CHAPTER 12 Lubna Pal and Shefali Pathy Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, CT, USA Polycystic ovarian syndrome (PCOS) is an endocrine and metabolic disorder characterized by androgen excess, ovulatory dysfunction, and/or polycystic ovaries. It was first described by Stein and Leventhal in 1935 [1]. The etiology is still unclear, and the diagnosis of PCOS is one of exclusion, i.e. other etiologies of these characteristics should be excluded before identifying this as the diagnosis. What is agreed upon is that PCOS is a syndrome consisting of four main features: chronic course, features of androgen excess, ovulatory dysfunction and a classic sonographic polycystic ovarian morphology (PCOM). The prevalence of PCOS varies depending on the criteria used to make the diagnosis; however, what is known is that PCOS is a worldwide women’s health issue, which is likely underappreciated given this controversy in defining it. This condition can have significant long‐term health consequences, with implications for a diverse array of disorders that range from diabetes, cardiovascular disease and mental health concerns to infertility, pregnancy‐related complications, to increased risk of endometrial cancer [2–5]. The definition of PCOS has been developed over time by various expert opinions established by leading health organizations. The three primary diagnostic criteria currently in use are: (i) the NIH criteria, developed in 1990; (ii) the Rotterdam criteria proposed at the ESHRE/ASRM conference in Rotterdam (2003); and (iii) the Androgen Excess Society (AES) criteria proposed in 2006 (Table 12.1). The primary criteria revolve around the presence or absence of features of hyperandrogenism, ovulatory dysfunction, and PCOM on ultrasound evaluation. Notably, all of the organizations require the exclusion of other endocrine disorders, which could result in a PCOS‐like phenotypic presentation (see Table 12.3) [1, 6, 7]. Table 12.1 Defining PCOS. Hirsutism and acne are commonly recognized as features of hyperandrogenism, whereas hyperandrogenemia refers to the presence of elevated circulating levels of androgens. The NIH, in 1990 established a broad definition of PCOS, identifying the three primary characteristics as: (i) hyperandrogenism (clinical or biochemical); (ii) ovulatory dysfunction; and (iii) exclusion of other endocrine disorders that could result in the constellation of signs and symptoms [8]. In 2003, The Rotterdam conference modified the diagnostic criteria by including the ultrasonographic findings of “polycystic ovarian morphology (PCOM)” to the inclusion criteria. This addition allowed for the identification of a subset of women who would be at an increased risk of ovarian hyperstimulation when undergoing ovulation induction treatment for the management of oligo‐anovulatory infertility. As per the Rotterdam criteria, PCOS diagnosis requires the presence of two of the following three criteria: (i) hyperandrogenism (clinical and/or biochemical); (ii) ovulatory dysfunction; and (iii) PCOM on sonography (evidence of any one or both of the following in either ovary: (i) presence of 12 or more follicles measuring 2–9 mm in diameter; and/or (ii) an increased ovarian volume (> 10 ml) in the absence of a dominant follicle or corpus luteum in either ovary). The most recent modification were proposed by the AES with an aim of minimizing potential for diagnostic heterogeneity that resulted from a widespread adoption of the Rotterdam criteria that allowed inclusion of milder phenotype variants of PCOS. Based on the AES criteria, diagnosis of PCOS is made in the presence of: (i) clinical and/or biochemical evidence of androgen excess; (ii) evidence of ovulatory dysfunction (either manifest as oligo‐anovulation and/sonographic evidence of PCOM); and (iii) after exclusion of other causes of androgen excess or ovarian dysfunction [8]. While diagnosis of PCOS based on the Rotterdam criteria allows identification of milder phenotypes wherein PCOS diagnosis may have minimal to no health consequences. PCOS diagnosis based on AES criteria allows identification of PCOS phenotypes that are at risk for recognized long‐term consequences created a broader criteria base to incorporate all women, with all phenotypes of PCOS who are at risk for the consequences. Further research is necessary to define particular risks in different ethnic groups and clearly define options for each phenotype. The prevalence of PCOS varies depending on the criteria used for diagnosis. For example, using the 1990 NIH criteria, the prevalence of PCOS varies between 6.5% and 8% [8], affecting 5 million women in the US and 105 million women worldwide. While there appears to be no significant difference among various ethnic backgrounds, this may be a reflection of insufficient sample size in most studies. In contrast, by incorporating a transvaginal ultrasound (TVUS) finding of PCOM to the Rotterdam criteria, there is an estimated 20–60% increase in prevalence in women with hirsutism and oligomenorrhea. [8, 9]. As a result, the documented prevalence of PCOS is strongly dependent on the criteria used to define the syndrome as well as on the population studied. [8] While the etiology of PCOS is not clearly understood, and there is some debate as to the exact definition, most women will present to their providers with a combination of complaints of menstrual abnormalities, facial and /or body hair excess, and/or with fertility problems. Menstrual abnormalities usually range from amenorrhea and oligomenorrhea to menometrorrhagia. For many women, menstrual dysfunction dates back to since menarche and hence may not even be apparent to her as being “abnormal.” Evaluation for other causes of menstrual abnormalities is critical, as a variety of hormonal (disorders of thyroid, pituitary, and adrenal gland) and structural (tumors secreting androgens or cortisol, as well as focal endometrial pathologies such as endometrial polyps, hyperplasia, and even cancer) disorders can result in the spectrum of menstrual dysfunction seen in PCOS. Clinical manifestations of hyperandrogenism commonly encountered in women with PCOS include excess of facial and/or body hair, and acne. While thinning of scalp hair (female pattern hair loss or androgenetic alopecia) is more common in women with PCOS compared to the general population, its relationship to androgen excess or signaling remains unclear. Hirsutism is the presence of excessive terminally differentiated hair in a male pattern distribution (primarily midline). Sometimes this concern surfaces only on questioning, when women will report difficulty with facial hair and history of trying various methods for hair removal (including shaving, waxing, and laser). Commonly, women with PCOS acknowledge a long‐standing history of some degree of acne and report having tried one or more non‐prescription over the counter formulations. Often, many would also have seen a dermatologist for this issue. Although menstrual dysfunction and symptoms of hyperandrogenism may be the reason for a woman seeking consultation, many are also concerned about their fertility potential, and this aspect merits attention. Since most women present during the reproductive years, given that ovulatory dysfunction underlies menstrual dysfunction, infertility will eventually be a concern. PCOS is the most common underlying diagnosis in women with ovulatory infertility, and may be seen in almost 80% of women with anovulatory infertility. Despite the obvious however, since infertility is often multifactorial and treatment modalities can be complex, these patients should preferentially be referred for specialty care with an infertility specialist. No single sign or symptom is pathognomonic for PCOS. Each of the prevailing diagnostic criterion emphasizes combinations of clinical and endocrine phenomenon commonly encountered in PCOS, namely: (i) hyperandrogenism (clinical and/or biochemical); (ii) oligo‐ovulation characterized by menstrual disturbance; and (iii) PCOM on ultrasound. Elimination through systemic testing of additional conditions that could potentially mimic PCOS is inherent to each one of the diagnostic paradigms. Diagnosis of PCOS should therefore be considered only after other etiologies (Table 12.3) have been excluded. A complete evaluation should begin with a complete history and physical exam. This would include a thorough menstrual history, focused history of hyperandrogenic symptoms (presence, duration and persistence, rapidity of progression, and features of virilization, such as temporal hair loss, deepening of voice, regression in breast size and clitoromegaly, that should alert one of a possible androgen secreting tumor) as well as inquiry of medication use (e.g. valproic acid as well as use of potent androgenic progestins are both associated with features of hyperandrogenism). While oligomenorrhea is the most common menstrual abnormality (menstrual length greater than 35 days and/or 8 or less menstrual periods during a year), menorrhagia (excessive and prolonged bleeding at time of menses), polymenorrhea (short menstrual cycles <21 days) and menometrorrhagia (erratic, unscheduled, and unpredictable bleeding) can all be encountered in the setting of PCOS and reflect an underlying ovulatory disturbance. Symptoms of hyperandrogenism typically encountered include acne and facial and/or body hair excess. Inquiry about pharmacologic and non‐pharmacologic treatments for hirsutism and acne, such as oral contraceptives, antiandrogen treatments as well as waxing and laser therapies are important. Physical examination should include an assessment of body habitus, features of insulin resistance (central obesity as reflected by body mass index and waist circumference, and evidence of acanthosis nigricans (AN)) are meaningful for risk quantification in addition to signs of androgen excess. Excessive terminal hair evident in a male pattern distribution (chin, upper lip, mid‐abdomen, and upper/medial aspects of thighs), and acne (face, forehead, and upper back) (Figure 12.1) are common symptoms of hyperandrogenism. Figure 12.1 Photographs depicting facial and body terminal hair growth scored according to the modified FG method. Source: Yildliz et al., 2010 [10]. Hirsutism: Unwanted hair growth is a commonly encountered complaint among women. In any setting of excessive hair growth, hypertrichosis (generalized increase in fine and non‐pigmented hair with a non‐sexual pattern of distribution, which commonly has a familial inheritance, but may also be associated with conditions such as malnutrition, thyroid dysfunction, and certain medications such as phenytoin, valproic acid, and minoxidil) must be distinguished from hirsutism (defined as the presence in females of terminal, or dark, coarse hairs that grow in a pattern normally seen in males). Hypertrichosis is generally not associated with androgen excess, although hyperandrogenism may exacerbate hypertrichosis. Regardless of the severity, hirsutism is a cause of much distress in the affected women and warrants further evaluation. Excessive facial and/or body hair growth is the presenting complaint in almost 2/3rd of women with PCOS. The presence and the severity of hirsutism should be objectively quantified based on the extent and severity of excess hair growth. The Ferriman‐Gallwey (FG) scoring system was developed in 1961 as a means of quantifying hirsutism for research purposes [3]. The original scoring system assessed the distribution and severity of hair growth on 11 body areas, whereas the modified scale limits assessment of hair distribution across nine facial and body areas (Table 12.2) [10]. Region‐specific hair density is scored on a scale from 0 (absence of terminal hairs) to 4 (extensive terminal hair growth). The modified FG scale is commonly utilized in clinical practice to objectively assess for the presence and severity of hirsutism and a score of >8 is commonly utilized as objective evidence of hirsutism Table 12.2 Objective Assessment of Hirsutism: modified Ferriman‐Gallwey (9 site) score Source: Yildliz et al., 2010 [10]. Site‐specific density of terminal hairs at each site is scored from 0 (absent) to 4 (dense) Hirsutism defined as total score > 8 Acne is another prevalent symptom of hyperandrogenism noted in women with PCOS (Figure 12.2). Exaggerated effects of androgens at the level of the pilosebaceous unit are recognized to underline a predisposition to acne in this population. Forehead, face, chin, chest, and upper back are common sites and acne lesions encountered can range from papules, to pustules, cysts, and nodules.
Polycystic ovarian syndrome
Clinical questions
Introduction
Features
1990 NIH criteria
ESHRE/ASRM (Rotterdam) 2003
AES 2006
Hyperandrogenism (acne and/or hirsutism)
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Hyperandrogenemia
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Ovulatory dysfunction/menstrual abnormalities
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Polycystic ovaries on ultrasound
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Epidemiology
Region
Site
Score
Face
Upper lip
Chin
Body
Mid chest
Upper back
Lower back
Upper abdomen
Lower abdomen
Thighs
Total score
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