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Causes of Anovulation: WHO Type 2: Polycystic Ovary Syndrome
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.
