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CHAPTER 17: Polycystic Ovarian Syndrome and

Hyperandrogenism
INTRODUCTION
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.
DEFINITION
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, a!ected 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.
TABLE 17-1
Definition of Polycystic Ovarian Syndrome
ESHRE/ASRM (Rotterdam) 2003
Two of the three:
Clinical and/or biochemical hyperandrogenism
Oligo-/anovulation
Polycystic ovaries
NIH (1990)
To include both:
Oligo-/anovulation
AE-PCOS (2006)
To include both:
Oligo-/anovulation and/or polycystic ovaries
AE-PCOS = Androgen Excess and PCOS Society; ASRM = American Society for Reproductive Medicine; ESHRE = European Society of Human Reproduction and Embryology; NIH = National
Institutes of Health. PCOS = polycystic ovarian syndrome.
Data from Azziz, 2006; The Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group, 2004; Zawadzki, 1990.
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 di!erence is that the NIH Conference defined PCOS without regard to ovarian sonographic appearance. Last, a third organizationThe 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
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controversy exists as to which is most appropriate.
Ovarian Hyperthecosis and HAIRAN Syndrome
Ovarian hyperthecosis, o"en considered a more severe form of PCOS, is a rare condition characterized by nests of luteinized theca cells distributed throughout the
ovarian stroma. A!ected 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.
INCIDENCE AND ETIOLOGY

PCOS is the most common endocrine disorder of reproductive-aged women and a!ects approximately 4 to 12 percent in general population studies (Asuncin, 2000;
Knochenhauer, 1998; Lauritsen, 2014). Although symptoms of androgen excess may vary among ethnicities, PCOS appears to a!ect 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 a!ected 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.
PATHOPHYSIOLOGY
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 a!ected women (van Santbrink, 1997). Similarly, LH:FSH ratios are elevated and rise above
2:1 in approximately 60 percent of patients (Rebar, 1976).
FIGURE 17-1
Model for the initiation and maintenance of polycystic ovarian syndrome (PCOS). Alterations in pulsatile gonadotropin-releasing hormone (GnRH) release may lead to
a relative increase in luteinizing hormone (LH) versus follicle-stimulating hormone (FSH) biosynthesis and secretion. LH stimulates ovarian androgen production,
while the relative paucity of FSH prevents adequate stimulation of aromatase activity within the granulosa cells, thereby decreasing androgen conversion to the
potent estrogen estradiol.
Increased intrafollicular androgen levels result in follicular atresia. Increased circulating androgen levels contribute to abnormalities in patient lipid profiles and the
development of hirsutism and acne. Increased circulating androgens can also be derived from the adrenal gland.
Elevated serum androgens (primarily androstenedione) are converted in the periphery to estrogens (primarily estrone). As conversion occurs primarily in the stromal
cells of adipose tissue, estrogen production will be augmented in obese PCOS patients. This conversion results in chronic feedback at the hypothalamus and pituitary
gland, in contrast to the normal fluctuations in feedback observed in the presence of a growing follicle and rapidly changing levels of estradiol. Unopposed estrogen
stimulation of the endometrium may lead to endometrial hyperplasia.
Insulin resistance due to genetic abnormalities and/or increased adipose tissue contributes to follicular atresia in the ovaries as well as the development of acanthosis
nigricans in the skin.
Lack of follicular development results in anovulation and subsequent oligo- or amenorrhea.
Note that this syndrome may develop from primary dysfunction of any one of a number of organ systems. For example, elevated ovarian androgen production may be
due to either an intrinsic abnormality in enzymatic function and/or abnormal hypothalamic-pituitary stimulation with LH and FSH.
The common denominator is development of a self-perpetuating noncyclic hormonal pattern.
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Insulin Resistance
Women with PCOS also display greater degrees of insulin resistance and compensatory hyperinsulinemia than nona!ected 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 nona!ected 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).
TABLE 17-2
Consequences of Polycystic Ovarian Syndrome
Short-term consequences
Obesity
Infertility
Depression
Sleep apnea
Irregular menses
Abnormal lipid levels
Non-alcoholic fatty liver disease
Hirsutism/acne/androgenic alopecia
Insulin resistance/acanthosis nigricans
Long-term consequences
Diabetes mellitus
Endometrial cancer
Cardiovascular disease
Androgens
Both insulin and LH stimulate androgen production by the ovarian theca cell (Dunaif, 1992). As a result, a!ected 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; ODriscoll, 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
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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).
SIGNS AND SYMPTOMS

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 o"en 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 una!ected adolescents, some advocate delaying the diagnosis of PCOS until a"er 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 so", 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).
FIGURE 17-2
A. Facial hirsutism. (Used with permission from Dr. Tamara Chao.) B. Male pattern escutcheon.
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TABLE 17-3
Medications That May Cause Hirsutism and/or Hypertrichosis
Hirsutism Hypertrichosis
Anabolic steroids Cyclosporine
Danazol Diazoxide
Metoclopramide Hydrocortisone
Methyldopa Minoxidil
Phenothiazines Penicillamine
Progestins Phenytoin
Reserpine Psoralens
Testosterone Streptomycin
Pathophysiolog y 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 5-reductase
to dihydrotestosterone (DHT) (Fig. 17-3). Although both testosterone and DHT convert short, so" vellus hair to coarse terminal hair, DHT is markedly more e!ective
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 a!ected 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.
FIGURE 17-3
Androgenic e!ects on the pilosebaceous unit. In some hair-bearing areas, androgens stimulate sebaceous glands, and vellus follicles (A) are converted to terminal
follicles (B)
(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)
(D).
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The concentration of hair follicles per unit area does not di!er between men and women, however, racial and ethnic di!erences 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 di!erences in 5-reductase activity and in target tissue sensitivity to androgens.
Ferriman-Gallwey Scoring System
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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).
FIGURE 17-4
Depiction of the Ferriman-Gallwey system for scoring hirsutism.
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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 5-
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 e!ect of acnescarring. 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 di!use thinning at the crown with
preservation of the frontal hairline (Quinn, 2014). Its pathogenesis involves an excess of 5-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, a!ected 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 di!icult to ascertain for lack of a simple method to determine insulin sensitivity in an o!ice 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).
FIGURE 17-5
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):11651174.)
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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 di!erential diagnosis, acanthosis nigricans rarely can be seen with genetic syndromes or gastrointestinal tract malignancy, such as
adenocarcinoma of the stomach or pancreas. To di!erentiate, acanthosis nigricans associated with malignancy usually has a more abrupt onset, and skin
involvement is more extensive (Moore, 2008).
FIGURE 17-6
Acanthosis nigricans and multiple small pedunculated acrochordons (skin tags) in the neck crease. Both are dermatologic signs of insulin resistance.
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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 a"er adjusting for body mass index (BMI), women with PCOS
remained more likely to have DM (Lo, 2006). Specifically, -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 o"en 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 e!ect 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
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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; Rebu!e-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).
FIGURE 17-7
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.)
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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 le" ventricular diastolic dysfunction and increased internal and external carotid artery sti!ness (Lakhani, 2000; Tiras, 1999). Moreover, in a!ected 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 e!ects 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 (Cli!ord, 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 e!ects 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 e!ect of metformin administration on miscarriage risk in women with
PCOS (Palomba, 2009). Until further randomized controlled trials are performed studying the e!ects 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.
DIAGNOSIS
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.
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TABLE 17-4
Di!erential Diagnoses of Ovulatory Dysfunction and Hyperandrogenism
Evaluation Indicative Results a
Causes of oligo- or anovulation
PCOS Total T level Mildly increased
DHEAS level May be mildly increased
LH:FSH ratio Typically >2:1
AMH level Increased
Hyperthyroidism TSH level Decreased
Hypothyroidism TSH level Increased
Hyperprolactinemia PRL level Increased
Hypogonadotropic hypogonadism FSH, LH, E2 levels All decreased
POI FSH, LH levels Increased
E2 levels Decreased
Causes of hyperandrogenism
PCOS
Late-onset CAH 17-OH-P level >200 ng/dL
Androgen-secreting ovarian tumor Total T level >200 ng/dL
Androgen-secreting adrenal tumor DHEAS level >700 g/dL
Cushing syndrome Cortisol level Increased
Exogenous androgen use Toxicology screen Increased
Summary of PCOS testing
Serum levels of FSH, LH, TSH, Total T, PRL, DHEAS, 17-OH-P
2hr-GTT, HbA1c, lipid profile
Measurement of BMI, waist circumference, BP
a
Based on reference laboratory ranges of normal.
AMH = antimllerian hormone; BMI = body mass index; BP = blood pressure; CAH = congenital adrenal hyperplasia; DHEAS = dehydroepiandrosterone sulfate; E2= estradiol; FSH =
follicle-stimulating hormone; GTT = glucose tolerance test; LH = luteinizing hormone; 17-OH-P = 17-hydroxyprogesterone; PCOS = polycystic ovarian syndrome; POI = premature ovarian
insu!iciency; PRL = prolactin; T = testosterone; TSH = thyroid-stimulating hormone.
FIGURE 17-8
Algorithm for evaluation of androgen excess. 17-OHP = 17-hydroxyprogesterone; ACTH = adrenocorticotropin hormone; CAH = congenital adrenal hyperplasia; DHEAS
= dehydroepiandrosterone sulfate; PCOS = polycystic ovarian syndrome; T = testosterone; TFTs = thyroid function tests.
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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
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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).
TABLE 17-5
Clinical Features of Virilization
Acne Androgenic alopecia
Hirsutism Decreased breast size
Amenorrhea Deepening of the voice
Clitoromegaly Increased muscle mass
FIGURE 17-9
Photograph of woman with virilization manifest by clitoromegaly. (Reproduced with permission from Ho!man BL, Schorge JO, Scha!er JI, et al (eds): Williams
Gynecology Clinical Pearls: Clitromegaly, 2nd edition. New York: McGraw-Hill; 2014.)
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).
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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 g/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
a!ected 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 a!ected, 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 a!ected 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 g, 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 ine!ective, steroid
precursors up to and including progesterone, 17-hydroxypregnenolone, and especially 17-hydroxyprogesterone accumulate in the adrenal cortex and in circulating
blood. Thus in a!ected individuals, serum levels of 17-hydroxyprogesterone can reach many times their normal concentrations. Levels >1000 ng/dL from blood drawn
a"er synthetic ACTH is given are indicative of late-onset CAH.
Antimllerian 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 antimllerian 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 nona!ected 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 g/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
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resistance are not required to diagnose or treat PCOS, these tests are o"en 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 a!irms 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 HbA1c level can be considered.
TABLE 17-6
Diagnosis of Impaired Glucose Tolerance and Diabetes Mellitus
Normal Range Impaired Glucose Tolerance Diabetes Mellitus
HbA1c <5.7% 5.76.4% 6.5%
Fasting blood glucose level <100 mg/dL 100125 mg/dL 126 mg/dL
2-hr GTT <140 mg/dL 140199 mg/dL 200 mg/dL
2-hr GTT = 2-hour oral glucose tolerance test; HbA1c = hemoglobin A1c.
Data from American Diabetes Association: Standards of medical care in diabetes2014. Diabetes Care 2014 Jan;37 Suppl 1:S1480.
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 su!icient 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).
FIGURE 17-10
Transvaginal sonography displays multiple small hypoechoic cysts. (Used with permission from Dr. Elysia Moschos.)
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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 o"en 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).
TREATMENT
The treatment choice for each symptom of PCOS depends on a womans goals and the severity of endocrine dysfunction. Thus, anovulatory women desiring
pregnancy will undergo significantly di!erent treatment than adolescents with menstrual irregularity and acne. Patients o"en 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
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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 a!ord only
short-term weight loss initially with lesser benefits over time (Legro, 1999; Skov, 1999). Thus, it appears that a well-balanced hypocaloric diet o!ers the most benefit in
treating obese women with PCOS.
Exercise is known to have a beneficial e!ect in treating patients with type 2 DM (Nestler, 1998). The most dramatic e!ect 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 e!ect 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, o"en 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 e!ect 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 womans 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 e!ects 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 e!ect.
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Lowered E!ective Androgen Levels
Several options are available to decrease androgen levels a!ecting hair follicles. First, as described earlier, COCs are e!ective 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 e!ectiveness in treating hirsutism, long-
term administration of GnRH agonists is not ideal due to associated bone loss, high cost, and menopausal side e!ects.
Last, 5-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 e!ective for hirsutism
treatment (Fruzzetti, 1994; Moghetti, 1994). Side e!ects are low with finasteride, although decreased libido has been noted. However, as with other antiandrogens, the
risk of male fetal teratogenicity is present, and e!ective contraception must be used concurrently.
Eflornithine Hydrochloride
This antimetabolite topical cream is applied twice daily to a!ected 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 a"er 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
e!ectively treat hirsutism, they carry a risk for several side e!ects. 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 e!ective contraception. None of the antiandrogen agents are FDA-
approved for treatment of hyperandrogenism and thus are used o!-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 e!ects, this drug also a!ects hair conversion from vellus to terminal by its direct inhibition of 5-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 o"en 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 e!ective. 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 sha" 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 e!ective 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
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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) 5-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 e!ective (Gold, 2006; Leyden, 2006). Initially, a pea-sized dab su!icient 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 e!ective 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 o"en used for acne include doxycycline, minocycline, and
erythromycin. Oral antibiotics are more e!ective than topical therapies but can have various side e!ects such as sun sensitivity and gastrointestinal upset.
Oral isotretinoin (Accutane) successfully treats severe recalcitrant acne. Despite its e!icacy, 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 e!ective 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.
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25/10/2017, 20)21

Williams Gynecology, 3e >

CHAPTER 17: Polycystic Ovarian Syndrome and

ESHRE/ASRM (Rotterdam) 2003

Two of the three:

Clinical and/or biochemical hyperandrogenism

Clinical and/or biochemical hyperandrogenism

Clinical and/or biochemical hyperandrogenism

Oligo-/anovulation and/or polycystic ovaries

controversy exists as to which is most appropriate.

Ovarian Hyperthecosis and HAIRAN Syndrome

INCIDENCE AND ETIOLOGY

Lack of follicular development results in anovulation and subsequent oligo- or amenorrhea.

The common denominator is development of a self-perpetuating noncyclic hormonal pattern.

Abnormal lipid levels

Non-alcoholic fatty liver disease

Insulin resistance/acanthosis nigricans

Sex Hormone-binding Globulin

SIGNS AND SYMPTOMS

Anabolic steroids Cyclosporine

Ferriman-Gallwey Scoring System

Other Endocrine Dysfunction

Impaired Glucose Tolerance and Type 2 Diabetes Mellitus

Obstructive Sleep Apnea

Metabolic Syndrome and Cardiovascular Disease

Evaluation Indicative Results a

Causes of oligo- or anovulation

PCOS Total T level Mildly increased

DHEAS level May be mildly increased

LH:FSH ratio Typically >2:1

AMH level Increased

Hyperthyroidism TSH level Decreased

Hypothyroidism TSH level Increased

Hyperprolactinemia PRL level Increased

Hypogonadotropic hypogonadism FSH, LH, E2 levels All decreased

POI FSH, LH levels Increased

Late-onset CAH 17-OH-P level >200 ng/dL

Androgen-secreting ovarian tumor Total T level >200 ng/dL

Androgen-secreting adrenal tumor DHEAS level >700 g/dL

Cushing syndrome Cortisol level Increased

Exogenous androgen use Toxicology screen Increased

Summary of PCOS testing

Serum levels of FSH, LH, TSH, Total T, PRL, DHEAS, 17-OH-P

2hr-GTT, HbA1c, lipid profile

Measurement of BMI, waist circumference, BP

Thyroid-stimulating Hormone and Prolactin

Acne Androgenic alopecia

Hirsutism Decreased breast size

Amenorrhea Deepening of the voice

Clitoromegaly Increased muscle mass

Measurements of Insulin Resistance and Dyslipidemia

Normal Range Impaired Glucose Tolerance Diabetes Mellitus

HbA1c <5.7% 5.76.4% 6.5%

2-hr GTT <140 mg/dL 140199 mg/dL 200 mg/dL

PCOS Diagnosis in Adolescence

levels (Huber-Buchholz, 1999; Kiddy, 1992; Pasquali, 1989).

Treatment of Oligo- and Anovulation

Insulin Sensitizing Agents

Lowered E!ective Androgen Levels

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