Causes of Anovulation: WHO Type 2: Polycystic Ovary Syndrome

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Causes of Anovulation: WHO Type 2: Polycystic Ovary Syndrome

Richard S. Legro

Introduction

WHO Type 2 ovulatory dysfunction is characterized by disordered hypothalmic–pituitary–ovarian communication and function. PCOS classically presents with oligomenorrhea and signs of androgen excess, usually hirsutism. It represents the most common cause of ovulatory dysfunction, and it is estimated that 80% of cases of oligomenorrhea and oligo-ovulation are due to polycystic ovary syndrome. It is difficult to ascertain whether the prevalence of PCOS is increasing in both developed and developing countries with increasing rates of obesity or whether increased recognition of the syndrome (or looser diagnostic criteria) are leading to an “epidemic” of polycystic ovary syndrome. The cause of PCOS is unknown. The evidence for intrauterine effects on development of PCOS is inconclusive and genetic studies, including GWAS, have identified several significant associations with several genetic variants, which unfortunately only account for a small proportion of the phenotype. In this chapter, we review diagnostic criteria and associated morbidities, including suggested evaluation of women with PCOS.

Overview of Existing Evidence for the Diagnosis and Evaluation of Women with PCOS

There are a variety of diagnostic criteria for PCOS, and many societies have made recommendations (1). All of these are expert based. But all agree that PCOS remains a diagnosis of exclusion. The most popular are the Rotterdam criteria (2), which recommends that the diagnosis of PCOS be made if two of the three following criteria are met: androgen excess (either biochemical based on elevated circulating testosterone levels or clinical based in hirustism), ovulatory dysfunction (usually based on patient’s self-report of menstrual history), or polycystic ovaries (usually diagnosed by transvaginal ultrasound of the basis of an elevated antral follicle count, usually >12 or an increased ovarian volume, usually >10 cm³). Because only two of three criteria need to be present, it is possible to make a diagnosis without a transvaginal ultrasound exam or, for that matter, without a serum testosterone level. At the same time, disorders that mimic the clinical features of PCOS should be excluded. These include in all women thyroid disease, hyperprolactinemia, and nonclassic congenital adrenal hyperplasia (primarily 21-hydroxylase deficiency by serum 17-OHP). In select women with amenorrhea and more severe phenotypes, for example, evidence of virilization, more extensive evaluation to identify other causes is indicated.

There are significant differences in phenotype according to race and ethnicity. For example, East Asian women may be unlikely to develop signs of clinical androgen excess, such as hirsutism and acne, despite having similar elevations in circulating testosterone levels as Caucasian women with PCOS (who present with hirsutism). Women of color may be more prone to metabolic abnormalities even if normal weight. Obesity in women with PCOS is also more prevalent among wealthy countries, most commonly the United States. Obesity can worsen both reproductive and metabolic aspects of PCOS.

The diagnosis of PCOS in adolescents is even more problematic. The diagnosis should be based on the presence of clinical and/or biochemical evidence of hyperandrogenism in the presence of persistent oligomenorrhea (oligomenorrhea can be a normal transition for 1–2 years post menarche). Hyperandrogenemia remains difficult to diagnose in adolescents because there are no age or Tanner stage specific cutoffs. Many testosterone assays have poor accuracy as levels approach normal female levels. Experts have recommended using mass spectrometry to measure testosterone levels in women because of the increased accuracy, but even these assays suffer from the same imprecision at low levels. Polycystic ovaries remains a nonspecific criterion for adolescents and young women as 20%–40% may meet criteria for polycystic ovaries given the large number of antral follicles common after menarche (3).

Recently, there has been discussion whether circulating anti-Mullerian hormone (AMH), which correlates directly with the number of antral follicles, could be used to diagnose polycystic ovaries in lieu of an ultrasound exam (4). Much of the debate about the diagnosis centers around which criteria identify the most metabolically challenged women, and generally, phenotypes that focus on the clinical criteria of androgen excess and oligomenorrhea tend to have higher prevalence of metabolic syndrome and glucose intolerance. There are currently no diagnostic criteria for PCOS in peri- and menopausal women. Part of the difficulty in diagnosing PCOS in older women is the fact that the ovary fails eventually in all women, so that androgen levels, ovarian volume, and antral follicle count decrease with age. There are data, however, to suggest that the larger initial cohort of follicles in women with PCOS may mean a slightly later menopause (5).

Evaluation and Counseling of Women with PCOS

Physical examination should search for cutaneous manifestations of PCOS: terminal hair growth acne, alopecia, acanthosis nigricans (often associated with hyperinsulinemia), and skin tags. Increased adiposity, particularly abdominal, is associated with hyperandrogenemia and increased metabolic risk; therefore, BMI and waist measurements should be obtained. Signs of hypercortisolism, including moon facies, buffalo hump, abdominal striae, and proximal muscle weakness (difficulty in rising from a chair) should trigger concern for possible Cushing’s syndrome. Given the low prevalence of this syndrome and the chance for false positive findings on screening tests, routine screening for Cushing’s is not indicated in women with PCOS.

Women with PCOS are at increased risk of anovulation and infertility; in the absence of anovulation, for example, in the woman with PCOS based on polycystic ovaries and hyperandrogenism, the risk of infertility is uncertain. Although anovulatory infertility is assumed to be the primary cause of infertility, other causes may be present in the couple, and therefore routine evaluation of the male factor and tubal factor is indicated. One large randomized controlled study showed that 10% of couples presenting with presumed anovulatory infertility due to PCOS also had significant oligospermia (6). Infertility may be more common among younger women with PCOS; long-term follow-up studies suggest that most women with PCOS conceive, and their number of children is similar to other women. Because women with PCOS are at increased risk of pregnancy complications (gestational diabetes, preterm delivery, and preeclampsia) exacerbated by obesity, women should be counseled and also assessed preconception for BMI, blood pressure, and oral glucose tolerance (7).

Menstrual abnormalities range from amenorrhea to abnormal uterine bleeding and are a frequent presenting complaint. Although, most times, this is due to anovulatory bleeding, endometrial pathology, including uterine polyps and endometrial hyperplasia, must also be considered. Obesity, hyperinsulin-ism, diabetes, and dysfunctional uterine bleeding are associated both with PCOS and increased risk of endometrial cancer. Although the data linking increased event rates of women with PCOS to endome-trial cancer are stronger than that for increased cardiovascular events, similar concerns about the lack of long-term follow-up of large cohorts is present. There is, however, no recommended screening test for endometrial cancer as both transvaginal ultrasound and routine endometrial biopsy have poor sensitivity and specificity for diagnosing endometrial cancer. Although it is unlikely that obesity, per se, can cause PCOS, obesity is associated with decreases in sex hormone binding globulin, which could increase bio-available androgen levels throughout the body (8).

Although women with PCOS clearly have increased risk factors for cardiovascular disease, the data do not support an earlier onset or a lifetime higher prevalence of cardiovascular events (9). The reasons for this discrepancy are uncertain, but lack of long-term longitudinal data hampers our ability to draw conclusions. Nonetheless, women with PCOS should receive cardiovascular risk stratification by screening for the following cardiovascular disease risk factors, which appear to be more common among women with PCOS: family history of early cardiovascular disease, cigarette smoking, impaired glucose tolerance or type 2 diabetes mellitus, hypertension, dyslipidemia, obstructive sleep apnea, and obesity (10). Women with PCOS are at increased risk for glucose intolerance and diabetes even if normal weight. They should be screened with preferably a 75-g oral glucose tolerance test, but if unable, a glycohemoglobin level should be obtained. Women should likely be rescreened over time, but the optimal interval has not been established although experts have recommended every 3–5 years. It is important to note that most women with PCOS, even those with impaired glucose tolerance, will have normal fasting glucose levels, and this test alone is likely insensitive for screening for eventual diabetes risk (11). Similarly, insulin levels have little clinical significance, and routine screening of insulin levels is not recommended.

Smoking appears to be more common among women with PCOS than other women. Smoking has been associated with altered testosterone levels and exacerbations of insulin sensitivity. There are a variety of other metabolic disorders as noted above, likely related to insulin resistance that may affect women with PCOS. Dyslipidemia may be the most common metabolic abnormality, and up to 50% of women will display at least one abnormal lipid level by U.S. National Cholesterol Education Program (NCEP) guidelines. Most commonly, these are LDL elevations and triglyceride elevations. Thus, all women should be screened with a fasting lipid profile. Sleep abnormalities, including disordered sleep breathing and sleep apnea, are also more common. When symptoms (for example, daytime sleepiness or snoring) exist, patients should be screened with polysomnography, but routine polysomnography is likely not indicated. Women may also be more prone to developing nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH). Routine screening of liver function is not indicated given the uncertainty of the long-term prognosis. Finally, women with PCOS have an increased incidence of mood disorders, including anxiety and depression, and symptoms should be routinely queried on initial exam. Many of the signs and symptoms of PCOS, for example, infertility, obesity, and male pattern hair distribution, are highly correlated with decreased quality of life and likely contribute to mood disorders (12).

Conclusion

PCOS is the most common cause of ovulatory dysfunction and is a leading cause of human infertility. Although the diagnosis can usually be made by history and physical exam, ultrasound exam and hormonal assays can assist in the diagnosis. Women with PCOS should be evaluated for associated reproductive and metabolic dysfunction.

TABLE 5.1

Level of Evidence of Statements

TABLE 5.2

Grade of Strength for Recommendations

REFERENCES

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4. Pigny P, Jonard S, Robert Y, Dewailly D. Serum anti-Mullerian hormone as a surrogate for antral follicle count for definition of the polycystic ovary syndrome. J Clin Endocrinol Metab. 2006 Mar; 91(3):941–5. PubMed PMID: 16368745. Epub 2005/12/22. eng.

5. Tehrani FR, Solaymani-Dodaran M, Hedayati M, Azizi F. Is polycystic ovary syndrome an exception for reproductive aging? Hum Reprod. 2010 Jul; 25(7):1775–81. PubMed PMID: 20435693. Epub 2010/05/04. eng.

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9. Polotsky AJ, Allshouse AA, Crawford SL, Harlow SD, Khalil N, Kazlauskaite R et al. Hyperandrogenic oligomenorrhea and metabolic risks across menopausal transition. J Clin Endocrinol Metabol. 2014 Jun; 99(6):2120–7. PubMed PMID: 24517154. Pubmed Central PMCID: 4037727

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11. Legro RS, Kunselman AR, Dodson WC, Dunaif A. Prevalence and predictors of risk for type 2 diabetes mellitus and impaired glucose tolerance in polycystic ovary syndrome: A prospective, controlled study in 254 affected women. J Clin Endocrinol Metabol. 1999; 84(1):165–9.

12. Veltman-Verhulst SM, Boivin J, Eijkemans MJ, Fauser BJ. Emotional distress is a common risk in women with polycystic ovary syndrome: A systematic review and meta-analysis of 28 studies. Hum Reprod Update. 2012 Nov–Dec; 18(6):638–51. PubMed PMID: 22824735. Epub 2012/07/25. eng.

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