CHAPTER 17: Polycystic Ovarian Syndrome and Hyperandrogenism

Polycystic ovarian syndrome (PCOS) is a common endocrinopathy typified by oligoovulation or anovulation, signs of androgen excess, and multiple small ovarian cysts. These signs and symptoms vary widely between women and within individuals over time. Women with this endocrine disorder also have higher rates of dyslipidemia and insulin resistance, which increase long-term health risks. As a result, women with PCOS may first present to various medical specialists, including pediatricians, gynecologists, internists, endocrinologists, or dermatologists.

Polycystic Ovarian Syndrome

In Rotterdam, The Netherlands, PCOS was redefined in a consensus meeting between the European Society of Human Reproduction and Embryology and the American Society for Reproductive Medicine (ESHRE/ASRM)—The Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group, 2004. As shown in Table 17-1, affected individuals must meet two out of three criteria. Importantly, because other etiologies, such as congenital adrenal hyperplasia, androgen-secreting tumors, and hyperprolactinemia, may also lead to oligoovulation and/or androgen excess, these must be excluded. Thus, PCOS currently is a diagnosis of exclusion.

The Rotterdam criteria constitute a broader spectrum than that formerly put forward by the National Institutes of Health (NIH) Conference in 1990 (Zawadzki, 1990). The prominent difference is that the NIH Conference defined PCOS without regard to ovarian sonographic appearance. Last, a third organization—The Androgen Excess and PCOS Society (AE-PCOS)—has also defined criteria for PCOS (Azziz, 2006). As is shown in Table 17-1, criteria are similar among these three groups, and controversy exists as to which is most appropriate.

Ovarian Hyperthecosis and HAIRAN Syndrome

Ovarian hyperthecosis, often considered a more severe form of PCOS, is a rare condition characterized by nests of luteinized theca cells distributed throughout the ovarian stroma. Affected women exhibit severe hyperandrogenism and may occasionally display frank virilization signs such as clitoromegaly, temporal balding, and voice deepening (Culiner, 1949). In addition, a much greater degree of insulin resistance and acanthosis nigricans typically is found (Nagamani, 1986).

The hyperandrogenic-insulin resistant-acanthosis nigricans (HAIRAN) syndrome is also uncommon and consists of marked hyperandrogenism, severe insulin resistance, and acanthosis nigricans (Barbieri, 1983). The etiology of this disorder is unclear, and HAIRAN syndrome may represent either a PCOS variant or a distinct genetic syndrome. Both ovarian hyperthecosis and HAIRAN are exaggerated phenotypes of PCOS, and their treatment mirrors that for PCOS described later in this chapter.

PCOS is the most common endocrine disorder of reproductive-aged women and affects approximately 4 to 12 percent in general population studies (Asunción, 2000; Knochenhauer, 1998; Lauritsen, 2014). Although symptoms of androgen excess may vary among ethnicities, PCOS appears to affect all races and nationalities equally.

The underlying cause of PCOS is unknown. However, a genetic basis that is both multifactorial and polygenic is suspected, as there is a well-documented aggregation of the syndrome within families (Franks, 1997). Specifically, an increased prevalence is noted between affected individuals and their sisters (32 to 66 percent) and mothers (24 to 52 percent) (Govind, 1999; Kahsar-Miller, 2001; Yildiz, 2003). Twin studies also suggest a prominent heritable influence (Vink, 2006).

Some have suggested an autosomal dominant inheritance with expression in both females and males. For example, first-degree male relatives of women with PCOS have been shown to have significantly higher rates of elevated circulating dehydroepiandrosterone sulfate (DHEAS) levels, early balding, and insulin resistance compared with male controls (Legro, 2000, 2002).

Identification of candidate genes linked to PCOS is a major research focus, given the large potential benefit for both diagnosis and management. In general, putative genes include those involved in androgen synthesis and those associated with insulin resistance. Genome-wide association studies in Chinese women have identified variants in 11 genomic regions as potential risk factors for PCOS (Chen, 2011; Shi, 2012).

In addition, epigenetic modification of genetic susceptibility within the maternal-fetal environment may influence adult PCOS development (Dumesic, 2014). Further investigation, however, is needed to determine the roles of these gene products in PCOS pathogenesis.

Gonadotropins

Anovulation in women with PCOS is characterized by inappropriate gonadotropin secretion (Fig. 17-1). Specifically, altered gonadotropin-releasing hormone (GnRH) pulsatility leads to preferential production of luteinizing hormone (LH) compared with follicle-stimulating hormone (FSH) (Hayes, 1998; Waldstreicher, 1988). It is currently unknown whether hypothalamic dysfunction is a primary cause of PCOS or is secondary to abnormal steroid feedback. In either case, serum LH levels rise, and increased levels are observed clinically in approximately 50 percent of affected women (van Santbrink, 1997). Similarly, LH:FSH ratios are elevated and rise above 2:1 in approximately 60 percent of patients (Rebar, 1976).

Insulin Resistance

Women with PCOS also display greater degrees of insulin resistance and compensatory hyperinsulinemia than nonaffected women. Insulin resistance is defined as a reduced glucose-uptake response to a given amount of insulin. This decreased insulin sensitivity appears to stem from a postbinding abnormality in insulin receptor-mediated signal transduction (Dunaif, 1997). Both lean and obese women with PCOS are found to be more insulin resistant than nonaffected weight-matched controls (Dunaif, 1989, 1992).

Insulin resistance has been associated with an increase in several disorders including type 2 diabetes mellitus (DM), hypertension, dyslipidemia, and cardiovascular disease. Therefore, PCOS is not simply a disorder of short-term consequences such as irregular periods and hirsutism, but also one of potential long-term health consequences (Table 17-2).

Androgens

Both insulin and LH stimulate androgen production by the ovarian theca cell (Dunaif, 1992). As a result, affected ovaries secrete elevated levels of testosterone and androstenedione. Specifically, elevated free testosterone levels are noted in 70 to 80 percent of women with PCOS, and 25 to 65 percent exhibit elevated levels of DHEAS (Moran, 1994, 1999; O’Driscoll, 1994). In turn, elevated androstenedione levels contribute to an increase in estrone levels through peripheral conversion of androgens to estrogens by aromatase.

Sex Hormone-binding Globulin

Women with PCOS display decreased levels of sex hormone-binding globulin (SHBG). This glycoprotein, produced in the liver, binds most sex steroids. Only approximately 1 percent of these steroids are unbound and thus free and bioavailable. The synthesis of SHBG is suppressed by insulin as well as androgens, corticoids, progestins, and growth hormone (Bergh, 1993). Because of suppressed SHBG production, less circulating androgen is bound and thus more remains available to bind with end-organ receptors. Accordingly, some women with PCOS will have total testosterone levels in the normal range, but will be clinically hyperandrogenic due to elevated free testosterone levels.

In addition to hyperandrogenism, low SHBG levels have also been linked to impaired glucose control and a risk for developing type 2 DM (Ding, 2009). The mechanism of this association is not fully understood and may reflect a role for SHBG in glucose homeostasis. For example, Veltman-Verhulst (2010) evaluated SHBG levels in women with PCOS and found an association between low SHBG levels and subsequent development of gestational diabetes mellitus.

Anovulation

The precise mechanism leading to anovulation is unclear, but altered GnRH pulsatility and inappropriate gonadotropin secretion have been implicated in menstrual irregularity.

Moreover, anovulation may result from insulin resistance, as a substantial number of anovulatory patients with PCOS may resume ovulatory cycles when treated with metformin, an insulin sensitizer (Nestler, 1998). It has been suggested that oligoovulatory women with PCOS exhibit a milder phenotype of ovarian dysfunction than anovulatory PCOS patients and have a more favorable response to ovulation induction agents (Burgers, 2010).

Finally, the large antral follicle cohort with increased intraovarian androgens seen in PCOS may contribute to anovulation. This is supported by the fact that some patients who have undergone ovarian wedge resection or laparoscopic ovarian drilling have improved menstrual regularity. One study demonstrated that 67 percent of PCOS patients developed regular menses following such surgery compared with only 8 percent prior to surgery (Amer, 2002).

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.

Menstrual Dysfunction

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).

Hyperandrogenism

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.

Hirsutism

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).

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.

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).

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

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.

Alopecia

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

Insulin Resistance

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).

Acanthosis Nigricans

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).

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).

Dyslipidemia

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).

Obesity

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.

Obstructive Sleep Apnea

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).

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).

Endometrial Neoplasia

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

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.

Pregnancy Loss

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).

Psychologic Health

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.

Other potentially serious disorders may clinically appear similar to PCOS and are excluded during patient evaluation (Table 17-4). For women, who present with complaints of hirsutism, the algorithm in Figure 17-8 can be used.

Thyroid-stimulating Hormone and Prolactin

Thyroid disease may frequently lead to menstrual dysfunction. Thus, a serum thyroid-stimulating hormone level is typically measured during evaluation, and treatment is discussed in Chapter 16. Similarly, hyperprolactinemia is a well-known cause of menstrual irregularities and occasionally amenorrhea. Elevated prolactin levels lead to anovulation through inhibition of GnRH pulsatile secretion. A list of potential causes of hyperprolactinemia is found in Table 12-2, and treatments are described in Chapter 15.

Testosterone

Tumors of the ovary or adrenal are a rare but serious cause of androgen excess. Various ovarian neoplasms, both benign and malignant, may produce testosterone and lead to virilization. Among others, these include the stromal tumors (Chap. 36). Importantly, an abrupt onset or sudden worsening of virilizing signs should prompt concern for a hormone-producing ovarian or adrenal tumor. Symptoms may include those in Table 17-5. Of these, hirsutism is quantified with the Ferriman-Gallwey score, whereas clitoromegaly is assessed using the clitoral index (Fig. 17-9). For the latter, clitoral length (mm) and width (mm) values are multiplied. Values greater than 35 mm² are abnormal (Tagatz, 1979; Verkauf, 1992).

Diagnostically, serum testosterone levels can aid ovarian tumor exclusion. Free testosterone levels are more sensitive than total testosterone levels as an indicator of hyperandrogenism. Although improving, however, current free testosterone assays lack a uniform laboratory standard (Faix, 2013). For this reason, total testosterone levels remain the best approach for identifying a possible tumor. Threshold values >200 ng/dL of total testosterone warrant evaluation for an ovarian lesion (Derksen, 1994).

Pelvic sonography is the preferred method to exclude an ovarian neoplasm in a female with very high androgen levels. Alternatively, computed tomography (CT) or magnetic resonance (MR) imaging may also be used.

Dehydroepiandrosterone Sulfate

This hormone is essentially produced exclusively by the adrenal gland. Therefore, serum DHEAS levels >700 μg/dL are highly suggestive of an adrenal neoplasm, and adrenal imaging with abdominal CT or MR imaging is warranted.

Gonadotropins

During evaluation of amenorrhea, FSH, LH, and estradiol levels are typically measured to exclude premature ovarian failure and hypogonadotropic hypogonadism (see Table 17-4). Although LH levels classically measure at least twofold higher than FSH levels, this is not found in all women with PCOS. Specifically, one third of women with PCOS have circulating LH levels in the normal range, a finding more common in obese patients (Arroyo, 1997; Taylor, 1997). Moreover, serum LH levels are affected by sample timing within a menstrual cycle, use of oral contraceptive pills, and BMI.

17-alpha Hydroxyprogesterone

The term congenital adrenal hyperplasia (CAH) describes several autosomal recessive disorders that result from complete or partial deficiency of an enzyme involved in cortisol and aldosterone synthesis, usually 21-hydroxylase or less frequently 11-hydroxylase (Fig. 15-5). As a result of these defects, precursors are shunted into pathways leading to androgen production. Thus, depending on the enzyme affected, symptoms of CAH vary. It may present in the neonate with ambiguous genitalia and life-threatening hypotension (Chap. 18). Alternatively, symptoms may be milder and delayed until adolescence or adulthood.

In this late-onset form of CAH, the enzyme deficiency leads to a relative cortisol deficiency. In response, adrenocorticotropic hormone (ACTH) levels are increased to normalize cortisol production. Consequent to this accommodation, adrenal gland hyperplasia and elevated androgen levels develop. Therefore, symptoms of late-onset CAH reflect accumulation of precursor C19 steroid hormones. These precursors are converted to dehydroepiandrosterone, androstenedione, and testosterone. Thus, signs of hyperandrogenism predominate.

With late-onset CAH, the most commonly affected enzyme is 21-hydroxylase, and deficiency leads to accumulation of its substrate, 17-hydroxyprogesterone. Serum values are drawn in the morning from a fasting patient. Threshold values of 17-hydroxyprogesterone that measure >200 ng/dL should prompt an ACTH stimulation test. With this test, synthetic ACTH, 250 μg, is injected intravenously, and a serum 17-hydroxyprogesterone level is measured 1 hour later.

To explain this test, the ACTH given during testing stimulates uptake of cholesterol and synthesis of pregnenolone. If 21-hydroxylase activity is ineffective, steroid precursors up to and including progesterone, 17-hydroxypregnenolone, and especially 17-hydroxyprogesterone accumulate in the adrenal cortex and in circulating blood. Thus in affected individuals, serum levels of 17-hydroxyprogesterone can reach many times their normal concentrations. Levels >1000 ng/dL from blood drawn after synthetic ACTH is given are indicative of late-onset CAH.

Antimüllerian Hormone

The classic polycystic ovary contains two- to threefold more growing preantral and antral follicles than normal ovaries (Hughesdon, 1982). Within the granulosa cells of these developing follicles, the dimeric glycoprotein antimüllerian hormone (AMH) is produced, and serum AMH levels correlate closely with the number of antral follicles. Not surprisingly, AMH levels are two- to threefold higher in women with PCOS compared with nonaffected age-matched controls (Cui, 2014: Homburg, 2013). For this reason, some view AMH as a potentially useful diagnostic marker for PCOS (Pigny, 2006). That said, data regarding this marker in both PCOS and controls are incomplete and require further investigation before it can be adopted as a formal diagnostic criterion (Dewailly, 2014).

Cortisol

Cushing syndrome results from prolonged exposure to elevated levels of either endogenous or exogenous glucocorticoids. Of these, the syndrome is most frequently caused by administration of exogenous glucocorticoids. Alternatively, the term Cushing disease is reserved for cases stemming from increased adrenocorticotropin hormone (ACTH) secretion by a pituitary tumor. Cushing syndrome shares many symptoms with PCOS such as menstrual dysfunction, signs of androgen excess, truncal obesity, dyslipidemia, and glucose intolerance. Classically, moon facies and purple abdominal striae are also noted. Cushing syndrome is rare, and routine screening in all women with oligomenorrhea is not indicated. However, in those with classic Cushing findings, proximal muscle weakness, and easy bruising, screening is strongly considered (Nieman, 2008).

Initial laboratory testing investigates excessive glucocorticoid production, and three are endorsed by the Endocrine Society (Nieman, 2008). Of these, a 24-hour urine collection for urinary free cortisol excretion can be obtained. Alternatively, a dexamethasone suppression test administers 1 mg of dexamethasone orally at 11 PM, and a plasma cortisol level is measured at 8 AM the following morning. In women with a normal functioning feedback loop, administration of the corticosteroid dexamethasone lowers ACTH secretion and thus diminishes adrenal cortisol production. Normal testing values are <5 μg/dL (Crapo, 1979). However, if a woman has an exogenous or an ectopic endogenous source of cortisol, then cortisol levels during suppression testing will remain elevated. Last, using a late-night salivary cortisol level measurement, patients collect saliva samples between 11 PM and midnight on two separate evenings. Once identified, Cushing syndrome is treated based on the underlying source of excess glucocorticosteroids.

Measurements of Insulin Resistance and Dyslipidemia

Many women with PCOS have insulin resistance and compensatory hyperinsulinemia. Although the consensus meeting in Rotterdam suggested that tests of insulin resistance are not required to diagnose or treat PCOS, these tests are often used to evaluate glucose metabolism and impaired insulin secretion in these women (The Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group, 2004).

The “gold standard” for evaluating insulin resistance has been the hyperinsulinemic euglycemic clamp. Unfortunately, this test as well as the intravenous glucose tolerance test (IV GTT) requires an intravenous line and frequent sampling, are labor and time intensive, and are not practical in a clinical setting. Accordingly, other less sensitive surrogate markers that evaluate insulin resistance are used and include: (1) 2-hour glucose tolerance test (2-hr GTT), (2) fasting serum insulin level, (3) homeostasis model assessment of insulin resistance (HOMA IR), (4) quantitative insulin sensitivity check (QUICKI), and (5) calculation of serum glucose:insulin ratios.

Of these, a 2-hr GTT is frequently used to exclude impaired glucose tolerance (IGT) and type 2 DM (Table 17-6). This test is particularly important in obese PCOS patients who are at higher risk for both. According to several organizations, women with PCOS should undergo such screening (American Diabetes Association, 2014; Conway, 2014; Fauser, 2012; Legro, 2013; Wild, 2010). Their recommendations vary as to whether all women or only specific PCOS subgroups are screened and as to the screening interval. The Amsterdam ESHRE/ASRM-Sponsored 3rd PCOS Consensus Workshop Group promotes evaluation in the following circumstances: hyperandrogenism with anovulation, acanthosis nigricans, obesity (BMI >30 kg/m² or >25 in Asian women), and a family history of DM or gestational DM. Women with PCOS may demonstrate a worsening of IGT over time, with a reported conversion rate of approximately 2 percent per year to type 2 DM. This affirms the importance of periodic assessment of glucose tolerance with a 2-hr GTT in women with PCOS (Legro, 1999, 2005). The AE-PCOS Society recommends that those with normal glucose tolerance be rescreened at least once every 2 years or more frequently if additional risks exist. Those with impaired glucose tolerance are tested annually. These same organizations counsel against use of a fasting glucose level and note that a surrogate HbA_1c level can be considered.

In addition to assessment of insulin resistance, a fasting lipid profile is used to evaluate dyslipidemia. Evaluation and treatment of dyslipidemia are further described in Chapter 1.

Endometrial Biopsy

An endometrial biopsy is recommended for abnormal bleeding in any woman older than 45 years and in those younger than this with a history of unopposed estrogen exposure such as seen in obesity or PCOS, failed medical management, and persistent bleeding (American College of Obstetricians and Gynecologists, 2012). Steps of this procedure are found in Chapter 8.

Sonography

Histologically, a polycystic ovary (PCO) displays increases in the number of ripening and atretic follicles, cortical stromal thickness, and number of hilar cell nests (Hughesdon, 1982). Many of these tissue changes can be seen sonographically, and pelvic sonography is commonly used to evaluate the ovaries in women with suspected PCOS. In the NIH criteria for PCOS, sonographic evaluation is not required. However, sonography is particularly important for women with PCOS seeking fertility and in women with signs of virilization to exclude an androgen-producing ovarian cancer. A high-definition transvaginal approach is superior and has a higher detection rate of PCO than the transabdominal route. However, a transabdominal route is preferred for virginal adolescents.

Sonographic criteria for polycystic ovaries from the 2003 Rotterdam conference include ≥12 small cysts (2 to 9 mm in diameter) or an increased ovarian volume (>10 mL) or both (Fig. 17-10). Only one ovary with these findings is sufficient to define PCOS. However, criteria do not apply to women taking combination oral contraceptive pills (The Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group, 2004).

Remarkably, studies using sonography have shown that at least 23 percent of young women have ovaries that exhibit PCO morphology, yet many of these women have no other PCOS symptoms (Clayton, 1992; Polson, 1988). In addition, a polycystic appearance of the ovaries can often be found in other conditions of androgen excess, such as congenital adrenal hyperplasia, Cushing syndrome, and exogenous use of androgenic medications. For this reason, PCO morphology found during sonographic examination is not used solely for PCOS diagnosis.

PCOS Diagnosis in Adolescence

Several independent prepubertal risk factors for PCOS have been identified. These include above-average or low birthweight for gestational age, premature adrenarche, atypical sexual precocity, and obesity with acanthosis nigricans (Rosenfield, 2007). The diagnosis of PCOS in adolescence is challenging because many symptoms of PCOS mimic the normal physiologic responses of puberty. As noted, adolescents frequently have irregular menses, and acne is common. Moreover, in adolescence, transabdominal rather than transvaginal pelvic sonography is generally performed, and image resolution is poorer. In adolescents with incomplete criteria for a firm diagnosis of PCOS, careful surveillance is warranted as they may be diagnosed at a later time (Carmina, 2010).

The treatment choice for each symptom of PCOS depends on a woman’s goals and the severity of endocrine dysfunction. Thus, anovulatory women desiring pregnancy will undergo significantly different treatment than adolescents with menstrual irregularity and acne. Patients often seek treatment for a singular complaint and may see various specialists such as dermatologists, nutritionists, aestheticians, and endocrinologists prior to evaluation by a gynecologist.

Conservative Treatment

Women with PCOS who have fairly regular cycle intervals (8 to 12 menses per year) and mild hyperandrogenism may choose not to be treated. In these women, however, periodic screening for dyslipidemia, diabetes mellitus, and metabolic syndrome is prudent.

For obese women with PCOS, important lifestyle changes focus on diet and exercise. Even modest weight loss (5 percent of body weight) can result in restoration of normal ovulatory cycles in some women. This improvement results from reductions in insulin and androgen levels, the latter mediated through increases in SHBG levels (Huber-Buchholz, 1999; Kiddy, 1992; Pasquali, 1989).

The optimal diet that best improves insulin sensitivity is not known. Diets high in carbohydrates increase insulin secretion rates, whereas diets high in protein and fat lower those rates (Bass, 1993; Nuttall, 1985). However, very-high-protein diets are concerning with respect to stresses on kidney function. Moreover, they afford only short-term weight loss initially with lesser benefits over time (Legro, 1999; Skov, 1999). Thus, it appears that a well-balanced hypocaloric diet offers the most benefit in treating obese women with PCOS.

Exercise is known to have a beneficial effect in treating patients with type 2 DM (Nestler, 1998). The most dramatic effect of lifestyle intervention was published in 2002 as the Diabetes Prevention Program. Women and men at risk for diabetes were asked to lose at least 7 percent of their weight and to exercise for 150 minutes each week. This group had a twofold greater benefit in delaying the onset of diabetes compared with a group given metformin alone. Both groups fared better than a placebo group (Knowler, 2002). Few studies, however, have looked specifically at the effect of exercise on insulin action in women with PCOS (Jaatinen, 1993). In addition to DM, women with PCOS may have comorbid risk factors for CVD. In patients with PCOS, exercise has been shown to improve cardiovascular capacity (Vigorito, 2007).

Treatment of Oligo- and Anovulation

Hormonal Agents

Women with oligo- or anovulation typically have fewer than eight menses per year, often skip menses for several months at a time, or simply have amenorrhea. Flow may be scanty or may be very long and heavy, resulting in iron-deficiency anemia.

A first-line treatment for menstrual irregularities is combination oral contraceptive pills (COCs), which induce regular menstrual cycles, lower androgen levels, and thin the endometrium. Specifically, COCs suppress gonadotropin release, which results in decreased ovarian androgen production. Moreover, the estrogen component increases levels of SHBG, which binds free androgen. Last, the progestin component antagonizes the endometrial proliferative effect of unopposed estrogen from PCOS, thus reducing the endometrial hyperplasia risk.

Theoretically, COCs that contain progestins with fewer androgenic properties are preferred. Such progestins include norethindrone; a third-generation progestin, such as norgestimate or desogestrel; or the newer progestin, drospirenone. However, no COC pill has shown superiority compared with another in reducing hirsutism (Sobbrio, 1990). Alternative combination hormonal contraceptive options include the contraceptive patch and vaginal ring. Before COC initiation, if a woman’s last menses was more than 4 weeks prior, a pregnancy test is indicated.

In patients who are not candidates for combination hormonal contraception, progesterone withdrawal is recommended every 1 to 3 months. Examples of regimens used include: medroxyprogesterone acetate (MPA), 5 to 10 mg orally daily for 12 days, or micronized progesterone, 200 mg orally each evening for 12 days. Patients are counseled that intermittent progestins will not reduce symptoms of acne or hirsutism, nor do they provide contraception. For those requiring birth control, a continuous progestin-only contraceptive pill, depot medroxyprogesterone acetate, or a progestin-releasing implant or intrauterine device may be used and will act to thin the endometrium.

Insulin Sensitizing Agents

Although use of insulin sensitizers for PCOS has not been approved by the Food and Drug Administration (FDA), they have been found to improve both metabolic and gynecologic issues. Of these agents, metformin is the most commonly prescribed, particularly in women with impaired glucose tolerance and insulin resistance. In clinical studies, 1500 to 2000 mg in divided doses daily with meals is typically used. More common side effects are gastrointestinal, and these can be minimized by starting at a low dose and gradually increasing the dose over several weeks to an optimal level.

Metformin decreases androgen levels in both lean and obese women with PCOS, leading to increased rates of spontaneous ovulation (Essah, 2006; Haas, 2003; Lord, 2003). Several studies demonstrate that up to 40 percent of anovulatory women with PCOS will ovulate, and many will achieve pregnancy with metformin alone (Diamanti-Kandarakis, 1998; Fleming, 2002; Neveu, 2007). Metformin is a category B drug and is safe to use as an ovulatory induction agent. As such, it may be used alone or in concert with other medications such as clomiphene citrate (Chap. 20). Specifically, metformin has been shown to increase the ovulatory response to clomiphene citrate in patients who were previously clomiphene-resistant (Nestler, 1998). Despite these positive findings regarding metformin and ovulation induction, Legro and colleagues (2007) in a randomized prospective study of 626 women found higher live-birth rates with clomiphene citrate alone (22 percent) than with metformin alone (7 percent). Based on data, the Thessaloniki ESHRE/ASRM Sponsored PCOS Consensus Workshop Group (2008) recommends against the routine use of metformin for ovulation induction, and first-line treatment remains clomiphene citrate. They note that the addition of metformin to clomiphene citrate may be indicated for women with PCOS and glucose intolerance.

The thiazolidinediones are another class of medications also used for patients with diabetes mellitus. Similar to metformin, rosiglitazone and pioglitazone improve ovulation rates in some patients (Azziz, 2001; Dunaif, 1996b; Ehrmann, 1997). However, the glitazones are category C drugs and should be discontinued if pregnancy is achieved.

Hirsutism

With hirsutism treatment, a primary goal is lowering androgen levels to halt further conversion of vellus hairs to terminal ones. However, medical therapies will not eliminate hair already present. Moreover, treatments may require 6 to 12 months before clinical improvement is apparent. For this reason, clinicians should be familiar with temporary hair removal methods that may be used in the interim. Permanent cosmetic therapies can then be implemented once medications have reached maximal therapeutic effect.

Lowered Effective Androgen Levels

Several options are available to decrease androgen levels affecting hair follicles. First, as described earlier, COCs are effective in establishing regular menses and lowering ovarian androgen production.

Second, GnRH agonists lower gonadotropin levels over time, and in turn subsequently lower androgen levels. Despite their effectiveness in treating hirsutism, long-term administration of GnRH agonists is not ideal due to associated bone loss, high cost, and menopausal side effects.

Last, 5α-reductase inhibitors block conversion of testosterone to DHT. Of these, finasteride is available as a 5-mg tablet for prostate cancer (Proscar) and a 1-mg tablet for the treatment of male alopecia (Propecia). Most studies have used 5-mg daily doses for women and have found finasteride to be modestly effective for hirsutism treatment (Fruzzetti, 1994; Moghetti, 1994). Side effects are low with finasteride, although decreased libido has been noted. However, as with other antiandrogens, the risk of male fetal teratogenicity is present, and effective contraception must be used concurrently.

Eflornithine Hydrochloride

This antimetabolite topical cream is applied twice daily to affected areas and is an irreversible inhibitor of ornithine decarboxylase. This enzyme is necessary for hair follicle cell division and function, and its inhibition results in slower hair growth. It does not permanently remove hair, and thus women must continue routine methods of hair removal while using this medicine.

Eflornithine hydrochloride (Vaniqa) may require 4 to 8 weeks of use before changes are noticed. However, approximately one third of patients have marked improvement after 24 weeks of eflornithine use compared with placebo, and 58 percent showed some overall improvement in hirsutism scores (Balfour, 2001).

Androgen-receptor Antagonists

Antiandrogens are competitive inhibitors of androgen binding to the androgen receptor (Brown, 2009; Moghetti, 2000; Venturoli, 1999). Although these agents effectively treat hirsutism, they carry a risk for several side effects. Metrorrhagia may frequently develop. In addition, as antiandrogens, these drugs bear a theoretical risk of interfering with external genitalia development in male fetuses of women using such medications in early pregnancy. Accordingly, these drugs are commonly used in conjunction with oral contraceptive pills, which prompt regular menses and provide effective contraception. None of the antiandrogen agents are FDA-approved for treatment of hyperandrogenism and thus are used off-label.

Spironolactone (Aldactone), in a dosage of 50 to 100 mg orally twice daily, is the primary antiandrogen used currently in the United States. In addition to its antiandrogen effects, this drug also affects hair conversion from vellus to terminal by its direct inhibition of 5α-reductase. Spironolactone is also a potassium-sparing diuretic. As such, it is not prescribed for chronic use in combination with agents that can also raise blood potassium levels, such as potassium supplements, angiotensin-converting enzyme (ACE) inhibitors, nonsteroidal antiinflammatory drugs such as indomethacin, or other potassium-sparing diuretics.

Of less prescribed alternatives, in Europe, Canada, and Mexico, the antiandrogen cyproterone acetate is used in an oral contraceptive pill. However, this agent is not FDA-approved largely based on its potential for liver injury. Flutamide is another nonsteroidal antiandrogen marketed for the treatment of prostate cancer. It is rarely used for hirsutism, again due to its potential hepatotoxicity.

Hair Removal

Hirsutism is often treated by mechanical means, and these include both depilation and epilation techniques. In addition to hair removal, lightening hair color with bleach is a cosmetic option.

Depilation describes hair removal above the skin surface. Shaving is the most common form and does not exacerbate hirsutism, contrary to the myth that it will increase hair follicle density. Alternatively, topical chemical depilatories are also effective. Available in gel, cream, lotion, aerosol, and roll-on forms, these agents contain calcium thioglycolate. This agent breaks disulfide bonds between hair protein chains, causing hair to break down and separate easily from the skin surface.

Epilation removes the entire hair shaft and root and includes techniques such as plucking, waxing, threading, electrolysis, and laser treatment. Threading, also known as “khite” in Arabic, is a fast method for removing entire hairs and is commonly used in the Middle East and India. Hairs are snared within an outstretched strand of twisted cotton thread and pulled out.

Although waxing and plucking allow effective temporary hair removal, permanent epilation may be achieved with thermal destruction of the hair follicle. Electrolysis, performed by a trained individual, involves placement of a fine electrode and passage of electric current to destroy individual follicles. It requires repetitive treatments over several weeks to months, can be painful, and can result in scarring.

Alternatively, laser therapy directs specific laser wavelengths to also permanently destroy follicles. During this process, termed selective photothermolysis, only target tissues absorb laser light and are heated. Surrounding tissues fail to absorb the selective wavelength and receive minimal thermal damage. For this reason, light-skinned women with dark hairs are better candidates for laser treatment due to the selective wavelength absorption by their hair. Advantageously, laser treatment can cover a wider surface area than electrolysis and therefore requires fewer treatments. It causes less pain, but is expensive and can result in dyspigmentation.

Prior to any epilation technique, topical anesthetics may be prescribed. Specifically, a topical cream combination of 2.5-percent lidocaine and 2.5-percent prilocaine (EMLA cream) can be applied as a thick layer that remains for 1 hour and is removed just prior to epilation. Recommended adult dosing is 1.5 g for each 2 × 2-inch area of skin treated.

Acne

One part of acne treatment is similar to that for hirsutism and involves lowering of androgen levels. As such, therapy may include: (1) COC pills, (2) an antiandrogen such as spironolactone, or (3) 5α-reductase inhibitors. In addition to lowering androgen levels, other therapies may be added.

In general, mild noninflammatory comedonal acne may be treated with topical retinoid monotherapy. If mild inflammatory pustules are present, topical retinoids are combined with topical antimicrobial therapy or benzoyl peroxide. Moderate to severe acne may require triple therapy with the above agents or use of oral retinoids or oral antibiotics. For this reason, women with moderate to severe acne may benefit from consultation with a dermatologist.

Topical retinoids regulate the follicular keratinocyte and normalize its desquamation. In addition, these agents also have direct antiinflammatory properties and thereby target two factors linked to acne vulgaris (Zaenglein, 2006). The most commonly used of these is tretinoin (Retin-A, Renova, others). Adapalene and tazarotene are also effective (Gold, 2006; Leyden, 2006). Initially, a pea-sized dab sufficient to cover the entire face is applied every third night and progressively increased as tolerated to nightly application (Krowchuk, 2005). Tretinoin may cause a transient worsening of acne during the first weeks of treatment. Concerning teratogenicity, tretinoin and adapalene are category C drugs and thus are not recommended for use during pregnancy or breast feeding. However, epidemiologic studies currently do not support a link between topical retinoids and birth defects (Jick, 1993; Loureiro, 2005). Tazarotene is category X and similarly is not used during these times or without highly effective contraception.

Topical benzoyl peroxide is bactericidal to P acnes by generating reactive oxygen species within the follicle. It also has weak comedolytic and antiinflammatory properties. Although it is the active ingredient in many over-the-counter acne products, some prescription preparations also combine benzoyl peroxide with topical clindamycin or erythromycin.

Topical antibiotics typically include erythromycin and clindamycin, whereas oral antibiotics most often used for acne include doxycycline, minocycline, and erythromycin. Oral antibiotics are more effective than topical therapies but can have various side effects such as sun sensitivity and gastrointestinal upset.

Oral isotretinoin (Accutane) successfully treats severe recalcitrant acne. Despite its efficacy, oral isotretinoin is teratogenic if taken during the first trimester of pregnancy. Malformations typically involve the cranium, face, heart, central nervous system, and thymus. Therefore, isotretinoin administration is limited to women using a highly effective method of contraception. Moreover, the iPLEDGE program is an FDA-mandated risk evaluation and mitigation strategy for isotretinoin that requires participation by involved patients, physicians, and pharmacies to eliminate embryofetal exposure.

Acanthosis Nigricans

Optimal treatment for acanthosis nigricans is directed toward decreasing insulin resistance and hyperinsulinemia (Field, 1961). Specifically, a few studies have shown an improvement in acanthosis nigricans with insulin sensitizers (Walling, 2003). Other methods, including topical antibiotics, topical and systemic retinoids, keratolytics, and topical corticosteroids, have been tried with limited success (Schwartz, 1994).

Surgical Therapy

Although ovarian wedge resection is now rarely performed, laparoscopic ovarian drilling restores ovulation in many women with PCOS that is resistant to clomiphene citrate (Section 44-7) (Farquhar, 2012). Rarely, oophorectomy is a viable option for women not seeking fertility who exhibit signs and symptoms of ovarian hyperthecosis and accompanying severe hyperandrogenism.