2015 Group Project 2

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2015 Projects: Three Person Embryos | Ovarian Hyper-stimulation Syndrome | Polycystic Ovarian Syndrome | Male Infertility | Oncofertility | Preimplantation Genetic Diagnosis | Students
2015 Group Project Topic - Assisted Reproductive Technology
This page is an undergraduate science embryology student and may contain inaccuracies in either description or acknowledgements.

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Ovarian Hyper-stimulation Syndrome (OHSS)

Ovarian Hyper stimulation Syndrome (OHSS) is an iatrogenic complication of assisted reproduction technology, in which women take medications to stimulate oocyte growth. It is generally identified by cystic enlargements of the ovaries a fluid shift from the intravascular to the third space due to the increased capillary permeability and ovarian neoangiogenesis [1]. It is an occurrence which is dependent on the administration of the Human Chorionic Gonadotropin (hCG). This wikipage aims to provide clear information on the epidemiology, causatives of OHSS, symptoms as well as treatment and prevention methods.

Epidemiology

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.[2]

Severe 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.[3] 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.

Causative Agents

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 find difficulty in becoming pregnant, they are given to assistive medication which help them to produce and release eggs to further increase their chances of fertilization and pregnancy. Ovarian Hyperstimulation Syndrome occurs when the ovaries are overstimulated by the assistive medication which causes the ovaries to swell, leaking fluids into the belly and abdomen. The main prevalence of OHSS onset is linked with the administration of injectable Follicular stimulating hormones (gonadotrophins), which are human chorionic gonadotropins


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Symptoms

OHSS is classified based on a criteria from mild, moderate and severe:

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 [2].

Classifications of Ovarian Hyper-stimulation Syndrome [1]

Classification Symptoms
Mild Grade 1 - Abdominal distention and discomfort

Grade 2 - Abdominal distention, discomfort with nausea, vomiting and/or diarrhea and ovarian enlargement from 5~12cm

Moderate Grade 3 - All features of Mild OHSS with ultrasonographic evidence of ascites
Severe 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


PMID 24996451 [4]

PMID 23378404 [5]

Diagnosis

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.

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 notices, 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 greater than 20 oocytes retrieved.

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 clinical 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).

If the clinician further suspects a women of having OHSS, an ultrasound can be done.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 hemoconcentration with a hematocrit.

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. [6]

Pathophysiology

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 [2].

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 [7]. 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. [7] showed that women experiencing OHSS had substantially higher plasma levels of VEGF and lower levels of VEGFR1.

Complications

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 [2].

1-2% of women who suffer from ovarian stimulation develop a severe form of OHSS. 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. [8] 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) [9].

Treatment

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.[6]

Mild to Moderate OHSS

Mild OHSS can often resolve on its own, however, moderate OHSS may include treatments such as[2]:

  • 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 [2]:

  • 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.

If there are serious complications then additional treatments are required:

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

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 involved managing the eliminating the symptoms until such time as the syndrome resolves itself.

Prevention

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.

1) Risk factors

Primary risk factors include preexisting factors likely to exacerbate the ovarian stimulation response. They 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 (AMH) markers are a valuable predictive tool to identify women with a high pretreatment basal AMH concentration and thus risk of OHSS, with a 90.5% sensitivity and 81.3% specificity. PMID 26074966

Secondary risk factors involve the monitoring of ovarian response parameters for rapidly rising E2 levels, E2 concentration larger than 2500 pg/mL, large number of developing follicles (10-14mm) on the day hCG is administered and a large number of oocytes retrieved, once COS has been initiated. These factors in combination, act as a predictive tool to assess the likelihood of severe OHSS development, with a 83% sensitivity and 84% specificity. PMID 19007627

2) Prevention

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


Secondary Prevention aims to prevent progression to OHSS once COS has been initiated and the patient has been found to mount an exaggerated response.

a) Coasting: This first-line secondary preventative strategy 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.

b) Cryopreservation of Embryos: After oocyte retrieval, the embryos are cryopreserved and 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.

c) Cycle cancellation: 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.

d) Use of alternative Agents

PMID 20416867

Genetics

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.

Dr. Botros Rizk, of the University of South Alabama College of Medicine [10], 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 [11]. 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).

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.

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.

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.[10]

Effect on the Newborn

Animal Models

Glossary

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

Oliguria- Decreased urine output/small amounts of urine produced

References

  1. 1.0 1.1 <pubmed>22065820</pubmed>
  2. 2.0 2.1 2.2 2.3 2.4 2.5 Wikipaedia, [ https://en.wikipedia.org/wiki/Ovarian_hyperstimulation_syndrome ], 'Ovarian Hyperstimulation Syndrome?'
  3. 12498425</pubmed>
  4. <pubmed>24996451</pubmed>
  5. <pubmed>23378404</pubmed>
  6. 6.0 6.1 <pubmed>22416285</pubmed>
  7. 7.0 7.1 <pubmed>21082502</pubmed>
  8. 24996451</pubmed>
  9. 23378404</pubmed>
  10. 10.0 10.1 <pubmed>19573286</pubmed>
  11. <pubmed>23499866</pubmed>