In women with PCOS, symptoms may include menstrual irregularities, infertility, manifestations of androgen excess, or other endocrine dysfunction. Symptoms classically become apparent within a few years of puberty.
In women with PCOS, menstrual dysfunction may range from amenorrhea to oligomenorrhea to episodic menometrorrhagia with associated iron-deficiency anemia. In most cases, amenorrhea and oligomenorrhea result from anovulation. Namely, without ovulation and endogenous progesterone production from the corpus luteum, a normal menstrual period is not triggered. Alternatively, amenorrhea can stem from elevated androgen levels. Specifically, androgens can counteract estrogen to produce an atrophic endometrium. Thus, with markedly elevated androgen levels, amenorrhea and a thin endometrial stripe can be seen.
In contrast to amenorrhea, women with PCOS may have heavy and unpredictable bleeding. In these cases, progesterone is absent due to anovulation, and chronic estrogen exposure results. This produces constant mitogenic stimulation of the endometrium. The instability of the thickened endometrium leads to unpredictable bleeding.
Characteristically, oligomenorrhea (fewer than eight menstrual periods in 1 year) or amenorrhea (absence of menses for 3 or more consecutive months) with PCOS begins with menarche. Those with PCOS fail to establish monthly ovulatory menstrual cycles by midadolescence, and they often continue to have irregularity. However, approximately 50 percent of all postmenarchal girls have irregular periods for up to 2 to 4 years because of hypothalamic-pituitary-ovarian axis immaturity. Thus, due to the frequency of both irregular cycles and acne in unaffected adolescents, some advocate delaying the diagnosis of PCOS until after age 18 (Shayya, 2011).
Last, some evidence suggests that PCOS patients with prior irregular cycle intervals may develop regular cycle patterns as they age. A decreasing antral follicle cohort as women enter their 30s and 40s may lead to a concurrent decrease in androgen production (Elting, 2000).
This condition is usually manifested clinically by hirsutism, acne, and/or androgenic alopecia. In contrast, signs of virilization such as increased muscle mass, voice deepening, and clitoromegaly are not typical of PCOS. Virilization reflects higher androgen levels and should prompt investigation for an androgen-producing tumor of the ovary or adrenal gland.
In a female, hirsutism is defined as coarse, dark, terminal hairs distributed in a male pattern (Fig. 17-2). This is distinguished from hypertrichosis, which is a generalized increase in lanugo, that is, the soft, lightly pigmented hair associated with some medications and malignancies. PCOS accounts for 70 to 80 percent of cases of hirsutism, which typically begins in late adolescence or the early 20s. Idiopathic hirsutism is the second most frequent cause (Azziz, 2003). Additionally, various drugs may also lead to hirsutism, and their use should be investigated (Table 17-3).
A. Facial hirsutism. (Used with permission from Dr. Tamara Chao.) B. Male pattern escutcheon.
TABLE 17-3Medications That May Cause Hirsutism and/or Hypertrichosis ||Download (.pdf) TABLE 17-3 Medications That May Cause Hirsutism and/or Hypertrichosis
Pathophysiology of Hirsutism
Elevated androgen levels play a major role in determining the type and distribution of hair. Within a hair follicle, testosterone is converted by the enzyme 5α-reductase to dihydrotestosterone (DHT) (Fig. 17-3). Although both testosterone and DHT convert short, soft vellus hair to coarse terminal hair, DHT is markedly more effective than testosterone. Conversion is irreversible, and only hairs in androgen-sensitive areas are changed in this manner to terminal hairs. As a result the most common areas affected with excess hair growth include the upper lip, chin, sideburns, chest, and linea alba of the lower abdomen. Specifically, escutcheon is the term used to describe the hair pattern of the lower abdomen. In women, this pattern is triangular and overlies the mons pubis, whereas in men it extends up the linea alba to form a diamond shape.
Androgenic effects on the pilosebaceous unit. In some hair-bearing areas, androgens stimulate sebaceous glands, and vellus follicles (A) are converted to terminal follicles (B), leading to hirsutism. Under the influence of androgens, terminal hairs that were not previously dependent on androgens (C) revert to a vellus form and balding results (D).
The concentration of hair follicles per unit area does not differ between men and women, however, racial and ethnic differences do exist. Individuals of Mediterranean descent have a higher concentration of hair follicles than Northern Europeans, and a much higher concentration than Asians. For this reason, Asians with PCOS are much less likely to present with overt hirsutism than other ethnic groups. Additionally, the familial tendency for the hirsutism development is strong and stems from genetic differences in 5α-reductase activity and in target tissue sensitivity to androgens.
Ferriman-Gallwey Scoring System
To quantify the degree of hirsutism for research purposes, the Ferriman-Gallwey scoring system was developed in 1961 and later modified in 1981 (Ferriman, 1961; Hatch, 1981). Within this system, abnormal hair distribution is assessed in nine body areas and scored from 0 to 4 (Fig. 17-4). Increasing numeric scores correspond to greater hair density within a given area. Many investigators define hirsutism as a score ≥8 using the modified scoring. Because of the lower follicle concentration in Far East Asians, the AE-PCOS Society suggests a threshold value ≥3 for this group (Escobar-Morreale, 2011).
Depiction of the Ferriman-Gallwey system for scoring hirsutism.
The Ferriman-Gallwey scoring system is cumbersome and thus is not used frequently in clinical settings. Nevertheless, it may be useful for following treatment responses in individual patients. Alternatively, an abbreviated score that combines only the upper and lower abdomen and chin scores may be a suitable surrogate (Cook, 2011). Also, many specialists choose to classify hirsutism more generally as mild, moderate, or severe depending on the location and density of hair growth.
Acne vulgaris is a frequent clinical finding in adolescents. However, acne that is particularly persistent or late onset suggests PCOS (Homburg, 2004). The prevalence of acne in women with PCOS is unknown, although one study found that 50 percent of adolescents with PCOS have moderate acne (Dramusic, 1997). In addition, androgen level elevation has been reported in 80 percent of women with severe acne, 50 percent with moderate acne, and 33 percent with mild acne (Bunker, 1989). Women with moderate to severe acne have an increased prevalence (52 to 83 percent) of polycystic ovaries identified during sonographic examination (Betti, 1990; Bunker, 1989).
The pathogenesis of acne vulgaris involves four factors: blockage of the follicular opening by hyperkeratosis, sebum overproduction, proliferation of commensal Propionibacterium acnes, and inflammation. As in the hair follicle, testosterone is converted within sebaceous glands to its more active metabolite, DHT, by 5α-reductase. In women with androgen excess, overstimulation of androgen receptors in the pilosebaceous unit increases sebum production that eventually leads to inflammation and comedone formation (see Fig. 17-3). Inflammation leads to the main long-term side effect of acne—scarring. Accordingly, treatment is directed at minimizing inflammation, decreasing keratin production, lowering colonization of P acnes, and reducing androgen levels to diminish sebum production.
Female androgenic alopecia is a less common finding in women with PCOS. Hair loss progresses slowly and is characterized by diffuse thinning at the crown with preservation of the frontal hairline (Quinn, 2014). Its pathogenesis involves an excess of 5α-reductase activity in the hair follicle leading to a rise in DHT levels. Moreover, androgen receptor expression in these individuals is increased (Chen, 2002).
Alopecia, however, may reflect other serious disease. For this reason, affected women are also evaluated to exclude thyroid dysfunction, anemia, or other chronic illness.
Other Endocrine Dysfunction
Although not well characterized, the association among insulin resistance, hyperandrogenism, and PCOS has long been recognized. The precise incidence of insulin resistance in women with PCOS has been difficult to ascertain for lack of a simple method to determine insulin sensitivity in an office setting. Although obesity is known to exacerbate insulin resistance, one classic study demonstrated that both lean and obese women with PCOS have increased rates of insulin resistance and type 2 DM compared with weight-matched controls without PCOS (Fig. 17-5) (Dunaif, 1989, 1992).
Insulin sensitivity is decreased in obese women with polycystic ovarian syndrome. NL = normal (those without PCOS); PCOS = polycystic ovarian syndrome. (Reproduced with permission from Dunaif A, Segal KR, Futterweit W, et al: Profound peripheral insulin resistance, independent of obesity, in polycystic ovary syndrome, Diabetes 1989 Sep;38(9):1165–1174.)
This skin condition is characterized by thickened, gray-brown velvety plaques seen in flexure areas such as the back of the neck, axillae, inframammary creases, waist, and groin (Fig. 17-6) (Panidis, 1995). Thought to be a cutaneous marker of insulin resistance, acanthosis nigricans may be found in individuals with or without PCOS. Insulin resistance leads to hyperinsulinemia, which is believed to stimulate keratinocyte and dermal fibroblast growth, producing the characteristic skin changes (Cruz, 1992). Acanthosis nigricans develops more frequently in obese women with PCOS (50 percent incidence) than in those with PCOS and normal weight (5 to 10 percent). As part of its differential diagnosis, acanthosis nigricans rarely can be seen with genetic syndromes or gastrointestinal tract malignancy, such as adenocarcinoma of the stomach or pancreas. To differentiate, acanthosis nigricans associated with malignancy usually has a more abrupt onset, and skin involvement is more extensive (Moore, 2008).
Acanthosis nigricans and multiple small pedunculated acrochordons (skin tags) in the neck crease. Both are dermatologic signs of insulin resistance.
Impaired Glucose Tolerance and Type 2 Diabetes Mellitus
Women with PCOS are at increased risk for impaired glucose tolerance (IGT) and type 2 DM. Based on oral glucose tolerance testing of obese women with PCOS, the prevalence of IGT and DM is approximately 30 percent and 7 percent, respectively (Legro, 1999). Even after adjusting for body mass index (BMI), women with PCOS remained more likely to have DM (Lo, 2006). Specifically, β-cell dysfunction that is independent of obesity has been reported in patients with PCOS (Dunaif, 1996a). Similar findings are reported in groups of obese and normal-weight adolescent girls with PCOS (Flannery, 2013; Palmert, 2002).
The classic atherogenic lipoprotein profile seen in PCOS shows increased low-density lipoprotein (LDL) and triglyceride levels, elevated total cholesterol:high-density lipoprotein (HDL) ratios, but depressed HDL levels (Banaszewska, 2006). Independent of total cholesterol levels, these changes may increase the cardiovascular disease risk in women with PCOS. The prevalence of dyslipidemia in PCOS approaches 70 percent (Legro, 2001; Talbott, 1998).
Compared with age-matched controls, women with PCOS are more likely to be obese, as reflected by elevated BMIs and waist:hip ratios (Talbott, 1995). This ratio reflects an android or central pattern of obesity, which itself is an independent risk factor for cardiovascular disease and predicts insulin resistance. As noted earlier, insulin resistance is believed to play a large role in the pathogenesis of PCOS and is often exacerbated by obesity (Dunaif, 1989). For example, obesity can worsen hyperandrogenism by lowering SHBG and therefore increasing bioavailable testosterone (Lim, 2013). Thus, obesity can have a synergistic effect on PCOS and can worsen ovulatory dysfunction, hyperandrogenism, and acanthosis nigricans.
This disorder is likely related to central obesity and insulin resistance (Fogel, 2001; Vgontzas, 2001). Women with PCOS have a 30- to 40-fold higher risk of sleep apnea compared with weight-matched controls. This suggests a link between obstructive sleep apnea and the metabolic and hormonal abnormalities associated with PCOS. Moreover, some theorize two subtypes of PCOS, that is, PCOS with or without obstructive sleep apnea. PCOS patients with this condition may be at much higher risk for DM and cardiovascular disease than women with PCOS but without obstructive sleep apnea (Nitsche, 2010).
Metabolic Syndrome and Cardiovascular Disease
The metabolic syndrome is characterized by insulin resistance, obesity, atherogenic dyslipidemia, and hypertension. It is associated with an increased risk of cardiovascular disease (CVD) and type 2 DM (Schneider, 2006). The prevalence of metabolic syndrome approximates 45 percent in women with PCOS compared with 4 percent in age-adjusted controls (Fig. 17-7) (Dokras, 2005). PCOS shares several endocrine features with the metabolic syndrome, although definitive evidence for an increased incidence of CVD in women with PCOS is lacking (Legro, 1999; Rebuffe-Scrive, 1989; Talbott, 1998). However, in a small group of women with PCOS, Dahlgren and colleagues (1992) predicted a relative risk of 7.4 for myocardial infarction. Another 10-year surveillance study showed an odds ratio of 5.91 for CVD in overweight white women with PCOS (Talbott, 1995). Thus, evidence suggests that women with PCOS should have CVD factors identified and treated (Table 1-8) (Wild, 2010).
A. Women with polycystic ovarian syndrome (PCOS) have an increased risk of metabolic syndrome compared with age-adjusted controls and with women from the Third National Health and Nutrition Survey (NHANES III). B. In women with PCOS, the risk of metabolic syndrome begins earlier than in controls or those from NHANES III. NHANES III collected data from a representative sample of the noninstitutionalized civilian U.S. population from 1988 through 1994. (Reproduced with permission from Dokras A, Bochner M, Hollinrake E: Screening women with polycystic ovary syndrome for metabolic syndrome. Obstet Gynecol 2005 Jul;106(1):131–137.)
In addition to components of the metabolic syndrome, other markers of subclinical disease link PCOS and CVD. Women with PCOS have been found to have a greater incidence of left ventricular diastolic dysfunction and increased internal and external carotid artery stiffness (Lakhani, 2000; Tiras, 1999). Moreover, in affected women, studies have found greater endothelial dysfunction, which is described as an early event in the evolution of atherosclerosis (Orio, 2004; Tarkun, 2004).
In women with PCOS, the risk of endometrial cancer is increased threefold. Endometrial hyperplasia and endometrial cancer are long-term risks of chronic anovulation, and neoplastic changes in the endometrium are felt to arise from chronic unopposed estrogen (Chap. 33) (Coulam, 1983). Moreover, the effects of hyperandrogenism, hyperinsulinemia, and obesity to lower SHBG levels and increase circulating estrogen levels may add to this risk.
Few women who develop endometrial cancer are younger than 40 years, and most of these premenopausal women are obese or have chronic anovulation or both (National Cancer Institute, 2014; Peterson, 1968). Thus, the American College of Obstetricians and Gynecologists (2012) recommends endometrial assessment in any woman older than 45 years with abnormal bleeding, and in those younger than 45 years with a history of unopposed estrogen exposure such as seen in obesity or PCOS, failed medical management, and persistent bleeding.
Infertility or subfertility is a frequent complaint in women with PCOS and results from anovulatory cycles. Moreover, in women with infertility secondary to anovulation, PCOS is the most common cause (Hull, 1987). Infertility evaluation and treatment in women with PCOS is described in more detail in Chapter 20.
Women with PCOS who become pregnant experience an increased rate (30 to 50 percent) of early miscarriage compared with a baseline rate of approximately 15 percent in the general population (Homburg, 1998b; Regan, 1990; Sagle, 1988). The etiology of early miscarriage in women with PCOS is unclear. Initially, retrospective and observational studies showed an association between LH hypersecretion and miscarriage (Homburg, 1998a; Howles, 1987). However, one prospective study showed that lowering LH levels with GnRH agonists failed to improve outcome (Clifford, 1996).
Others have suggested that insulin resistance is related to miscarriage in these women. To lower loss rates, an insulin level lowering drug, metformin (Glucophage), has been investigated. Metformin, a biguanide, lowers serum insulin levels by reducing hepatic glucose production and increasing the sensitivity of liver, muscle, fat, and other tissues to the uptake and effects of insulin.
Some retrospective studies have indicated that women with PCOS taking metformin during pregnancy have a lower incidence of miscarriage (Glueck, 2001; Jakubowicz, 2002). In addition, a prospective study demonstrated a lower miscarriage rate for women conceiving while taking metformin compared with those using clomiphene citrate (Palomba, 2005). However, a metaanalysis of 17 studies failed to show an effect of metformin administration on miscarriage risk in women with PCOS (Palomba, 2009). Until further randomized controlled trials are performed studying the effects of metformin (a category B drug) on pregnancy outcome, the use of this medication in gestation for miscarriage prevention is not recommended.
Complications in Pregnancy
Several pregnancy and neonatal complications have been associated with PCOS. One large metaanalysis found that women with PCOS have a two- to threefold higher risk of gestational diabetes, pregnancy-induced hypertension, preterm birth, and perinatal mortality, unrelated to multifetal gestations (Boomsma, 2006). Metformin has been studied as a tool to mitigate these complications in those with PCOS but without DM. However, investigators in one study found that metformin treatment during pregnancy did not reduce rates of these complications (Vanky, 2010).
Many women with PCOS require the use of ovulation induction medications or in vitro fertilization to conceive. These practices substantially increase the risk of multifetal gestations, which are associated with increased rates of maternal and neonatal complications (Chap. 20).
Women with PCOS may present with various psychosocial problems such as anxiety, depression, low self-esteem, reduced quality of life, and negative body image (Deeks, 2010; Dokras, 2011, 2012). If depression is suspected, screening tools such as those found in Chapter 13 are implemented.