Receptor 2'''</span> <ref name="PMID25217874"><pubmed>25217874</pubmed></ref>

This research was carried out to investigate a possibility in whether a Dopamine Receptor 2 agonist '''(D2-ag)''' can assist in the prevention of Ovarian Hyperstimulation Syndrome, using rat models, by decreasing the ovarian vascular endothelial growth factor '''(VEGF)''' production. Using Immature Wistar rats (22 days old) as their animal model, the rats were initially stimulated with Gonadotrophins to mimic the onset and effects of OHSS and then subjected to treatment with a D2-agonist and/or a D2-antagonist (D2-ant). The vascular permeability was measured at the endpoint after day 26 by measuring the peritoneal extravasion of a previously injected dye and ovaries from all subjects were collected to assess the effects of D2-ag and D2-ant on the production of Ovarian VEGF. The expression of VEGF mRNA was measured by quantitative real time PCR and the levels of VEGF proteins were measured by Western Blots.

Results showed that the D2-ag caused a large reduction in the vascular permeability which was in turn associated with the great decreased in VEGF protein production in the OHSS rat ovaries, whereas the introduction of D2-ant showed opposite results with a increase in the vascular permeability leading to the increase of VEGF protein production in the ovaries. Ovarian VEGF mRNA levels were found to be unaffected by the introduction of these drugs in OHSS rat subjects. Conclusions were drawn on the fact that Dopamine Receptor 2 agonists prevent the increase of vascular permeability in subjects with OHSS by decreasing the ovarian production of VEGF and also that due to the dose-dependent inhibitory effect of the D2-ag on ovarian VEGF, current OHSS therapies used in humans can benefit by increasing the intraovarian concentration of D2-ag.
|}
</div>

==Glossary==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

'''Ascites'''- An accumulation of fluid in the peritoneal cavity with resultant abdominal swelling

'''Cabergoline''' - A dopamine receptor agonist used to treat hormone imbalance.

'''GnRH antagonist''' - Gonadotropin Releasing Hormone - A class of compounds that are similar in terms of the structure of natural Gonadotropin Releasing Hormone but has a antagonistic effect.

'''hCG'''- Human Chorionic Gonadotropin

'''Hemoconcentration'''- An increase in the concentration of circulating red blood cells in response to a decrease in blood plasma volume

'''Hypovolemic'''- A decrease in circulating blood volume

'''Iatrogenic'''- Illness caused as a result of a medical examination or treatment

'''Intravenous fluids''' - Is the infusion of liquid substances directly into a vein.

'''IVF'''- In-vitro Fertilization

'''NSAID'''- Non-steroidal Anti-Inflammatory Drug e.g. Ibuprofen

'''OHSS'''- Ovarian Hyper-stimulation Syndrome

'''FSH''' - Follicle Stimulating Hormone

'''LH''' - Luteinizing Hormone

'''Oliguria'''- Decreased urine output/small amounts of urine produced

</div>

==References==

2015 Group Project 2

2015-10-22T20:49:37Z

Z3372824: /* Causative Agents */

{{ANAT2341Project2015header}}

==<span style="font-size:120%">'''Ovarian Hyper-stimulation Syndrome (OHSS)'''</span>==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

Ovarian Hyper stimulation Syndrome (OHSS) is an iatrogenic complication of '''Assisted Reproduction Technology''' (ART), in which women take medications to stimulate oocyte growth. It is generally identified by cystic enlargements of the ovaries and fluid accumulation in the peritoneal cavity due to the increased capillary permeability and ovarian neoangiogenesis <ref name="PMID22065820"><pubmed>22065820</pubmed></ref>. It is an occurrence which is dependent on the controlled stimulation of the ovaries in preparation for IVF i.e. administration of human Chorionic Gonadotropin (hCG).

OHSS was first described in 1943 as ''“syndrome d’hyperluteinisation massive
des ovaries”''. It was during this time that gonadotropins were prepared from animals such as sheep to bring on ovulation in women. The first recorded death as a result of OHSS occurred in 1951 and was due to renal failure as a result of oligouria, a complication of the syndrome <ref name="OHSS"> Marie M. Budev, DO, MPH; Alejandro C. Arroliga, MD; Tommaso Falcone, MD, [ http://utilis.net/Morning%20Topics/REI/Ovarian%20Hyperstimulation.pdf ], 'Ovarian Hyperstimulation Syndrome'</ref> <ref name="PMID12638783"><pubmed>12638783</pubmed></ref>.

<span style="color:#FA58D0">This wikipage aims to provide clear information on various areas surrounding OHSS such as diagnosis, prevention and complications and will look into the genetics behind the disorder and the various animals models used to research it.</span>

<html5media height="350" width="450">https://www.youtube.com/watch?v=aXmjJw234a4</html5media>

'''Overview of the Ovarian Hyperstimulation Syndrome''' <ref> Howcast (2013, August 27) Ovarian Hyperstimulation Syndrome | Infertility. Retrieved from https://www.youtube.com/watch?v=aXmjJw234a4</ref>

</div>

==Epidemiology==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

Ovarian Hyper-Stimulation Syndrome (OHSS) rarely occurs sporadically, and if it does, it is usually the result of an underlying genetic problem. The majority of OHSS is due to the ovaries being stimulated to mature and release an abundance of oocytes, in response to hormones Human Chorionic Gonadotropin (hCG) and Follicle Stimulating hormone (FSH), during IVF. Rarely, Clomifene Citrate therapy can cause OHSS.<ref name="WikiOHSS"> Wikipedia, [ https://en.wikipedia.org/wiki/Ovarian_hyperstimulation_syndrome ], 'Ovarian Hyperstimulation Syndrome'</ref>

OHSS only affects '''0.5-5%''' of women undergoing Ovarian Hyper-stimulation, but despite its small prevalence, it is a potentially fatal outcome of a non-vital procedure and remains a prevalent problem for fertility specialists <ref name="PMID12498425"><pubmed>12498425</pubmed></ref> <ref name="PMID12638783"><pubmed>12638783</pubmed></ref>. Age has been cited as a factor affecting those with OHSS, with younger women more at risk. Additionally, women with allergies were seen to have a higher incidence of OHSS. It is important to note that at this point in time, there is no positive correlation between gonadotropin dose and OHSS.

Of the 0.5-5% of women affected with OHSS mentioned above, 2% of those women will require hospitalisation. As of 2011, it has been reported that the incidence of OHSS was '''increasing''', resulting in approximately 3 deaths per 100,000 women undergoing ovarian stimulation per year <ref name="PMID21828116"><pubmed>21828116</pubmed></ref>. This is particularly worrying as in 2008, in the United States alone, there were around 150,000 IVF cycles undertaken.

{|
|-bgcolor="F8E0F1"
|
'''With the field of Assisted Reproductive Technologies expanding and more women partaking in IVF treatments, the threat of women developing OHSS is an ongoing and increasing one''' <ref name="PMID21828116" />.
|}
{| class="wikitable mw-collapsible mw-collapsed"
! Characteristics of women by complication group <ref name="PMID19591989"><pubmed>19591989</pubmed></ref>
|-
! scope="col" width="100px" height="60px" style="text-align:center| '''Characteristic'''
! scope="col" width="100px" height="60px" style="text-align:center| '''No Complications
(N = 212,041)'''
! scope="col" width="100px" height="60px" style="text-align:center| '''Moderate OHSS
(N = 1,523)'''
! scope="col" width="100px" height="60px" style="text-align:center| '''Severe OHSS
(N = 655)'''
|-
|style="text-align:center; background: #FF99FF;"| '''Maternal Age (Mean ± SD)'''
|style="text-align:center; background: #F6CEEC;"| 35.6 ± 4.6
|style="text-align:center; background: #F6CEEC;"| 33.0 ± 4.3
|style="text-align:center; background: #F6CEEC;"| 33.1 ± 4.4
|-
|style="text-align:center; background: #FF99FF;"| '''Maternal Age (%)'''
|-
|style="text-align:left; background: #F6CEEC;"| <30 years
|style="text-align:center; background: #F6CEEC;"| 10 %
|style="text-align:center; background: #F6CEEC;"| 21.1 %
|style="text-align:center; background: #F6CEEC;"| 20.6 %
|-
|style="text-align:left; background: #F6CEEC;"| 30-34 years
|style="text-align:center; background: #F6CEEC;"| 30.4 %
|style="text-align:center; background: #F6CEEC;"| 43.2 %
|style="text-align:center; background: #F6CEEC;"| 40.5 %
|-
|style="text-align:left; background: #F6CEEC;"| 35-39 years
|style="text-align:center; background: #F6CEEC;"| 37.8 %
|style="text-align:center; background: #F6CEEC;"| 27.2 %
|style="text-align:center; background: #F6CEEC;"| 32.5 %
|-
|style="text-align:left; background: #F6CEEC;"| >40 years
|style="text-align:center; background: #F6CEEC;"| 21.8 %
|style="text-align:center; background: #F6CEEC;"| 8.4 %
|style="text-align:center; background: #F6CEEC;"| 6.4 %
|-
|style="text-align:center; background: #FF99FF;"| '''Nulligravida (%)'''
|style="text-align:center; background: #F6CEEC;"| 45.8 %
|style="text-align:center; background: #F6CEEC;"| 51.5 %
|style="text-align:center; background: #F6CEEC;"| 51.8 %
|-
|style="text-align:center; background: #FF99FF;"| '''Infertility Diagnosis (%)'''
|-
|style="text-align:left; background: #F6CEEC;"| Male factor
|style="text-align:center; background: #F6CEEC;"| 37.7 %
|style="text-align:center; background: #F6CEEC;"| 41.0 %
|style="text-align:center; background: #F6CEEC;"| 33.4 %
|-
|style="text-align:left; background: #F6CEEC;"| Endometriosis
|style="text-align:center; background: #F6CEEC;"| 13.5 %
|style="text-align:center; background: #F6CEEC;"| 13.5 %
|style="text-align:center; background: #F6CEEC;"| 10.7 %
|-
|style="text-align:left; background: #F6CEEC;"| Ovulation Disorders
|style="text-align:center; background: #F6CEEC;"| 14.0 %
|style="text-align:center; background: #F6CEEC;"| 29.5 %
|style="text-align:center; background: #F6CEEC;"| 22.4 %
|-
|style="text-align:left; background: #F6CEEC;"| Diminished ovarian reserve
|style="text-align:center; background: #F6CEEC;"| 16.9 %
|style="text-align:center; background: #F6CEEC;"| 3.2 %
|style="text-align:center; background: #F6CEEC;"| 2.4 %
|-
|style="text-align:left; background: #F6CEEC;"| Tubal factors
|style="text-align:center; background: #F6CEEC;"| 20.4 %
|style="text-align:center; background: #F6CEEC;"| 22.6 %
|style="text-align:center; background: #F6CEEC;"| 22.3 %
|-
|style="text-align:left; background: #F6CEEC;"| Uterine factors
|style="text-align:center; background: #F6CEEC;"| 5.1 %
|style="text-align:center; background: #F6CEEC;"| 4.3 %
|style="text-align:center; background: #F6CEEC;"| 3.1 %
|-
|style="text-align:left; background: #F6CEEC;"| Other factors
|style="text-align:center; background: #F6CEEC;"| 13.9 %
|style="text-align:center; background: #F6CEEC;"| 13.1 %
|style="text-align:center; background: #F6CEEC;"| 10.4 %
|-
|style="text-align:left; background: #F6CEEC;"| Unexplained factor
|style="text-align:center; background: #F6CEEC;"| 12.7 %
|style="text-align:center; background: #F6CEEC;"| 11.8 %
|style="text-align:center; background: #F6CEEC;"| 18.6 %
|-
|}
</div>

==Causative Agents==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

[[File:Follicular Development.jpeg|right|500px|alt=Infertility treatments aim to facilitate follicular development to improve chances of fertilisation]]

Normally a woman produces one egg per month from the ovaries, which travel down the Fallopian tube to be fertilized or be released from the body. In cases where women have difficulty falling pregnant, they are given medication which help them to produce and release eggs (as shown in the diagram to the right), further increasing their chances of fertilization and pregnancy <ref><pubmed>19573285</pubmed></ref>. Ovarian Hyper stimulation Syndrome generally occurs during infertility treatments when the ovaries are overstimulated by the fertility medication which causes the ovaries to swell and leak fluids into the belly and abdomen. The prevalence of OHSS onset is linked with excessive number of follicle development in response to the administration of injectable Follicle Stimulating Hormones (FSH) followed by the '''Human Chorionic Gonadotrophins''' (hCG) which triggers the release of the oocytes <ref><pubmed>26190539</pubmed></ref>.

'''Follicle Stimulating Hormones''' (FSH) <ref name="PMID9020850"><pubmed>9020850</pubmed></ref> are glycoprotein hormones that are produced and secreted from the Anterior Pituitary gland into the bloodstream, which regulate the developmental, growth, maturation and the reproductive processes within the body. In females, the Follicle Stimulating Hormones initiates the stages of growth and development of immature ovarian follicles within the ovaries before the release of an egg from a follicle at ovulation. When FSH is administered to a patient who is suffering from infertility, the increase FSH levels affect the rate of development and production, in turn increasing the amount of follicles which are ready to be released during ovulation.

</div>

==Symptoms==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

OHSS is classified based on a criteria from mild, moderate and severe <ref name="WikiOHSS" />:

'''Mild Symptoms'''- abdominal bloating, minimal weight gain, nausea, diarrhoea and a feeling of fullness.

'''Moderate Symptoms'''- Substantial weight gain (on average 2 or more pounds a day), increased abdominal girth, darkend urine and excessive thirst in addition to the mild symptoms.

'''Severe Symptoms'''- In addition to the symptoms associated with Mild and Moderate OHSS, in severe OHSS, you see shortness of breath, calf and chest pains and pleural effusion.

<span style="font-size:100%">'''Classifications of Ovarian Hyper-stimulation Syndrome:'''</span> <ref name="PMID22065820"><pubmed>22065820</pubmed></ref>
{| class="wikitable" style="text-align:center
|-
! scope="col" width="70px"| '''Classification'''
! scope="col" width="650px"| '''Symptoms'''
|-
|style="text-align:center; background: #F6CEEC;"| '''Mild'''
|style="height: 60px; background: #F6CEEC;"| '''Grade 1''' - Abdominal distention and discomfort
'''Grade 2''' - Abdominal distention, discomfort with nausea, vomiting and/or diarrhea and ovarian enlargement from 5~12cm
|-
|style="text-align:center; background: #F8E0F1;"| '''Moderate'''
|style="height: 60px; background: #F8E0F1;"| '''Grade 3''' - All features of Mild OHSS with ultrasonographic evidence of ascites
|-
|style="text-align:center; background: #F6CEEC;"| '''Severe'''
|style="height: 60px; background: #F6CEEC;"| '''Grade 4''' - All features of Moderate OHSS with the addition of clinical evidence of ascites and breathing difficulties present
'''Grade 5''' - All of the above symptoms along with a change in the blood volume, increased blood viscosity due to coagulation and diminished renal function
|}

</div>

==Diagnosis==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

Whilst symptoms of OHSS can occur as soon as 24 hours post hCG administration, they are usually seen in women 7-10 days post administration. Initially women with OHSS will present with abdominal bloating, as a result of fluid in the peritoneal cavity and an increase in ovary size. When women present with severe OHSS they are often dehydrated, due to increased vascular permeability, and have hemoconcentration. The above results in a decrease in intravascular volume, leading to oligouria <ref name="PMID22416285" />.

===History===

Initially a thorough history of the patient is taken during which the clinician looks for evidence of ovarian stimulation, followed by ovulation. During this history taking, the clinician will inquire into any weight gain noticed, urine output, and the woman's ability to maintain oral hydration. A key diagnostic tool for clinicians regarding women who are taking gonadotropins is to identify if they are at an increased risk of developing OHSS. Some risk factors include woman aged less than 30, women who have polycystic ovaries, woman with a previous history of OHSS and women who have had greater than 20 oocytes retrieved <ref name="PMID22416285" />.

===Physical Exam===
[[File:Vaginal_Ultrasonography_in_Sagittal_Plane.jpg|right|thumbnail|600px|Vaginal Ultrasonography in Sagittal plane <ref name="Wikiversity Journal of Medicine"> Häggström, Mikael. "Medical gallery of Mikael Häggström 2014". Wikiversity Journal of Medicine 1 (2). DOI:10.15347/wjm/2014.008. ISSN 20018762</ref>]]
After a history of the patient is taken, the next step is to perform a physical exam on the patient. Women who present with abdominal bloating will produce a shifting dullness upon abdominal percussion. Additionally the clinician will test the woman's vital signs, measure her abdominal girth, weight and will look for evidence of ascites or increase in calf size (usually unilateral)<ref name="PMID22416285" />.

===Investigations===

If the clinician further suspects a women of having OHSS, various investigations can be done such as an ultrasound.The intraperitoneal fluid is best imaged via vaginal ultrasound due to the enlarged ovaries making it difficult to image the pelvis using transabdominal ultrasound. The clinician can also order laboratory testing to look for urine specific gravity and and complete blood count to look for hemoconcentration with a hematocrit. Additionally, liver function tests can be ordered to look for elevated function. The clinician will also look for evidence of elevated D-dimers and fibrinogen and decreased levels of anti-thrombin 3 <ref name="SAHealth"> Government of South Australia Health [ http://www.sahealth.sa.gov.au/wps/wcm/connect/9b61ed004ee5348da663afd150ce4f37/Ovarian-hyperstimulation-syndrome-WCHN-PPG-17072012.pdf?MOD=AJPERES&CACHEID=9b61ed004ee5348da663afd150ce4f37 ], 'South Australian Paediatric Clinical Guidelines OHSS'</ref>.

====Ultrasound====

Typical appearances of the ultrasound include <ref name="Ultrasound"> Radiopaedia [ http://radiopaedia.org/articles/ovarian-hyperstimulation-syndrome-1 ], 'Ovarian Hyperstimulation Syndrome'</ref>:

*Bilaterally and symmetrically enlarged ovaries (>12cm)
* "Spoke-Wheel appearance" - presence of multiple cysts of varying size
*May also see ascites (fluid)

===Severity===

Once a clinician has deduced a women is suffering from OHSS, the severity of their condition needs to be established as either mild, moderate or severe. This is done by referring to the criteria under the sub-heading [[Symptoms]].The subsequent course of treatment for the woman will be based upon this evaluation.

{|
|-bgcolor="F6CEEC"
|
'''Further investigations''' can be done including a Chest X-ray to check for pleural effusions and oedema and USS with Doppler's to check for ascites or possible ovary torsion. <ref name="PMID22416285"><pubmed>22416285</pubmed></ref>
|}

===Differential Diagnosis===

Conditions presenting with similar symptoms or ultrasound images include <ref name="Ultrasound" />:

*Polycystic Ovaries (PO)
:: The difference is that with PO is that the cycts are typically smaller than OHSS cysts and there is no evidence of ascited or pleural effusion
*Mucinous Ovarian Malignancy
:: A type of Ovarian Epithelial tumour
*Ectopic Pregnancy <ref name="Casereport"> Australian Medical Student Journal [ http://www.amsj.org/wpcontent/uploads/files/articles/amsj_v2_i1/AMSJ_v2_i1_pg58-60.pdf ], 'Ovarian hyperstimulation syndrome'</ref>
::A pregnancy in which the foetus develops outside of the uterus e.g. in the fallopian tube

</div>

==Pathophysiology==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

[[File:Pathogenesis_of_OHSS.png|600px|thumb|Pathogenesis of OHSS <ref name="PMID20416867"><pubmed>20416867</pubmed></ref>]]

The definition of Ovarian Stimulation is enlarged ovaries with many luteinized cysts, that can present with secondary complications. What distinguishes Ovarian Stimulation from OHSS is the presence of vascular hyper-permeability that results in fluids being redirected elsewhere in the body.

The key process to OHSS appears to be caused by '''Vascular Endothelial Growth Factor''' (VEGF), that is released along with other cytokines, estrogen and progesterone, due to the ovary undergoing luteinization as a result of stimulation by hCG. VEGF increases vascular permeability and as a result the capillaries become more "leaky" to the fluids in them. These fluids can then escape the capillaries and accumulate in the pleural and abdominal cavities as ascites. The woman then becomes hypovolemic and is at an increased risk of circulatory, renal and respiratory issues such as arterial thromboembolism due to the thickening of the blood. Note, the blood is thickened as fluid is leaving the capillaries, leaving behind red blood cells and other cellular components of the blood <ref name="WikiOHSS" />.

The increase in expression of VEGF and VEGF Receptor 2 (VEGFR2) is attributed to the greatly increased amount of their mRNA present in the body after stimulation with hCG <ref name="PMID21082502"><pubmed>21082502</pubmed></ref>. VEGF interacts with VEGF2 and VEGF Receptor 1 (VEGFR1) to create a strong angiogenic effect. Both VEGFR2 and VEGFR1 belong to a family of receptors called tyrosine kinases. VEGF2 is involved in the regulation of angiogenesis and vascular permeability whilst VEGF1 has a slightly contradictory role in that is is involved in the maintenance of the tight junctions between endothelial cells in blood vessels. A study by Gómez ''et. al.'' <ref name="PMID21082502" /> showed that women experiencing OHSS had substantially higher plasma levels of VEGF and lower levels of VEGFR1.

</div>

==Complications==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

Ovarian torsion or rupture, renal insufficiency and thrombophlebitis can all complicate OHSS. If a pregnancy occurs, symptoms may persist longer than the usual 1 to 2 weeks and become more severe, however, even with severe OHSS, they do not extend past the first trimester <ref name="WikiOHSS" />.

<span style="color:#FA58D0"> '''1-2% of women who suffer from ovarian stimulation develop a severe form of OHSS''' </span>. Complications from severe OHSS include:

*Fluid collection in the abdomen
*Electrolyte disturbances (sodium and potassium)
*Kidney failure
*Ovary twisting
*Rupture of a cyst in an ovary
*Breathing problems
*Blood clots in large vessels (most commonly the legs)
*Pregnancy loss from miscarriage or termination
*Rarely, death

A study by Nouri ''et. al.'' <ref name="PMID24996451"><pubmed>24996451</pubmed></ref> found that women with '''Polycystic Ovarian Syndrome''' (PCOS) and those that were induced with hCG experienced longer recovery times from severe OHSS than women who were not pregnant. They looked at a cohort of women hospitalised for the first time with severe OHSS and subject them to the same treatments. Based on a defined criteria, they established the recovery time of these women and compared the times between those that were pregnant to those that were not pregnant. They also found that whether a woman had PCOS or ovulation induction did not affect her risk of developing OHSS if she was not pregnant. It is only a risk factor for pregnant women.

===Thromboembolic events===

A frequent and deadly complication of OHSS are thromboembolic events due to increased blood clotting. This increase in blood clotting has been attributed to a variety of complications such as hemoconcentration (which thickens the blood), hypolvolemia and an increase in the permeability of blood vessels as a result of increased vasoactive substances in the body of ovarian origin. Thromboembolic events include venous thromboses often in the upper extremities and arterial thromboses such as those in the cerebrovascular region. These events can lead to amputations of extremities, brain damage, miscarriage and death. To avoid this, anti-coagulants are given to pateitns with OHSS and they are fitted with compression stockings (see [[Treatment]]) <ref name="PMID23378404"><pubmed>23378404</pubmed></ref>.

{|
|-bgcolor="F8E0F1"
|
The risk of a woman developing OHSS is higher if she is having a '''twin pregnancy''', as she is exposed to higher concentration of hCG. <ref name="PMID9756273"><pubmed>9756273</pubmed></ref>
|}

</div>

==Treatment==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

'''General treatment
'''
*''Acetaminophen'' with or without a narcotic agent- used to treat abdominal discomfort
*Women are encouraged to drink 2-3 litres of water a day to prevent hemoconcentration
*Women are advised to avoid sexual intercourse and vigorous exercise at the risk of torsion or rupture of the ovaries
*NSAID's with anti-platelet properties should NOT be used as they may effect renal function in a women with OHSS
*Patients with significantly painful ascites or breathing problems may undergo ''Paracentesis'' (drainage of the ascites)
*''Culdocentesis'' (extraction of fluid from recto-uterine pouch) can be done to decrease the likelihood of a woman with moderate OHSS progressing to severe OHSS.<ref name="PMID22416285" />

===Mild to Moderate OHSS===

Mild OHSS can often resolve on its own, however, moderate OHSS may include treatments such as<ref name="WikiOHSS" />:

*Anti-nausea medication and prescription painkillers
*Regular physical examinations and ultrasounds
*Daily weigh-ins and waist measurements
*Measuring the amount of urine produced each day
*Frequent blood tests for monitoring dehydration and electrolyte imbalance
*Maintaining a high balance of fluids
*Drainage of excess abdominal fluid by inserting a needle in the abdominal cavity
*Wearing support stockings which help prevent blood clots/thrombosis

===Severe OHSS===

Severe OHSS requires hospital care in order for constant monitoring and treatment such as <ref name="WikiOHSS" />:

*Intravenous fluids with a crystalloid solution (100-150mL/hr)
*Intravenous Albumin is administered is IV fluids are insufficient (15-20mL/hr of 25% albumin for 4 hrs)
*In addition to Acetaminophen, ''Opioid analgesics'' can be administered for pain relief
*''Antiemetics'' can be used to subside nauseas and/or vomiting
*Woman administered to hospital of OHSS are considered at high risk of thromboembolic complications and are given low molecular weight ''heparin'', an anti-coagulant
*''Cabergoline''- lessens OHSS symptoms
*''GnRH agonist''- suppresses ovarian activity
**If at risk of OHSS, alternates include using a GnRH agonist instead of hCG however its effects on pregnancy rates are questionable. Using a GnRH agonist to replace the use of hCG for final oocyte stimulation will see a 6% decrease in delivery rate.

*Daily monitoring of creatine, urea, creatine clearance C-reactive protein (to rule out infection) are all required in combination with weekly tests such as liver and renal function tests and chest x-rays (to check for pleural effusion) <ref name="PMID12638783" />.

If there are serious complications then additional treatments are required:

*Surgery for a ruptured ovarian cyst
*Intensive care for the liver or lung complications

====Paracentesis====

For women with severe/grade 3 OHSS, paracentesis, the removal of fluid from the body using an aspiration needle, can be undertaken. It is a diagnostic and a therapeutic method that can be done trans-abdominally and trans-vaginally. It is used to relieve symptoms, improve haemodynamics e.g. Urinary output, and shorten the women's hospital stay. Complications of paracentesis include bleeding, infection and organ injury, however are note common <ref name="Paracentesis"> S. Monica Soni, HMS 3, Gillian Lieberman, MD [ http://eradiology.bidmc.harvard.edu/LearningLab/genito/Soni.pdf ], 'Ovarian Hyperstimulation Syndrome'</ref>.

{|
|-bgcolor="F8E0F1"
|
The most important aspect of treatment for any women with OHSS is close and constant '''monitoring''' with her healthcare professional. Counselling may also be provided to women and their partners or families in order to provide them with the best possible knowledge base to manage and treat their OHSS. It is important to note that there is '''no one cure or treatment''' for OHSS. Treatment involves managing and eliminating the symptoms until such time as the syndrome resolves itself <ref name="WikiOHSS" />.
|}

</div>

==Prevention==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

There are three key avenues through which the incidence of OHSS may be prevented. These include identifying risk factors to predict OHSS development, modifying treatment regimes on the basis of the identified risk factors and intervention to prevent progression to OHSS once the patient has undergone Controlled Ovarian Stimulation.

=== Risk factors===

'''Primary risk factors'''

Pre-existing factors likely to exacerbate the ovarian stimulation response. Primary risk factors include <ref name="PMID26074966"><pubmed>26074966</pubmed></ref>:

*Young age
*Low body weight
*History of elevated response to gonadotropins
*Polycystic Ovary Syndrome (PCOS)
*Isolated PCOS characteristic
*A previous history of OHSS.
*Hormonal markers (e.g. Anti-Mullerian Hormone markers)
*Ultrasonographic markers (e.g. Antral Follicle Count)

'''Secondary risk factors'''

Secondary risk factors involve the monitoring of ovarian response parameters once COS has been initiated. These parameters are monitored for <ref name="PMID19007627"><pubmed>19007627</pubmed></ref>:

*rapidly rising E2 levels
*E2 concentration larger than 2500 pg/mL
*large number of developing follicles (10-14mm) on the day hCG is administered
*large number of oocytes retrieved

These factors in combination, act as a predictive tool to assess the likelihood of severe OHSS development, with a 83% sensitivity and 84% specificity. <ref name="PMID19007627"/>

=== Primary Prevention===

Primary Prevention involves the modification of treatment regimens on the basis of OHSS risk classifications, in order to prevent OHSS occurrence.

'''Ovulation Induction'''

Unifollicular Ovulation Induction through Ovulation Induction (OI) is a primary means of avoiding OHSS in women with Polycystic Ovarian Syndrome, who are at an increased risk. In order to promote unifollicular development, the ovaries are stimulated with a low starting dose of FSH (75 IU).<ref name="PMID20416867"><pubmed>20416867</pubmed></ref> Studies suggests that a minimum gonadotropin dose lowers OHSS risk and thus a step-up regimen is utilised to achieve an ovarian response, whereby the FSH dosage is increased every 7 days until follicular development of greater than 10mm is noted <ref name="PMID26074966" />. Alternatively, a step-down regimen may be followed, whereby a high initial FSH dosage is lowered according to the ovarian response. Another method to increase FSH levels during OI, is through Aromatase Inhibitors which promote folliculogenesis by increasing pituitary secretion of FSH, and downregulate oestrogen production through a negative feedback loop. However, Aromatase Inhibitors have not been shown to reduce OHSS incidence in comparison to other methods of OI. During OI, a key objective is to prevent early cycle cancellation due to premature luteinisation from pituitary secretion of LH. In order to downregulate LH secretion, Gonadotropin-releasing hormone agonists (GnRHa) are administered in addition to gonadotropins. The duration of exposure to gonadotropins and subsequent risk of OHSS may also be minimised through mild stimulation protocols which administer FSH only in the mid to late follicular phase.<ref name="PMID20416867" />

'''Adjuvant Metformin Therapy'''

Adjuvant Metformin Therapy has been found to lower the risk of OHSS by 63% <ref name="PMID25406011"><pubmed>25406011</pubmed></ref>. It involves the administration of metformin at a daily dosage of 1000 to 2000mg, 2 months prior to Controlled Ovarian Stimulation <ref name="PMID26074966"/>. Metformin lowers the elevated insulin levels in PCOS which consequently reduce intraovarian androgen levels. This leads to a reduced sensitivity and expression of granulosa cell-follicle stimulating hormone receptors which result in a less exaggerated response to gonadotropins. Furthermore, it is suggested that Metformin prevents OHSS by controlling vascular permeability through the inhibition of various vasoactive molecules, including VEGF.

'''Avoiding hCG during Luteal Phase Support

Following Controlled Ovarian Stimulation, the steroid levels of E2 and P4 are reduced during the luteal phase due to the negative feedback on the pituitary. This leads to low endogenous LH levels, which consequently reduce endometrial receptivity as well as the luteal phase duration itself. As a result, implantation and pregnancy rates are reduced and early pregnancy loss rates are increased.<ref name="PMID20416867" /> Luteal Phase Support (LPS) serves to combat these adverse events with the use of hCG. However, hCG has been found to increase the risk of OHSS. Alternatively, the use of progesterone has been found to not only halve the risk of OHSS, but also induce similar improvements in pregnancy and miscarriage rates as hCG.<ref name="PMID26148507"><pubmed>26148507</pubmed></ref>

===Secondary Prevention===

Secondary Prevention aims to prevent progression to OHSS once COS has been initiated and the patient has been found to mount an exaggerated response. <ref name="PMID20416867" />

'''Coasting'''

Coasting is a first-line secondary preventative strategy. It consists of the withdrawal of gonadotrophins when a critical number of follicles and/or E2 concentration is reached. hCG is administered once the E2 concentration reduces to a safe level, before the process of oocyte retrieval commences. This preventative strategy is conducted for a period of less than 3 days in order to avoid compromising IVF outcomes.

'''Cryopreservation'''

Cryopreservation of embryos after oocyte retrieval is another avenue which may avert OHSS progression. The cryopreserved embryos are only reimplanted once the patient's hormone serum levels have normalised. Using oocyte vitrification, crystal formation within embryo tissue is avoided and so cryopreserved embryos have been found to produce better pregnancy rates with a 32% increase, than fresh embryo transfer. Recent studies suggest cryopreservation itself does not reduce OHSS rates, but must be followed by a GnRHa trigger to avert OHSS.

'''Cycle cancellation'''

Cycle cancellation is a guaranteed method to prevent early OHSS whereby hCG is withheld. This is a last resort strategy as it carries the risk of significant psychological distress and financial loss for the patient.

</div>

==Effect on the Newborn==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

</div>
Women who develop OHSS while undergoing Assisted Reproductive Technologies (ART) treatment are not only more likely to achieve a pregnancy, but have a live birth as the pregnancy outcome. This live birth is also more likely to be a multiple birth of two, three or more children. <ref name="PMID19591989"><pubmed>19591989</pubmed></ref> It has been postulated that a multifetal pregnancy leads to a more rapid increase in hCG levels, resulting in an increased risk of OHSS. However, the causal nature between multifetal pregnancy and OHSS development is disputed and further research is required to distinguish correlation from causation. <ref name="PMID19573292"><pubmed>19573292</pubmed></ref>

OHSS development is also associated with an increased risk of adverse outcomes including stillbirth, premature birth and low birthweight.<ref name="PMID19591989" /> Although the cause for the increased risk in adverse pregnancy outcomes is unknown, it is suggested that as the incidence of OHSS is reduced through various prevention strategies, the risk of such outcomes may be also be reduced.

==Genetics==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

Despite OHSS typically being of iatrogenic origin as a result of ovarian stimulation with gonadotropins, research has been conducted into the potential genetics behind OHSS as many sporadic and familial cases have been observed. '''Mutations''' in the receptor for hormones such as Follicle Simulating Hormone (FSH), Lutenizing Hormone (LH) and hCG have all been targets of OHSS genetics research. Interestingly, they too also arise from a common ancestral gene.

===Follicle Stimulating Hormome===

Dr. Botros Rizk, of the University of South Alabama College of Medicine <ref name="PMID19573286"><pubmed>19573286</pubmed></ref>, has written extensively regarding the genetics behind OHSS. In particular, he talks about '''FSH receptors''' (FSHR) and their role in the syndrome. He hypothesises that mutations in these receptors could be activating or inactivating, leading to an increased risk of developing OHSS or sterility respectively. Currently, 744 single nucleotide polymorphisms (a type of mutation) have been found in the gene encoding the FSHR, 8 of which are located in its exons (coding regions of the gene). How the ovary responds is resultant on the FSHR genotype. For example, Ser680Asn, a polymorphism in the FSHR gene has been shown to aid in predicting the severity of a woman's OHSS. Ordinarily FSH stimulates the growth of ovarian follicles, however, when mutated, it is stimulated by the hCG resulting in excessive follicle development.

Spontaneous OHSS, OHSS that arises and cannot be attributed to any form of ovarian stimulation or Assisted Reproductive Technology, has been linked to activating mutations in the FSHR <ref name="PMID23499866"><pubmed>23499866</pubmed></ref>. This familial disorder is an autosomal dominant one. In most cases the FSHR can be stimulated by the presence of Thyroid Stimulating Hormone (TSH) or hCG, in the absence of FSH (the ligand for FSHR).

===Lutenizing Hormome===

The '''Lutenizing Hormone Receptor''' (LHR) gene in humans is comprised of 11 exons. Animal studies have shown that many primates exhibit a similar gene which is comprised of only 10 exons, however a gene lacking the 10th exon has been identified and termed the type 2 LHR. Expression of the type 2 LHR has been seen in humans. The type 2 LHR, compared to the wild-type LHR appears to be repaired with regard to its function. Defects in the type 2 LHR include a decrease in efficiency of transport to the plasma membrane and irregularities in signal transduction. Inactivating mutations in the LHR have been seen to cause infertility in women as well as amenorrhoea. Activating LHR gene mutations are asymptomatic and are not associated with OHSS in women.

===Bone Morphogenic Protein===

An imporant growth factor, derived from oocytes called '''BMP-15''' (Bone Morphogenic Protein 15) is vital for female fertility. It belongs to the family of growth factors, Transforming Growth Factor β (TGF-β) and is heavily involved in folliculogenesis. It has been found that mutations in the BMP-15 gene caused infertility in female sheep. Conversely, it has also been indicated in enhanced fertility when BMP-15 is present is high amounts in follicular fluid <ref name="PMID19573286" />.

A case study done by Hanevik ''et. al.'' in 2013 <ref name="PMID21565556"><pubmed>21565556</pubmed></ref> found that a Single Nuclear Polymorphism (SNP) in the BMP-15 gene is responsible for a high response to ovarian hyper-stimulation. The aim of the study was to test the effect the SNP had on BMP-15 with regard to high and low responders buy taking blood from 53 high responders, 38 low responders and 100 non-responders (controls) and analysing 5 noted SNP's. Results from their study showed a correlation between a high response to ovarian hyper-stimulation and the BMP-15 9G allele. The article does state however, that further research is required into the molecular effects of SNP's on the function of BMP-15.

===Vascular Endothelial Growth Factor===

'''Vascular endothelial growth factor''' (VEGF) has been indicated as one of the key agents causing vascular permeability and subsequent ascites in OHSS. The gene, which is located on chromosome 12, is made up of 8 exons (coding regions), of which exons 6 and 7 do not always appear due to the exons being spliced out.The splicing of this gene allows for various isoforms of the gene to exist of which VEGF 121 and 165 appear to play a role in angiogenesis. There are two VEGF Receptors, VEGFR-1 and VEGFR-2 that belong to the tyrosine kinase family of receptors (for more information on VEGF see [[Pathophysiology]]). Because of its distinct role in OHSS, it has been targeted as an area for research for potential treatments. The idea is that if the genetic expression of VEGF and its receptors can be controlled, OHSS can be avoided or treated.<ref name="PMID19573286" />

A different study by Hanevik ''et. al.'' , <ref name="PMID22587628"><pubmed>22587628</pubmed></ref> done in 2012 involved analysing blood samples from 53 women with OHSS and 100 women without it (controls) and analysing 6 SNP's in the VEGFR2 gene to find any genetic variations. They found a correlation between women with the VEGF +405cc genotype and the development of OHSS indicating women that undergo controlled ovarian hyper-stimulation and posses his genotype, are at an increased risk of developing OHSS.

</div>

== Current Research on Animal Models==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">
{|
|-bgcolor="F8E0F1"
|
<span style="font-size:120%">'''Inhibition of Cyclooxygenase-2 (COX-2) by Meloxican decreasing the incidence of OHSS in Rat Model'''</span> <ref name="PMID18166186"><pubmed>18166186</pubmed></ref>

Reasearch was carried out to investigate the effects of selective inhibition of the enzyme COX-2 on the Ovarian Hyperstimulation Syndrome (OHSS) using Female Wistar rates as the subjects. The research aimed to find results by measuring the number of antral and luteinized follicles, ovarian weight, vascualr endothelial growth factors and COX-2 immunohistochemistry. The rats being tested were all 22 days old and were divided into four equal groups;

'''Group 1 (Control group)''' was subject to a 0.1 ml of Intraperitoneal Saline from days 22 ~ 26

'''Group 2 (Mildly-stimulated group)''' subject to 10IU of pregnant mare serum gonadotrophin (PMSG) on day 24 and then 10IU of Human Chorionic Gonadotrophin (hCG) on day 26

'''Group 3 (OHSS positive group)''' was subject to 10IU of PMSG from days 22 ~ 26 and then administered 30IU of hCG on day 26 to induce OHSS

'''Group 4 (OHSS positive variant group)''' received 15mg/ml of Meloxicam 2 hours prior to administration of 10IU PMSG from days 22 ~ 26

Results showed there was no difference in ovarian weight in samples from Group 1 and Group 2, however Group 3 showed signs of significant ovarian weight increase which in group 4 was suppressed by the introduction of Meloxicam. No differences were observed in the number of antral follicles amongst the four test groups. Results from Group 2 and Group 3 showed that the granulosa cells of preovulatory follicles and the stromal cells were highly VEGF immunoreactive, however the Meloxicam treated Group 4 showed less immunoreactivity than Group 2 and Group 3 which indicated the correlation between Meloxicam and the diminished VEGF expression. Group 3 presented an increased COS-2 immunoreactivity which was highly diminished than in Group 4.

The research concluded that in a rat model, the enzyme Meloxicam has a beneficial effect on OHSS by reducing the increase of ovarian weight and the expression of VEGF associated with OHSS, the effects of which may be mediated by the inhibitory capacity of COX-2 on Meloxicam
|}

{|
|-bgcolor="FF99FF"
|
<span style="font-size:120%">'''Inhibition of Ovarian VEGF secretion by activation of Dopamine Receptor 2'''</span> <ref name="PMID25217874"><pubmed>25217874</pubmed></ref>

This research was carried out to investigate a possibility in whether a Dopamine Receptor 2 agonist '''(D2-ag)''' can assist in the prevention of Ovarian Hyperstimulation Syndrome, using rat models, by decreasing the ovarian vascular endothelial growth factor '''(VEGF)''' production. Using Immature Wistar rats (22 days old) as their animal model, the rats were initially stimulated with Gonadotrophins to mimic the onset and effects of OHSS and then subjected to treatment with a D2-agonist and/or a D2-antagonist (D2-ant). The vascular permeability was measured at the endpoint after day 26 by measuring the peritoneal extravasion of a previously injected dye and ovaries from all subjects were collected to assess the effects of D2-ag and D2-ant on the production of Ovarian VEGF. The expression of VEGF mRNA was measured by quantitative real time PCR and the levels of VEGF proteins were measured by Western Blots.

Results showed that the D2-ag caused a large reduction in the vascular permeability which was in turn associated with the great decreased in VEGF protein production in the OHSS rat ovaries, whereas the introduction of D2-ant showed opposite results with a increase in the vascular permeability leading to the increase of VEGF protein production in the ovaries. Ovarian VEGF mRNA levels were found to be unaffected by the introduction of these drugs in OHSS rat subjects. Conclusions were drawn on the fact that Dopamine Receptor 2 agonists prevent the increase of vascular permeability in subjects with OHSS by decreasing the ovarian production of VEGF and also that due to the dose-dependent inhibitory effect of the D2-ag on ovarian VEGF, current OHSS therapies used in humans can benefit by increasing the intraovarian concentration of D2-ag.
|}
</div>

==Glossary==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

'''Ascites'''- An accumulation of fluid in the peritoneal cavity with resultant abdominal swelling

'''Cabergoline''' - A dopamine receptor agonist used to treat hormone imbalance.

'''GnRH antagonist''' - Gonadotropin Releasing Hormone - A class of compounds that are similar in terms of the structure of natural Gonadotropin Releasing Hormone but has a antagonistic effect.

'''hCG'''- Human Chorionic Gonadotropin

'''Hemoconcentration'''- An increase in the concentration of circulating red blood cells in response to a decrease in blood plasma volume

'''Hypovolemic'''- A decrease in circulating blood volume

'''Iatrogenic'''- Illness caused as a result of a medical examination or treatment

'''Intravenous fluids''' - Is the infusion of liquid substances directly into a vein.

'''IVF'''- In-vitro Fertilization

'''NSAID'''- Non-steroidal Anti-Inflammatory Drug e.g. Ibuprofen

'''OHSS'''- Ovarian Hyper-stimulation Syndrome

'''FSH''' - Follicle Stimulating Hormone

'''LH''' - Luteinizing Hormone

'''Oliguria'''- Decreased urine output/small amounts of urine produced

</div>

==References==

2015 Group Project 2

2015-10-22T20:47:03Z

Z3372824: /* Causative Agents */

{{ANAT2341Project2015header}}

==<span style="font-size:120%">'''Ovarian Hyper-stimulation Syndrome (OHSS)'''</span>==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

Ovarian Hyper stimulation Syndrome (OHSS) is an iatrogenic complication of '''Assisted Reproduction Technology''' (ART), in which women take medications to stimulate oocyte growth. It is generally identified by cystic enlargements of the ovaries and fluid accumulation in the peritoneal cavity due to the increased capillary permeability and ovarian neoangiogenesis <ref name="PMID22065820"><pubmed>22065820</pubmed></ref>. It is an occurrence which is dependent on the controlled stimulation of the ovaries in preparation for IVF i.e. administration of human Chorionic Gonadotropin (hCG).

OHSS was first described in 1943 as ''“syndrome d’hyperluteinisation massive
des ovaries”''. It was during this time that gonadotropins were prepared from animals such as sheep to bring on ovulation in women. The first recorded death as a result of OHSS occurred in 1951 and was due to renal failure as a result of oligouria, a complication of the syndrome <ref name="OHSS"> Marie M. Budev, DO, MPH; Alejandro C. Arroliga, MD; Tommaso Falcone, MD, [ http://utilis.net/Morning%20Topics/REI/Ovarian%20Hyperstimulation.pdf ], 'Ovarian Hyperstimulation Syndrome'</ref> <ref name="PMID12638783"><pubmed>12638783</pubmed></ref>.

<span style="color:#FA58D0">This wikipage aims to provide clear information on various areas surrounding OHSS such as diagnosis, prevention and complications and will look into the genetics behind the disorder and the various animals models used to research it.</span>

<html5media height="350" width="450">https://www.youtube.com/watch?v=aXmjJw234a4</html5media>

'''Overview of the Ovarian Hyperstimulation Syndrome''' <ref> Howcast (2013, August 27) Ovarian Hyperstimulation Syndrome | Infertility. Retrieved from https://www.youtube.com/watch?v=aXmjJw234a4</ref>

</div>

==Epidemiology==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

Ovarian Hyper-Stimulation Syndrome (OHSS) rarely occurs sporadically, and if it does, it is usually the result of an underlying genetic problem. The majority of OHSS is due to the ovaries being stimulated to mature and release an abundance of oocytes, in response to hormones Human Chorionic Gonadotropin (hCG) and Follicle Stimulating hormone (FSH), during IVF. Rarely, Clomifene Citrate therapy can cause OHSS.<ref name="WikiOHSS"> Wikipedia, [ https://en.wikipedia.org/wiki/Ovarian_hyperstimulation_syndrome ], 'Ovarian Hyperstimulation Syndrome'</ref>

OHSS only affects '''0.5-5%''' of women undergoing Ovarian Hyper-stimulation, but despite its small prevalence, it is a potentially fatal outcome of a non-vital procedure and remains a prevalent problem for fertility specialists <ref name="PMID12498425"><pubmed>12498425</pubmed></ref> <ref name="PMID12638783"><pubmed>12638783</pubmed></ref>. Age has been cited as a factor affecting those with OHSS, with younger women more at risk. Additionally, women with allergies were seen to have a higher incidence of OHSS. It is important to note that at this point in time, there is no positive correlation between gonadotropin dose and OHSS.

Of the 0.5-5% of women affected with OHSS mentioned above, 2% of those women will require hospitalisation. As of 2011, it has been reported that the incidence of OHSS was '''increasing''', resulting in approximately 3 deaths per 100,000 women undergoing ovarian stimulation per year <ref name="PMID21828116"><pubmed>21828116</pubmed></ref>. This is particularly worrying as in 2008, in the United States alone, there were around 150,000 IVF cycles undertaken.

{|
|-bgcolor="F8E0F1"
|
'''With the field of Assisted Reproductive Technologies expanding and more women partaking in IVF treatments, the threat of women developing OHSS is an ongoing and increasing one''' <ref name="PMID21828116" />.
|}
{| class="wikitable mw-collapsible mw-collapsed"
! Characteristics of women by complication group <ref name="PMID19591989"><pubmed>19591989</pubmed></ref>
|-
! scope="col" width="100px" height="60px" style="text-align:center| '''Characteristic'''
! scope="col" width="100px" height="60px" style="text-align:center| '''No Complications
(N = 212,041)'''
! scope="col" width="100px" height="60px" style="text-align:center| '''Moderate OHSS
(N = 1,523)'''
! scope="col" width="100px" height="60px" style="text-align:center| '''Severe OHSS
(N = 655)'''
|-
|style="text-align:center; background: #FF99FF;"| '''Maternal Age (Mean ± SD)'''
|style="text-align:center; background: #F6CEEC;"| 35.6 ± 4.6
|style="text-align:center; background: #F6CEEC;"| 33.0 ± 4.3
|style="text-align:center; background: #F6CEEC;"| 33.1 ± 4.4
|-
|style="text-align:center; background: #FF99FF;"| '''Maternal Age (%)'''
|-
|style="text-align:left; background: #F6CEEC;"| <30 years
|style="text-align:center; background: #F6CEEC;"| 10 %
|style="text-align:center; background: #F6CEEC;"| 21.1 %
|style="text-align:center; background: #F6CEEC;"| 20.6 %
|-
|style="text-align:left; background: #F6CEEC;"| 30-34 years
|style="text-align:center; background: #F6CEEC;"| 30.4 %
|style="text-align:center; background: #F6CEEC;"| 43.2 %
|style="text-align:center; background: #F6CEEC;"| 40.5 %
|-
|style="text-align:left; background: #F6CEEC;"| 35-39 years
|style="text-align:center; background: #F6CEEC;"| 37.8 %
|style="text-align:center; background: #F6CEEC;"| 27.2 %
|style="text-align:center; background: #F6CEEC;"| 32.5 %
|-
|style="text-align:left; background: #F6CEEC;"| >40 years
|style="text-align:center; background: #F6CEEC;"| 21.8 %
|style="text-align:center; background: #F6CEEC;"| 8.4 %
|style="text-align:center; background: #F6CEEC;"| 6.4 %
|-
|style="text-align:center; background: #FF99FF;"| '''Nulligravida (%)'''
|style="text-align:center; background: #F6CEEC;"| 45.8 %
|style="text-align:center; background: #F6CEEC;"| 51.5 %
|style="text-align:center; background: #F6CEEC;"| 51.8 %
|-
|style="text-align:center; background: #FF99FF;"| '''Infertility Diagnosis (%)'''
|-
|style="text-align:left; background: #F6CEEC;"| Male factor
|style="text-align:center; background: #F6CEEC;"| 37.7 %
|style="text-align:center; background: #F6CEEC;"| 41.0 %
|style="text-align:center; background: #F6CEEC;"| 33.4 %
|-
|style="text-align:left; background: #F6CEEC;"| Endometriosis
|style="text-align:center; background: #F6CEEC;"| 13.5 %
|style="text-align:center; background: #F6CEEC;"| 13.5 %
|style="text-align:center; background: #F6CEEC;"| 10.7 %
|-
|style="text-align:left; background: #F6CEEC;"| Ovulation Disorders
|style="text-align:center; background: #F6CEEC;"| 14.0 %
|style="text-align:center; background: #F6CEEC;"| 29.5 %
|style="text-align:center; background: #F6CEEC;"| 22.4 %
|-
|style="text-align:left; background: #F6CEEC;"| Diminished ovarian reserve
|style="text-align:center; background: #F6CEEC;"| 16.9 %
|style="text-align:center; background: #F6CEEC;"| 3.2 %
|style="text-align:center; background: #F6CEEC;"| 2.4 %
|-
|style="text-align:left; background: #F6CEEC;"| Tubal factors
|style="text-align:center; background: #F6CEEC;"| 20.4 %
|style="text-align:center; background: #F6CEEC;"| 22.6 %
|style="text-align:center; background: #F6CEEC;"| 22.3 %
|-
|style="text-align:left; background: #F6CEEC;"| Uterine factors
|style="text-align:center; background: #F6CEEC;"| 5.1 %
|style="text-align:center; background: #F6CEEC;"| 4.3 %
|style="text-align:center; background: #F6CEEC;"| 3.1 %
|-
|style="text-align:left; background: #F6CEEC;"| Other factors
|style="text-align:center; background: #F6CEEC;"| 13.9 %
|style="text-align:center; background: #F6CEEC;"| 13.1 %
|style="text-align:center; background: #F6CEEC;"| 10.4 %
|-
|style="text-align:left; background: #F6CEEC;"| Unexplained factor
|style="text-align:center; background: #F6CEEC;"| 12.7 %
|style="text-align:center; background: #F6CEEC;"| 11.8 %
|style="text-align:center; background: #F6CEEC;"| 18.6 %
|-
|}
</div>

==Causative Agents==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

Normally a woman produces one egg per month from the ovaries, which travel down the Fallopian tube to be fertilized or be released from the body. In cases where women have difficulty falling pregnant, they are given medication which help them to produce and release eggs (as shown in the diagram to the right), further increasing their chances of fertilization and pregnancy <ref><pubmed>19573285</pubmed></ref>. Ovarian Hyper stimulation Syndrome generally occurs during infertility treatments when the ovaries are overstimulated by the fertility medication which causes the ovaries to swell and leak fluids into the belly and abdomen. The prevalence of OHSS onset is linked with excessive number of follicle development in response to the administration of injectable Follicle Stimulating Hormones (FSH) followed by the '''Human Chorionic Gonadotrophins''' (hCG) which triggers the release of the oocytes <ref><pubmed>26190539</pubmed></ref>.

'''Follicle Stimulating Hormones''' (FSH) <ref name="PMID9020850"><pubmed>9020850</pubmed></ref> are glycoprotein hormones that are produced and secreted from the Anterior Pituitary gland into the bloodstream, which regulate the developmental, growth, maturation and the reproductive processes within the body. In females, the Follicle Stimulating Hormones initiates the stages of growth and development of immature ovarian follicles within the ovaries before the release of an egg from a follicle at ovulation. When FSH is administered to a patient who is suffering from infertility, the increase FSH levels affect the rate of development and production, in turn increasing the amount of follicles which are ready to be released during ovulation.

[[File:Follicular Development.jpeg|right|400px|alt=Infertility treatments aim to facilitate follicular development to improve chances of fertilisation]]

</div>

==Symptoms==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

OHSS is classified based on a criteria from mild, moderate and severe <ref name="WikiOHSS" />:

'''Mild Symptoms'''- abdominal bloating, minimal weight gain, nausea, diarrhoea and a feeling of fullness.

'''Moderate Symptoms'''- Substantial weight gain (on average 2 or more pounds a day), increased abdominal girth, darkend urine and excessive thirst in addition to the mild symptoms.

'''Severe Symptoms'''- In addition to the symptoms associated with Mild and Moderate OHSS, in severe OHSS, you see shortness of breath, calf and chest pains and pleural effusion.

<span style="font-size:100%">'''Classifications of Ovarian Hyper-stimulation Syndrome:'''</span> <ref name="PMID22065820"><pubmed>22065820</pubmed></ref>
{| class="wikitable" style="text-align:center
|-
! scope="col" width="70px"| '''Classification'''
! scope="col" width="650px"| '''Symptoms'''
|-
|style="text-align:center; background: #F6CEEC;"| '''Mild'''
|style="height: 60px; background: #F6CEEC;"| '''Grade 1''' - Abdominal distention and discomfort
'''Grade 2''' - Abdominal distention, discomfort with nausea, vomiting and/or diarrhea and ovarian enlargement from 5~12cm
|-
|style="text-align:center; background: #F8E0F1;"| '''Moderate'''
|style="height: 60px; background: #F8E0F1;"| '''Grade 3''' - All features of Mild OHSS with ultrasonographic evidence of ascites
|-
|style="text-align:center; background: #F6CEEC;"| '''Severe'''
|style="height: 60px; background: #F6CEEC;"| '''Grade 4''' - All features of Moderate OHSS with the addition of clinical evidence of ascites and breathing difficulties present
'''Grade 5''' - All of the above symptoms along with a change in the blood volume, increased blood viscosity due to coagulation and diminished renal function
|}

</div>

==Diagnosis==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

Whilst symptoms of OHSS can occur as soon as 24 hours post hCG administration, they are usually seen in women 7-10 days post administration. Initially women with OHSS will present with abdominal bloating, as a result of fluid in the peritoneal cavity and an increase in ovary size. When women present with severe OHSS they are often dehydrated, due to increased vascular permeability, and have hemoconcentration. The above results in a decrease in intravascular volume, leading to oligouria <ref name="PMID22416285" />.

===History===

Initially a thorough history of the patient is taken during which the clinician looks for evidence of ovarian stimulation, followed by ovulation. During this history taking, the clinician will inquire into any weight gain noticed, urine output, and the woman's ability to maintain oral hydration. A key diagnostic tool for clinicians regarding women who are taking gonadotropins is to identify if they are at an increased risk of developing OHSS. Some risk factors include woman aged less than 30, women who have polycystic ovaries, woman with a previous history of OHSS and women who have had greater than 20 oocytes retrieved <ref name="PMID22416285" />.

===Physical Exam===
[[File:Vaginal_Ultrasonography_in_Sagittal_Plane.jpg|right|thumbnail|600px|Vaginal Ultrasonography in Sagittal plane <ref name="Wikiversity Journal of Medicine"> Häggström, Mikael. "Medical gallery of Mikael Häggström 2014". Wikiversity Journal of Medicine 1 (2). DOI:10.15347/wjm/2014.008. ISSN 20018762</ref>]]
After a history of the patient is taken, the next step is to perform a physical exam on the patient. Women who present with abdominal bloating will produce a shifting dullness upon abdominal percussion. Additionally the clinician will test the woman's vital signs, measure her abdominal girth, weight and will look for evidence of ascites or increase in calf size (usually unilateral)<ref name="PMID22416285" />.

===Investigations===

If the clinician further suspects a women of having OHSS, various investigations can be done such as an ultrasound.The intraperitoneal fluid is best imaged via vaginal ultrasound due to the enlarged ovaries making it difficult to image the pelvis using transabdominal ultrasound. The clinician can also order laboratory testing to look for urine specific gravity and and complete blood count to look for hemoconcentration with a hematocrit. Additionally, liver function tests can be ordered to look for elevated function. The clinician will also look for evidence of elevated D-dimers and fibrinogen and decreased levels of anti-thrombin 3 <ref name="SAHealth"> Government of South Australia Health [ http://www.sahealth.sa.gov.au/wps/wcm/connect/9b61ed004ee5348da663afd150ce4f37/Ovarian-hyperstimulation-syndrome-WCHN-PPG-17072012.pdf?MOD=AJPERES&CACHEID=9b61ed004ee5348da663afd150ce4f37 ], 'South Australian Paediatric Clinical Guidelines OHSS'</ref>.

====Ultrasound====

Typical appearances of the ultrasound include <ref name="Ultrasound"> Radiopaedia [ http://radiopaedia.org/articles/ovarian-hyperstimulation-syndrome-1 ], 'Ovarian Hyperstimulation Syndrome'</ref>:

*Bilaterally and symmetrically enlarged ovaries (>12cm)
* "Spoke-Wheel appearance" - presence of multiple cysts of varying size
*May also see ascites (fluid)

===Severity===

Once a clinician has deduced a women is suffering from OHSS, the severity of their condition needs to be established as either mild, moderate or severe. This is done by referring to the criteria under the sub-heading [[Symptoms]].The subsequent course of treatment for the woman will be based upon this evaluation.

{|
|-bgcolor="F6CEEC"
|
'''Further investigations''' can be done including a Chest X-ray to check for pleural effusions and oedema and USS with Doppler's to check for ascites or possible ovary torsion. <ref name="PMID22416285"><pubmed>22416285</pubmed></ref>
|}

===Differential Diagnosis===

Conditions presenting with similar symptoms or ultrasound images include <ref name="Ultrasound" />:

*Polycystic Ovaries (PO)
:: The difference is that with PO is that the cycts are typically smaller than OHSS cysts and there is no evidence of ascited or pleural effusion
*Mucinous Ovarian Malignancy
:: A type of Ovarian Epithelial tumour
*Ectopic Pregnancy <ref name="Casereport"> Australian Medical Student Journal [ http://www.amsj.org/wpcontent/uploads/files/articles/amsj_v2_i1/AMSJ_v2_i1_pg58-60.pdf ], 'Ovarian hyperstimulation syndrome'</ref>
::A pregnancy in which the foetus develops outside of the uterus e.g. in the fallopian tube

</div>

==Pathophysiology==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

[[File:Pathogenesis_of_OHSS.png|600px|thumb|Pathogenesis of OHSS <ref name="PMID20416867"><pubmed>20416867</pubmed></ref>]]

The definition of Ovarian Stimulation is enlarged ovaries with many luteinized cysts, that can present with secondary complications. What distinguishes Ovarian Stimulation from OHSS is the presence of vascular hyper-permeability that results in fluids being redirected elsewhere in the body.

The key process to OHSS appears to be caused by '''Vascular Endothelial Growth Factor''' (VEGF), that is released along with other cytokines, estrogen and progesterone, due to the ovary undergoing luteinization as a result of stimulation by hCG. VEGF increases vascular permeability and as a result the capillaries become more "leaky" to the fluids in them. These fluids can then escape the capillaries and accumulate in the pleural and abdominal cavities as ascites. The woman then becomes hypovolemic and is at an increased risk of circulatory, renal and respiratory issues such as arterial thromboembolism due to the thickening of the blood. Note, the blood is thickened as fluid is leaving the capillaries, leaving behind red blood cells and other cellular components of the blood <ref name="WikiOHSS" />.

The increase in expression of VEGF and VEGF Receptor 2 (VEGFR2) is attributed to the greatly increased amount of their mRNA present in the body after stimulation with hCG <ref name="PMID21082502"><pubmed>21082502</pubmed></ref>. VEGF interacts with VEGF2 and VEGF Receptor 1 (VEGFR1) to create a strong angiogenic effect. Both VEGFR2 and VEGFR1 belong to a family of receptors called tyrosine kinases. VEGF2 is involved in the regulation of angiogenesis and vascular permeability whilst VEGF1 has a slightly contradictory role in that is is involved in the maintenance of the tight junctions between endothelial cells in blood vessels. A study by Gómez ''et. al.'' <ref name="PMID21082502" /> showed that women experiencing OHSS had substantially higher plasma levels of VEGF and lower levels of VEGFR1.

</div>

==Complications==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

Ovarian torsion or rupture, renal insufficiency and thrombophlebitis can all complicate OHSS. If a pregnancy occurs, symptoms may persist longer than the usual 1 to 2 weeks and become more severe, however, even with severe OHSS, they do not extend past the first trimester <ref name="WikiOHSS" />.

<span style="color:#FA58D0"> '''1-2% of women who suffer from ovarian stimulation develop a severe form of OHSS''' </span>. Complications from severe OHSS include:

*Fluid collection in the abdomen
*Electrolyte disturbances (sodium and potassium)
*Kidney failure
*Ovary twisting
*Rupture of a cyst in an ovary
*Breathing problems
*Blood clots in large vessels (most commonly the legs)
*Pregnancy loss from miscarriage or termination
*Rarely, death

A study by Nouri ''et. al.'' <ref name="PMID24996451"><pubmed>24996451</pubmed></ref> found that women with '''Polycystic Ovarian Syndrome''' (PCOS) and those that were induced with hCG experienced longer recovery times from severe OHSS than women who were not pregnant. They looked at a cohort of women hospitalised for the first time with severe OHSS and subject them to the same treatments. Based on a defined criteria, they established the recovery time of these women and compared the times between those that were pregnant to those that were not pregnant. They also found that whether a woman had PCOS or ovulation induction did not affect her risk of developing OHSS if she was not pregnant. It is only a risk factor for pregnant women.

===Thromboembolic events===

A frequent and deadly complication of OHSS are thromboembolic events due to increased blood clotting. This increase in blood clotting has been attributed to a variety of complications such as hemoconcentration (which thickens the blood), hypolvolemia and an increase in the permeability of blood vessels as a result of increased vasoactive substances in the body of ovarian origin. Thromboembolic events include venous thromboses often in the upper extremities and arterial thromboses such as those in the cerebrovascular region. These events can lead to amputations of extremities, brain damage, miscarriage and death. To avoid this, anti-coagulants are given to pateitns with OHSS and they are fitted with compression stockings (see [[Treatment]]) <ref name="PMID23378404"><pubmed>23378404</pubmed></ref>.

{|
|-bgcolor="F8E0F1"
|
The risk of a woman developing OHSS is higher if she is having a '''twin pregnancy''', as she is exposed to higher concentration of hCG. <ref name="PMID9756273"><pubmed>9756273</pubmed></ref>
|}

</div>

==Treatment==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

'''General treatment
'''
*''Acetaminophen'' with or without a narcotic agent- used to treat abdominal discomfort
*Women are encouraged to drink 2-3 litres of water a day to prevent hemoconcentration
*Women are advised to avoid sexual intercourse and vigorous exercise at the risk of torsion or rupture of the ovaries
*NSAID's with anti-platelet properties should NOT be used as they may effect renal function in a women with OHSS
*Patients with significantly painful ascites or breathing problems may undergo ''Paracentesis'' (drainage of the ascites)
*''Culdocentesis'' (extraction of fluid from recto-uterine pouch) can be done to decrease the likelihood of a woman with moderate OHSS progressing to severe OHSS.<ref name="PMID22416285" />

===Mild to Moderate OHSS===

Mild OHSS can often resolve on its own, however, moderate OHSS may include treatments such as<ref name="WikiOHSS" />:

*Anti-nausea medication and prescription painkillers
*Regular physical examinations and ultrasounds
*Daily weigh-ins and waist measurements
*Measuring the amount of urine produced each day
*Frequent blood tests for monitoring dehydration and electrolyte imbalance
*Maintaining a high balance of fluids
*Drainage of excess abdominal fluid by inserting a needle in the abdominal cavity
*Wearing support stockings which help prevent blood clots/thrombosis

===Severe OHSS===

Severe OHSS requires hospital care in order for constant monitoring and treatment such as <ref name="WikiOHSS" />:

*Intravenous fluids with a crystalloid solution (100-150mL/hr)
*Intravenous Albumin is administered is IV fluids are insufficient (15-20mL/hr of 25% albumin for 4 hrs)
*In addition to Acetaminophen, ''Opioid analgesics'' can be administered for pain relief
*''Antiemetics'' can be used to subside nauseas and/or vomiting
*Woman administered to hospital of OHSS are considered at high risk of thromboembolic complications and are given low molecular weight ''heparin'', an anti-coagulant
*''Cabergoline''- lessens OHSS symptoms
*''GnRH agonist''- suppresses ovarian activity
**If at risk of OHSS, alternates include using a GnRH agonist instead of hCG however its effects on pregnancy rates are questionable. Using a GnRH agonist to replace the use of hCG for final oocyte stimulation will see a 6% decrease in delivery rate.

*Daily monitoring of creatine, urea, creatine clearance C-reactive protein (to rule out infection) are all required in combination with weekly tests such as liver and renal function tests and chest x-rays (to check for pleural effusion) <ref name="PMID12638783" />.

If there are serious complications then additional treatments are required:

*Surgery for a ruptured ovarian cyst
*Intensive care for the liver or lung complications

====Paracentesis====

For women with severe/grade 3 OHSS, paracentesis, the removal of fluid from the body using an aspiration needle, can be undertaken. It is a diagnostic and a therapeutic method that can be done trans-abdominally and trans-vaginally. It is used to relieve symptoms, improve haemodynamics e.g. Urinary output, and shorten the women's hospital stay. Complications of paracentesis include bleeding, infection and organ injury, however are note common <ref name="Paracentesis"> S. Monica Soni, HMS 3, Gillian Lieberman, MD [ http://eradiology.bidmc.harvard.edu/LearningLab/genito/Soni.pdf ], 'Ovarian Hyperstimulation Syndrome'</ref>.

{|
|-bgcolor="F8E0F1"
|
The most important aspect of treatment for any women with OHSS is close and constant '''monitoring''' with her healthcare professional. Counselling may also be provided to women and their partners or families in order to provide them with the best possible knowledge base to manage and treat their OHSS. It is important to note that there is '''no one cure or treatment''' for OHSS. Treatment involves managing and eliminating the symptoms until such time as the syndrome resolves itself <ref name="WikiOHSS" />.
|}

</div>

==Prevention==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

There are three key avenues through which the incidence of OHSS may be prevented. These include identifying risk factors to predict OHSS development, modifying treatment regimes on the basis of the identified risk factors and intervention to prevent progression to OHSS once the patient has undergone Controlled Ovarian Stimulation.

=== Risk factors===

'''Primary risk factors'''

Pre-existing factors likely to exacerbate the ovarian stimulation response. Primary risk factors include <ref name="PMID26074966"><pubmed>26074966</pubmed></ref>:

*Young age
*Low body weight
*History of elevated response to gonadotropins
*Polycystic Ovary Syndrome (PCOS)
*Isolated PCOS characteristic
*A previous history of OHSS.
*Hormonal markers (e.g. Anti-Mullerian Hormone markers)
*Ultrasonographic markers (e.g. Antral Follicle Count)

'''Secondary risk factors'''

Secondary risk factors involve the monitoring of ovarian response parameters once COS has been initiated. These parameters are monitored for <ref name="PMID19007627"><pubmed>19007627</pubmed></ref>:

*rapidly rising E2 levels
*E2 concentration larger than 2500 pg/mL
*large number of developing follicles (10-14mm) on the day hCG is administered
*large number of oocytes retrieved

These factors in combination, act as a predictive tool to assess the likelihood of severe OHSS development, with a 83% sensitivity and 84% specificity. <ref name="PMID19007627"/>

=== Primary Prevention===

Primary Prevention involves the modification of treatment regimens on the basis of OHSS risk classifications, in order to prevent OHSS occurrence.

'''Ovulation Induction'''

Unifollicular Ovulation Induction through Ovulation Induction (OI) is a primary means of avoiding OHSS in women with Polycystic Ovarian Syndrome, who are at an increased risk. In order to promote unifollicular development, the ovaries are stimulated with a low starting dose of FSH (75 IU).<ref name="PMID20416867"><pubmed>20416867</pubmed></ref> Studies suggests that a minimum gonadotropin dose lowers OHSS risk and thus a step-up regimen is utilised to achieve an ovarian response, whereby the FSH dosage is increased every 7 days until follicular development of greater than 10mm is noted <ref name="PMID26074966" />. Alternatively, a step-down regimen may be followed, whereby a high initial FSH dosage is lowered according to the ovarian response. Another method to increase FSH levels during OI, is through Aromatase Inhibitors which promote folliculogenesis by increasing pituitary secretion of FSH, and downregulate oestrogen production through a negative feedback loop. However, Aromatase Inhibitors have not been shown to reduce OHSS incidence in comparison to other methods of OI. During OI, a key objective is to prevent early cycle cancellation due to premature luteinisation from pituitary secretion of LH. In order to downregulate LH secretion, Gonadotropin-releasing hormone agonists (GnRHa) are administered in addition to gonadotropins. The duration of exposure to gonadotropins and subsequent risk of OHSS may also be minimised through mild stimulation protocols which administer FSH only in the mid to late follicular phase.<ref name="PMID20416867" />

'''Adjuvant Metformin Therapy'''

Adjuvant Metformin Therapy has been found to lower the risk of OHSS by 63% <ref name="PMID25406011"><pubmed>25406011</pubmed></ref>. It involves the administration of metformin at a daily dosage of 1000 to 2000mg, 2 months prior to Controlled Ovarian Stimulation <ref name="PMID26074966"/>. Metformin lowers the elevated insulin levels in PCOS which consequently reduce intraovarian androgen levels. This leads to a reduced sensitivity and expression of granulosa cell-follicle stimulating hormone receptors which result in a less exaggerated response to gonadotropins. Furthermore, it is suggested that Metformin prevents OHSS by controlling vascular permeability through the inhibition of various vasoactive molecules, including VEGF.

'''Avoiding hCG during Luteal Phase Support

Following Controlled Ovarian Stimulation, the steroid levels of E2 and P4 are reduced during the luteal phase due to the negative feedback on the pituitary. This leads to low endogenous LH levels, which consequently reduce endometrial receptivity as well as the luteal phase duration itself. As a result, implantation and pregnancy rates are reduced and early pregnancy loss rates are increased.<ref name="PMID20416867" /> Luteal Phase Support (LPS) serves to combat these adverse events with the use of hCG. However, hCG has been found to increase the risk of OHSS. Alternatively, the use of progesterone has been found to not only halve the risk of OHSS, but also induce similar improvements in pregnancy and miscarriage rates as hCG.<ref name="PMID26148507"><pubmed>26148507</pubmed></ref>

===Secondary Prevention===

Secondary Prevention aims to prevent progression to OHSS once COS has been initiated and the patient has been found to mount an exaggerated response. <ref name="PMID20416867" />

'''Coasting'''

Coasting is a first-line secondary preventative strategy. It consists of the withdrawal of gonadotrophins when a critical number of follicles and/or E2 concentration is reached. hCG is administered once the E2 concentration reduces to a safe level, before the process of oocyte retrieval commences. This preventative strategy is conducted for a period of less than 3 days in order to avoid compromising IVF outcomes.

'''Cryopreservation'''

Cryopreservation of embryos after oocyte retrieval is another avenue which may avert OHSS progression. The cryopreserved embryos are only reimplanted once the patient's hormone serum levels have normalised. Using oocyte vitrification, crystal formation within embryo tissue is avoided and so cryopreserved embryos have been found to produce better pregnancy rates with a 32% increase, than fresh embryo transfer. Recent studies suggest cryopreservation itself does not reduce OHSS rates, but must be followed by a GnRHa trigger to avert OHSS.

'''Cycle cancellation'''

Cycle cancellation is a guaranteed method to prevent early OHSS whereby hCG is withheld. This is a last resort strategy as it carries the risk of significant psychological distress and financial loss for the patient.

</div>

==Effect on the Newborn==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

</div>
Women who develop OHSS while undergoing Assisted Reproductive Technologies (ART) treatment are not only more likely to achieve a pregnancy, but have a live birth as the pregnancy outcome. This live birth is also more likely to be a multiple birth of two, three or more children. <ref name="PMID19591989"><pubmed>19591989</pubmed></ref> It has been postulated that a multifetal pregnancy leads to a more rapid increase in hCG levels, resulting in an increased risk of OHSS. However, the causal nature between multifetal pregnancy and OHSS development is disputed and further research is required to distinguish correlation from causation. <ref name="PMID19573292"><pubmed>19573292</pubmed></ref>

OHSS development is also associated with an increased risk of adverse outcomes including stillbirth, premature birth and low birthweight.<ref name="PMID19591989" /> Although the cause for the increased risk in adverse pregnancy outcomes is unknown, it is suggested that as the incidence of OHSS is reduced through various prevention strategies, the risk of such outcomes may be also be reduced.

==Genetics==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

Despite OHSS typically being of iatrogenic origin as a result of ovarian stimulation with gonadotropins, research has been conducted into the potential genetics behind OHSS as many sporadic and familial cases have been observed. '''Mutations''' in the receptor for hormones such as Follicle Simulating Hormone (FSH), Lutenizing Hormone (LH) and hCG have all been targets of OHSS genetics research. Interestingly, they too also arise from a common ancestral gene.

===Follicle Stimulating Hormome===

Dr. Botros Rizk, of the University of South Alabama College of Medicine <ref name="PMID19573286"><pubmed>19573286</pubmed></ref>, has written extensively regarding the genetics behind OHSS. In particular, he talks about '''FSH receptors''' (FSHR) and their role in the syndrome. He hypothesises that mutations in these receptors could be activating or inactivating, leading to an increased risk of developing OHSS or sterility respectively. Currently, 744 single nucleotide polymorphisms (a type of mutation) have been found in the gene encoding the FSHR, 8 of which are located in its exons (coding regions of the gene). How the ovary responds is resultant on the FSHR genotype. For example, Ser680Asn, a polymorphism in the FSHR gene has been shown to aid in predicting the severity of a woman's OHSS. Ordinarily FSH stimulates the growth of ovarian follicles, however, when mutated, it is stimulated by the hCG resulting in excessive follicle development.

Spontaneous OHSS, OHSS that arises and cannot be attributed to any form of ovarian stimulation or Assisted Reproductive Technology, has been linked to activating mutations in the FSHR <ref name="PMID23499866"><pubmed>23499866</pubmed></ref>. This familial disorder is an autosomal dominant one. In most cases the FSHR can be stimulated by the presence of Thyroid Stimulating Hormone (TSH) or hCG, in the absence of FSH (the ligand for FSHR).

===Lutenizing Hormome===

The '''Lutenizing Hormone Receptor''' (LHR) gene in humans is comprised of 11 exons. Animal studies have shown that many primates exhibit a similar gene which is comprised of only 10 exons, however a gene lacking the 10th exon has been identified and termed the type 2 LHR. Expression of the type 2 LHR has been seen in humans. The type 2 LHR, compared to the wild-type LHR appears to be repaired with regard to its function. Defects in the type 2 LHR include a decrease in efficiency of transport to the plasma membrane and irregularities in signal transduction. Inactivating mutations in the LHR have been seen to cause infertility in women as well as amenorrhoea. Activating LHR gene mutations are asymptomatic and are not associated with OHSS in women.

===Bone Morphogenic Protein===

An imporant growth factor, derived from oocytes called '''BMP-15''' (Bone Morphogenic Protein 15) is vital for female fertility. It belongs to the family of growth factors, Transforming Growth Factor β (TGF-β) and is heavily involved in folliculogenesis. It has been found that mutations in the BMP-15 gene caused infertility in female sheep. Conversely, it has also been indicated in enhanced fertility when BMP-15 is present is high amounts in follicular fluid <ref name="PMID19573286" />.

A case study done by Hanevik ''et. al.'' in 2013 <ref name="PMID21565556"><pubmed>21565556</pubmed></ref> found that a Single Nuclear Polymorphism (SNP) in the BMP-15 gene is responsible for a high response to ovarian hyper-stimulation. The aim of the study was to test the effect the SNP had on BMP-15 with regard to high and low responders buy taking blood from 53 high responders, 38 low responders and 100 non-responders (controls) and analysing 5 noted SNP's. Results from their study showed a correlation between a high response to ovarian hyper-stimulation and the BMP-15 9G allele. The article does state however, that further research is required into the molecular effects of SNP's on the function of BMP-15.

===Vascular Endothelial Growth Factor===

'''Vascular endothelial growth factor''' (VEGF) has been indicated as one of the key agents causing vascular permeability and subsequent ascites in OHSS. The gene, which is located on chromosome 12, is made up of 8 exons (coding regions), of which exons 6 and 7 do not always appear due to the exons being spliced out.The splicing of this gene allows for various isoforms of the gene to exist of which VEGF 121 and 165 appear to play a role in angiogenesis. There are two VEGF Receptors, VEGFR-1 and VEGFR-2 that belong to the tyrosine kinase family of receptors (for more information on VEGF see [[Pathophysiology]]). Because of its distinct role in OHSS, it has been targeted as an area for research for potential treatments. The idea is that if the genetic expression of VEGF and its receptors can be controlled, OHSS can be avoided or treated.<ref name="PMID19573286" />

A different study by Hanevik ''et. al.'' , <ref name="PMID22587628"><pubmed>22587628</pubmed></ref> done in 2012 involved analysing blood samples from 53 women with OHSS and 100 women without it (controls) and analysing 6 SNP's in the VEGFR2 gene to find any genetic variations. They found a correlation between women with the VEGF +405cc genotype and the development of OHSS indicating women that undergo controlled ovarian hyper-stimulation and posses his genotype, are at an increased risk of developing OHSS.

</div>

== Current Research on Animal Models==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">
{|
|-bgcolor="F8E0F1"
|
<span style="font-size:120%">'''Inhibition of Cyclooxygenase-2 (COX-2) by Meloxican decreasing the incidence of OHSS in Rat Model'''</span> <ref name="PMID18166186"><pubmed>18166186</pubmed></ref>

Reasearch was carried out to investigate the effects of selective inhibition of the enzyme COX-2 on the Ovarian Hyperstimulation Syndrome (OHSS) using Female Wistar rates as the subjects. The research aimed to find results by measuring the number of antral and luteinized follicles, ovarian weight, vascualr endothelial growth factors and COX-2 immunohistochemistry. The rats being tested were all 22 days old and were divided into four equal groups;

'''Group 1 (Control group)''' was subject to a 0.1 ml of Intraperitoneal Saline from days 22 ~ 26

'''Group 2 (Mildly-stimulated group)''' subject to 10IU of pregnant mare serum gonadotrophin (PMSG) on day 24 and then 10IU of Human Chorionic Gonadotrophin (hCG) on day 26

'''Group 3 (OHSS positive group)''' was subject to 10IU of PMSG from days 22 ~ 26 and then administered 30IU of hCG on day 26 to induce OHSS

'''Group 4 (OHSS positive variant group)''' received 15mg/ml of Meloxicam 2 hours prior to administration of 10IU PMSG from days 22 ~ 26

Results showed there was no difference in ovarian weight in samples from Group 1 and Group 2, however Group 3 showed signs of significant ovarian weight increase which in group 4 was suppressed by the introduction of Meloxicam. No differences were observed in the number of antral follicles amongst the four test groups. Results from Group 2 and Group 3 showed that the granulosa cells of preovulatory follicles and the stromal cells were highly VEGF immunoreactive, however the Meloxicam treated Group 4 showed less immunoreactivity than Group 2 and Group 3 which indicated the correlation between Meloxicam and the diminished VEGF expression. Group 3 presented an increased COS-2 immunoreactivity which was highly diminished than in Group 4.

The research concluded that in a rat model, the enzyme Meloxicam has a beneficial effect on OHSS by reducing the increase of ovarian weight and the expression of VEGF associated with OHSS, the effects of which may be mediated by the inhibitory capacity of COX-2 on Meloxicam
|}

{|
|-bgcolor="FF99FF"
|
<span style="font-size:120%">'''Inhibition of Ovarian VEGF secretion by activation of Dopamine Receptor 2'''</span> <ref name="PMID25217874"><pubmed>25217874</pubmed></ref>

This research was carried out to investigate a possibility in whether a Dopamine Receptor 2 agonist '''(D2-ag)''' can assist in the prevention of Ovarian Hyperstimulation Syndrome, using rat models, by decreasing the ovarian vascular endothelial growth factor '''(VEGF)''' production. Using Immature Wistar rats (22 days old) as their animal model, the rats were initially stimulated with Gonadotrophins to mimic the onset and effects of OHSS and then subjected to treatment with a D2-agonist and/or a D2-antagonist (D2-ant). The vascular permeability was measured at the endpoint after day 26 by measuring the peritoneal extravasion of a previously injected dye and ovaries from all subjects were collected to assess the effects of D2-ag and D2-ant on the production of Ovarian VEGF. The expression of VEGF mRNA was measured by quantitative real time PCR and the levels of VEGF proteins were measured by Western Blots.

Results showed that the D2-ag caused a large reduction in the vascular permeability which was in turn associated with the great decreased in VEGF protein production in the OHSS rat ovaries, whereas the introduction of D2-ant showed opposite results with a increase in the vascular permeability leading to the increase of VEGF protein production in the ovaries. Ovarian VEGF mRNA levels were found to be unaffected by the introduction of these drugs in OHSS rat subjects. Conclusions were drawn on the fact that Dopamine Receptor 2 agonists prevent the increase of vascular permeability in subjects with OHSS by decreasing the ovarian production of VEGF and also that due to the dose-dependent inhibitory effect of the D2-ag on ovarian VEGF, current OHSS therapies used in humans can benefit by increasing the intraovarian concentration of D2-ag.
|}
</div>

==Glossary==
<div class="mw-collapsible" data-expandtext="↓" data-collapsetext="↑">

'''Ascites'''- An accumulation of fluid in the peritoneal cavity with resultant abdominal swelling

'''Cabergoline''' - A dopamine receptor agonist used to treat hormone imbalance.

'''GnRH antagonist''' - Gonadotropin Releasing Hormone - A class of compounds that are similar in terms of the structure of natural Gonadotropin Releasing Hormone but has a antagonistic effect.

'''hCG'''- Human Chorionic Gonadotropin

'''Hemoconcentration'''- An increase in the concentration of circulating red blood cells in response to a decrease in blood plasma volume

'''Hypovolemic'''- A decrease in circulating blood volume

'''Iatrogenic'''- Illness caused as a result of a medical examination or treatment

'''Intravenous fluids''' - Is the infusion of liquid substances directly into a vein.

'''IVF'''- In-vitro Fertilization

'''NSAID'''- Non-steroidal Anti-Inflammatory Drug e.g. Ibuprofen

'''OHSS'''- Ovarian Hyper-stimulation Syndrome

'''FSH''' - Follicle Stimulating Hormone

'''LH''' - Luteinizing Hormone

'''Oliguria'''- Decreased urine output/small amounts of urine produced

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==References==