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A major diagnostic tool for PCOS is a pelvic ultrasound, but PCOS diagnosis cannot be completely dependent on just pelvic ultrasounds. A patient with PCOS may not necessarily have polycystic ovaries, and those with ovarian cysts may not necessarily have PCOS. A range of diagnostic assessments and associated symptoms have to be thoroughly investigated
A major diagnostic tool for PCOS is a pelvic ultrasound, but PCOS diagnosis cannot be completely dependent on just pelvic ultrasounds. A patient with PCOS may not necessarily have polycystic ovaries, and those with ovarian cysts may not necessarily have PCOS. A range of diagnostic assessments and associated symptoms have to be thoroughly investigated


Diagnostic Assessment
==Medical history and examination==
Medical history and examination
Clinical questions are asked or filled out in the form of a questionnaire to assess and assist in the diagnosis of PCOS. Studies show that those with a history:
Clinical questions are asked or filled out in the form of a questionnaire to assess and assist in the diagnosis of PCOS. Studies show that those with a history:
infrequent and irregular menstruation
*infrequent and irregular menstruation
hirsutism (related to high levels of androgens in the blood – hyperandrogenism)
*hirsutism (related to high levels of androgens in the blood – hyperandrogenism)
obesity
*obesity
acne production  
*acne production  
are at a higher predictive risk of PCOS. But questions regarding failed pregnancy attempts and history of nipple discharge proved no correlation in diagnosing PCOS. <ref> http://www.ncbi.nlm.nih.gov/pubmed/17872783 </ref>
are at a higher predictive risk of PCOS. But questions regarding failed pregnancy attempts and history of nipple discharge proved no correlation in diagnosing PCOS. <ref> http://www.ncbi.nlm.nih.gov/pubmed/17872783 </ref>


Blood Test
==Blood Test==
A patient with elevated levels of androgens, hyperandrogenism, is very highly likely to have PCOS. <ref> https://www.ncbi.nlm.nih.gov/pubmed/20591140 </ref>
A patient with elevated levels of androgens, hyperandrogenism, is very highly likely to have PCOS. <ref> https://www.ncbi.nlm.nih.gov/pubmed/20591140 </ref>
Androgens, such as testosterone, and free androgen index (FAI) are the two tests best used in diagnosing hyperandrogenism.
Androgens, such as testosterone, and free androgen index (FAI) are the two tests best used in diagnosing hyperandrogenism.
Line 112: Line 111:
A study in 2014 showed that Anti-Müllerian hormone (AMH) is found to be elevated in patients with PCOS <ref> https://www.ncbi.nlm.nih.gov/pubmed/24821925 </ref>, giving rise to its potential clinical implication in diagnosing PCOS. AMH is exclusively produced in ovarian follicles, with individual AMH concentration reflecting the quantity of remaining primordial follicles and measure of ovarian reserve.  
A study in 2014 showed that Anti-Müllerian hormone (AMH) is found to be elevated in patients with PCOS <ref> https://www.ncbi.nlm.nih.gov/pubmed/24821925 </ref>, giving rise to its potential clinical implication in diagnosing PCOS. AMH is exclusively produced in ovarian follicles, with individual AMH concentration reflecting the quantity of remaining primordial follicles and measure of ovarian reserve.  


Gynecologic ultrasonography
==Gynecologic ultrasonography==
Gynecologic ultrasonography is a pelvic ultrasound, specifically to the female pelvic region, with regards to the uterus, ovaries and the fallopian tube. The examination can be performed by transabdominal ultrasonography, with a full bladder, or transvaginal ultrasonography with a vaginal transducer. Typically transvaginal imaging shows a better and clearer image than transabdominal ultrasonography, as it uses higher frequency imaging, but is limited to areas it can reach. In the case of PCOS, both techniques can provide an image of the ovaries. Studies suggest that if more than 25 follicles are seen in an ovary, predominantly in the periphery, in women between 18-35 years, it is described to have a polycystic ovarian morphology. <ref> https://www.ncbi.nlm.nih.gov/pubmed/24345633 </ref>
Gynecologic ultrasonography is a pelvic ultrasound, specifically to the female pelvic region, with regards to the uterus, ovaries and the fallopian tube. The examination can be performed by transabdominal ultrasonography, with a full bladder, or transvaginal ultrasonography with a vaginal transducer. Typically transvaginal imaging shows a better and clearer image than transabdominal ultrasonography, as it uses higher frequency imaging, but is limited to areas it can reach. In the case of PCOS, both techniques can provide an image of the ovaries. Studies suggest that if more than 25 follicles are seen in an ovary, predominantly in the periphery, in women between 18-35 years, it is described to have a polycystic ovarian morphology. <ref> https://www.ncbi.nlm.nih.gov/pubmed/24345633 </ref>
Magnetic Resonance Imaging
 
==Magnetic Resonance Imaging==
Ovaries can also be seen on MRIs. On MRIs, PCOS is characterized by numberous peripheral cysts where the ovaries affected to be slightly larger than normal. Although MRI is seen to be effective in ovarian imaging, the finding of peripheral ovarian cysts in MRIsmay not be PCOS specific. <ref>  http://www.ncbi.nlm.nih.gov/pubmed/8888256 </ref> But studies have seen that MR imaging in adolescence uncover distinct differences between young patients with and without PCOS <ref> http://www.ncbi.nlm.nih.gov/pubmed/23292744 </ref>, with also great diagnostic sensitivity with patients between the age of 21-30 <ref> http://www.ncbi.nlm.nih.gov/pubmed/19241321 </ref>, providing assistance of imagery in patients whom may be opposed to transvaginal ultrasounds.
Ovaries can also be seen on MRIs. On MRIs, PCOS is characterized by numberous peripheral cysts where the ovaries affected to be slightly larger than normal. Although MRI is seen to be effective in ovarian imaging, the finding of peripheral ovarian cysts in MRIsmay not be PCOS specific. <ref>  http://www.ncbi.nlm.nih.gov/pubmed/8888256 </ref> But studies have seen that MR imaging in adolescence uncover distinct differences between young patients with and without PCOS <ref> http://www.ncbi.nlm.nih.gov/pubmed/23292744 </ref>, with also great diagnostic sensitivity with patients between the age of 21-30 <ref> http://www.ncbi.nlm.nih.gov/pubmed/19241321 </ref>, providing assistance of imagery in patients whom may be opposed to transvaginal ultrasounds.



Revision as of 15:52, 7 October 2015

2015 Student Projects 
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.

Female Infertility

Prevalence of Primary Infertility in 2010

Female Infertility refers to the failure to conceive after one year of regular unprotected intercourse in females [1]. In 2010, infertility affected 48.5 million couples world wide and the areas of highest prevalence included North Africa and Middle East, South Asia, Central/Eastern Europe and Central Asia and Sub-Saharan Africa [2]. As there are several causes of female infertility, we will be focusing on infertility that is caused by Polycystic Ovarian Syndrome (PCOS), the most common cause of infertility that is medically treatable [1].

Polycystic Ovarian Syndrome

Polycystic Ovarian Syndrome (PCOS) is a common endocrine disorder, affecting up to 20% of reproductive aged women [3] It is the most common cause of anovulatory infertility [1] which refers to infertility caused by the the absence of ovulation.

Causes

PCOS is a disorder of heterogeneous origin with unknown aetiology [3]. Studies have shown that both genetic and environmental factors contribute to the development of PCOS in women however there is limited research into the actual interactions between these two factors [4].

Genetic Factors

Despite the lack of information regarding its aetiology, there is increasing evidence for a genetic involvement in the endocrine disorder. Studies have shown that genes play an important role in contributing towards the clinical and biochemical features of the disease [3]. This evidence includes the family clustering of cases, greater unanimity between monozygotic twins than heterozygotic twins and the ability to inherit endocrine and metabolic features of PCOS [3].

In one study, 115 sisters of women with PCOS were examined and results showed that half of these sisters had high testosterone levels, suggesting that hyperandrogenemia is a common trait with a dominant pattern of inheritance. These results strongly supported the idea of the familial clustering of biochemical features such as hyperandrogenism in first degree relatives [5].

Several genes have been considered to play an important role in the development of PCOS such as CYP11A, the insulin gene, the follistatin gene and a region near the insulin receptor gene. Yet, the evidence supporting most of these genes has been refuted by larger studies, except for the region near the insulin receptor gene [5].

There has been strong evidence linking the gene CYP11a with hyperandrogenism in women with PCOS. [6] While it doesn't isolate this gene as the sole cause of PCOS, variation of the genotype at this locus contributes to production of excess androgen [7].

Studies have also shown that there is strong evidence for linkage between the alleles at the Variable Number Tandem Repeats (VNTR) which is situated 5' to the insulin gene and PCOS. The data from the study suggests that it is a very susceptible region in PCOS and also may play a role in the development of hyperinsulinaemia [8].

Environmental Factors

The prevalence of PCOS in populations where there has been a constant gene pool indicates that environmental factors play a significant role in the aetiology of PCOS.

Obesity and Diet

Obesity is the major environmental factor driving the development of PCOS in susceptible individuals. The rising rates of PCOS have been paralleled by the widespread emergence of obesity and type 2 diabetes which are prevalent in developed countries. The risk of developing PCOS from obesity is compounded by poor dietary choices and lack of physical activity which has begun to characterise the lifestyle in developed countries [5].

Medication

Studies have shown that valproic acid in medication used to treat epilepsy and bipolar disorders contributes to the development of PCOS. Women with these disorders may develop the typical features of PCOS such as polycystic ovaries, anovulation, hyperandrogenism and obesity [9]. Recent studies also suggest that the weight gain from medication is significant as it can lead to the development of PCOS [5].

Pathogenesis

The pathogenesis of polycystic ovarian syndrome is poorly understood, however it is believed that insulin resistance and excess androgens such as testosterone play a fundamental role. Underlying factors such as obesity and genetic predispositions likely contribute to the onset of polycystic ovarian syndrome through the development of a combination of hyperinsulinemia and hyperandrogenemia.[10]

Hyperinsulinemia

Hyperinsulinemia is a term that defines the presence of excessive amounts of insulin in the blood relative to the amount of glucose. [11] This phenomenon is typically associated with obesity and excess adipose tissue, both of which are associated with insulin resistance. In order to overcome this resistance, insulin secretion is increased in an attempt to normalise blood glucose levels, thereby leading to hyperinsulineamia. [12] Excessive levels of insulin typically cause disruption to the hypothalamus-hypophysis-ovary axis whilst insulin resistance in ovarian tissues leads to decreased metabolic signalling. However, steroidogenic activity is largely unaffected by the impaired metabolic signalling, thereby paving the way androgens to become more effect and paving the way towards hyperandrogenemia. [13]

The impact of hyperinsulinemia and hyperandrogenemia on the development of polycystic ovarian syndrome

Hyperandrogenemia

Hyperandrogenemia is a hallmark of the development of polycystic ovarian syndrome, with 80% of women presenting with excess androgen also having polycystic ovaries.[14] The disruption of the hypothalamus hypophysis ovary axis as a result of hyperinsulinemia increases the release of GnRH and LH, leading to increased androgen production in the ovarian theca cells. Hyperandrogenemia decreases the feedback sensitivity of both estradiol and progesterone within gonadotropic hypothalmic cells. [15] A deficiency of FSH is observed and correlates with the increased secretion of GnRH and LH. As a result of this deficiency, graunlosa cell aromatisation to oestrogens as well as follicle maturation and ovulation will be drastically impaired. [16]

As a consequence of the impairment of follicle maturation, small antral follicles will accumulate within the periphery of the ovary and develop a cystic morphology. Ovulation will be unable to occur due to the absence of mature follicles, culminating in infertility. [17]

Hyperandrogenism

Animal Models

Studies conducted on female rhesus monkeys have supported evidence for the foetal origins of the clinical features of PCOS [18]. It has been shown that in human females, an excess of androgen exposure at any stage from the development of the ovaries to the onset of puberty manifests as characteristic features of PCOS, such as resistance to insulin and Luteinising Hormone (LH) hypersecretion. After exposure to levels of testosterone matching those of fetal males, in utero, female rhesus monkeys were found to display the clinical and biochemical features typical of PCOS such as hypersecretion of LH and abnormal insulin action. These results correlated to those of similar studies conducted on sheep, where the pregnant ewe was exposed to excessive levels of testosterone and LH secretion and abnormality in ovarian cycles were again prominent features [19]. While these studies indicate that similar biochemical and clinical manifestations in humans originate from excess androgen exposure of the female fetus, it must be noted that it is very unlikely for any excess androgen production to be passed across the placenta from the mother to her daughter. This is because mechanisms such as androgen binding proteins and placental metabolism of androgen prevent excess androgen entering the circulation of the fetus [20].

Cell Culture Models

While studies have shown that the adrenal could be a source of excess androgen such as the adrenal [21], they were followed by various studies using cell culture models which demonstrated that the ovary was the major source of excess androgen [7] [22]. In vitro studies have shown that the production of steroids is abnormal in theca cells [21]. In women affected by PCOS, stimulation by human chorionic gonadotrophin (hCG) is followed by an increase in thecal steroid production after suppression of LH by a GnRH analogue [22]. Theca cells cultured from polycystic ovaries produce 20 times as much androstenedione as those from normal ovaries [7] with increased expression of mRNA for enzymes responsible for making steroids also reported in following studies. [23] These results have prompted many studies on genes encoding these steroidogeneic enzymes.

An example of polycysts present in the polycystic ovaries of a rat specimen

The Genetics of Infertility: Current Status of the Field

<pubmed>PMC3885174</pubmed> This article attempted to determine the role that genetics plays in female infertility. It was noted that several prominent causes of female infertility such as Galactosemia and Primary Ovarian Failure (POF) were associated with specific genes, with the GALT gene contributing to the former condition and the FMR1 gene contributing to the latter.

Causes of Sterility in Bosnia-Herzegovina Population

<pubmed>PMC4499307</pubmed> The study conducted as laid out in this article examined the causes of female sterility in the Bosnia-Herzegovina population. Married participants were arranged into various groups based upon their age. The experiment came to the conclusion that in approximately 42% of infertile married couples, female sterility was the primary cause. The two primary causes of female infertility were tubal deficiencies (31% of cases) and Diminished Ovarian Reserves (38% of cases)

Epidemiology, diagnosis, and management of polycystic ovary syndrome

<pubmed>PMC3872139</pubmed> This research article examines the causes of polycystic ovary syndrome (POS), a common cause of infertility in women. The article concluded that 50-70% of women suffer from insulin resistance secondary to Type 2 Diabetes and in many cases obseity, which may contribute partially to POS. Furthermore, 85-90% of women with oligomenorrhea also had POS, suggesting that it is an underlying cause. However, the exact pathophysiology of POS was not determined.


Signs and Symptoms

The symptoms of PCOS are different for each women. The three cardinal signs of PCOS are hyperandrogenism, polycystic ovaries and ovarian dysfunction [24]. Common clinical symptoms include [25] ;

- Infertility- Due to anovulation caused by PCOS. - Irregular Menstrual Cycles - Hirsutism - Ovarian Cysts - Obesity - Male Pattern Baldness - Skin Tags - Pelvic Pain

Along with obesity, PCOS is also associated with other metabolic issues such as insulin resistance, hyperinsulinemia and type 2 diabetes mellitus. It has also been associated with cardiovascular problems and cancers of the breast and endometrium [26].


Diagnosis

A major diagnostic tool for PCOS is a pelvic ultrasound, but PCOS diagnosis cannot be completely dependent on just pelvic ultrasounds. A patient with PCOS may not necessarily have polycystic ovaries, and those with ovarian cysts may not necessarily have PCOS. A range of diagnostic assessments and associated symptoms have to be thoroughly investigated

Medical history and examination

Clinical questions are asked or filled out in the form of a questionnaire to assess and assist in the diagnosis of PCOS. Studies show that those with a history:

  • infrequent and irregular menstruation
  • hirsutism (related to high levels of androgens in the blood – hyperandrogenism)
  • obesity
  • acne production

are at a higher predictive risk of PCOS. But questions regarding failed pregnancy attempts and history of nipple discharge proved no correlation in diagnosing PCOS. [27]

Blood Test

A patient with elevated levels of androgens, hyperandrogenism, is very highly likely to have PCOS. [28] Androgens, such as testosterone, and free androgen index (FAI) are the two tests best used in diagnosing hyperandrogenism. Androgen excess in PCOS is a result from increased synthesis and release of ovarian androgens. Dehydroepiandrosterone sulfate (DHEA-S) levels are used as a biomarker for testing androgen levels, as it is made exclusively by the adrenal glands. DHEA-S levels of above 1890 micromol/L is extremely suggestive of hyperandrogenism. [29] Free androgen index (FAI) is the ratio of total testosterone measurement to levels of sex hormone-binding globulin (SHBG). Those with PCOS will have high FAI, as this indicates a high ration of free testosterone in the body. Other blood tests are also done to help exclude other predisposing factors such as levels of Thyroid Stimulating Hormone (LSH) and Follicle-stimulating hormone (FSH). An elevated ratio of LSH to FSH, of above 2:1 [30], indicates a possibility, but not definitively, of PCOS. The effect of insulin on blood can also be tested for insulin resistance. Insulin resistance augments androgen production and increases free androgen levels by reducing SHBG. This can used as an indication marker for the possibility of PCOS A study in 2014 showed that Anti-Müllerian hormone (AMH) is found to be elevated in patients with PCOS [31], giving rise to its potential clinical implication in diagnosing PCOS. AMH is exclusively produced in ovarian follicles, with individual AMH concentration reflecting the quantity of remaining primordial follicles and measure of ovarian reserve.

Gynecologic ultrasonography

Gynecologic ultrasonography is a pelvic ultrasound, specifically to the female pelvic region, with regards to the uterus, ovaries and the fallopian tube. The examination can be performed by transabdominal ultrasonography, with a full bladder, or transvaginal ultrasonography with a vaginal transducer. Typically transvaginal imaging shows a better and clearer image than transabdominal ultrasonography, as it uses higher frequency imaging, but is limited to areas it can reach. In the case of PCOS, both techniques can provide an image of the ovaries. Studies suggest that if more than 25 follicles are seen in an ovary, predominantly in the periphery, in women between 18-35 years, it is described to have a polycystic ovarian morphology. [32]

Magnetic Resonance Imaging

Ovaries can also be seen on MRIs. On MRIs, PCOS is characterized by numberous peripheral cysts where the ovaries affected to be slightly larger than normal. Although MRI is seen to be effective in ovarian imaging, the finding of peripheral ovarian cysts in MRIsmay not be PCOS specific. [33] But studies have seen that MR imaging in adolescence uncover distinct differences between young patients with and without PCOS [34], with also great diagnostic sensitivity with patients between the age of 21-30 [35], providing assistance of imagery in patients whom may be opposed to transvaginal ultrasounds.


Prevention

Impact of physical activity on ovarian reserve markers in normal, overweight and obese reproductive age women

<pubmed>25509968</pubmed> This study focuses on the effect of physical activity on fertility in three groups of women at reproductive age; normal, overweight and obese. The results from the study suggest that there was a marked improvement in fertility as shown by the ovarian reserve markers for all 3 groups, however it was most significant in the overweight and obese groups. This study is relevant to our project as it gives an insight into the preventative measures that can be taken for infertility.

Risk factors of polycystic ovarian syndrome among Li People

<pubmed>26276294</pubmed> This study examined the risk factors entailed in Polycystic Ovarian Syndrdome (PCOS) amoung Li people. Using the method of a case control study, questionnaires were given to female Li people with and without PCOS. Analysis of the questionnaires showed that family history of diabetes, family history of infertility, bad mood, lack of physical exercise are all high risk factors of PCOS. As a result, management of these risk factors can be taken into consideration when preventing infertility through PCOS.

Vitamin D and female fertility

<pubmed>24717915</pubmed> This article is a review focusing on research regarding Vitamin D and fertility over the past year. The review found that the levels of Vitamin D is crucial for women undergoing in-vitro fertilisation. It was also found that Vitamin D was beneficial for women with PCOS and carried a protective effect against endometriosis. These observations suggest that having sufficient Vitamin D in your body can be preventative for problems associated with fertility.


Treatment

Current Treatments

CURRENT TREATMENT DISADVANTAGES
General Practitioners tend to prescribe oral anti-oestrogens, most commonly the contraceptive pill, to restore ovulation. This method only has a 50% success rate in PCOS patients. It does not directly increase fertility rates, but restores the menstrual cycle.
Lifestyle changes are highly encouraged by medical practitioners. Diet and exercise regimes can be designed with a dietitian or nutritionist. Exercise and diet plans do not directly increase fertility. They are designed to enhance weight loss, which in some patients can encourage normal hormone levels from the pituitary and thyroid.
Clomiphene citrate administration (generally in pill form, as prescribed by a GP). Such pills stimulate the pituitary gland to release GnRH to simulate ovulation (with a 72% success rate in the ___ trial). Clomiphene can cause multiple side effects, most notably abnormal uterine bleeding and pelvic pain to due enlargement of the ovaries.

Thus, it cannot be as frequently prescribed as the contraceptive pill, and careful patient monitoring is imperative.

Higher fertility rates are observed in treatments combining clomiphene citrate and metformin (79% success). Similar disadvantages as clomiphene, above.

New Trials

Some studies have found that regular Selenium supplements can encourage fertility among PCOS patients. The program, which is still in its early trial period, requires women to consume selenium tablets for 8 weeks. This study has found a significant decrease in dehydroepiandrosterone (DHEA) levels in patients, thus reducing excessive hair growth associated with PCOS. A direct link to increased fertility is yet to be established, and thus further testing is required.


References

  1. 1.0 1.1 <pubmed>26150870</pubmed>
  2. <pubmed>23271957</pubmed>
  3. 3.0 3.1 3.2 <pubmed>21896560</pubmed>
  4. <pubmed>17185788</pubmed>
  5. 5.0 5.1 5.2 5.3 <pubmed>9843997</pubmed>
  6. <pubmed>9147642</pubmed>
  7. 7.0 7.1 7.2 <pubmed>7962289</pubmed>
  8. <pubmed>9455828</pubmed>
  9. <pubmed>8413434</pubmed>
  10. <pubmed>PMC4556908</pubmed>
  11. <pubmed>PMC4114053</pubmed>
  12. <pubmed>PMC2782313</pubmed>
  13. <pubmed>PMC4334071</pubmed>
  14. <pubmed>PMC3872139</pubmed>
  15. <pubmed>PMC4334071</pubmed>
  16. <pubmed>PMC3453528</pubmed>
  17. <pubmed>PMC4562327</pubmed>
  18. <pubmed>18406243</pubmed>
  19. Padmanabhan V, Evans NP, Taylor JA, Robinson JE1997 Prenatal exposure to androgens leads to the development of cystic ovaries in the sheep. Biol Reprod 56:194
  20. <pubmed>12098657</pubmed>
  21. 21.0 21.1 <pubmed>7962325</pubmed>
  22. 22.0 22.1 <pubmed>9302378</pubmed>
  23. <pubmed>10852468</pubmed>
  24. <pubmed>14688154</pubmed>
  25. Women's Heath, U.S. Department of Health and Human Services ,[ http://www.womenshealth.gov/publications/our-publications/fact-sheet/polycystic-ovary-syndrome.html#d ], 'Polycystic ovary syndrome (PCOS) fact sheet'
  26. <pubmed>PMC4341818</pubmed>
  27. http://www.ncbi.nlm.nih.gov/pubmed/17872783
  28. https://www.ncbi.nlm.nih.gov/pubmed/20591140
  29. https://www.ncbi.nlm.nih.gov/pubmed/18844715
  30. https://www.ncbi.nlm.nih.gov/pubmed/14737959
  31. https://www.ncbi.nlm.nih.gov/pubmed/24821925
  32. https://www.ncbi.nlm.nih.gov/pubmed/24345633
  33. http://www.ncbi.nlm.nih.gov/pubmed/8888256
  34. http://www.ncbi.nlm.nih.gov/pubmed/23292744
  35. http://www.ncbi.nlm.nih.gov/pubmed/19241321


2015 Student Projects 
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.