Polycystic Ovary Syndrome and Hyperandrogenic States

Prevalence

The initial estimated prevalence for NIH-defined PCOS ranged from 4% to 10% of women in their reproductive years, which designates PCOS as the most common endocrinopathy in women. In a study of 277 unselected women undergoing employee entrance physical examinations, 4.6% were found to have PCOS. This rate agrees with an 8.0% prevalence of PCOS among 230 young women with menstrual irregularity and hirsutism, confirming earlier reports that the diagnosis of PCOS was highly likely in women with hirsutism and oligomenorrhea. ^,

The subsequent expanded criteria by the Rotterdam Consensus Conference and the AE-PCOS Society increased the prevalence of this disorder. Using Rotterdam criteria, a prevalence of 19.9% was detected in approximately 400 women of Turkish descent versus 6.1% as defined by NIH criteria. The prevalence of PCOS in an indigenous population of 248 Aboriginal and/or Torres Strait Islanders was 20.9%, as defined by Rotterdam, versus 15.3% according to NIH criteria. Diagnostic criteria for PCOS established by the AE-PCOS Society also led to an increased prevalence of 15.3% in Turkish women.

A meta-analysis was performed to determine the prevalence of PCOS according to menstrual irregularity, androgen excess, and ovarian morphology. The prevalence of PCOS was 6% by NIH criteria and 10% by Rotterdam or AE-PCOS Society criteria. The reduced frequency of PCOS by the latter two criteria may reflect population selection bias, geographic heterogeneity, and insufficient data in some regions, such as Africa.

In the absence of hirsutism, women with anovulation have a high incidence of hyperandrogenemia, conferring a diagnosis of PCOS. In 87 women with oligomenorrhea, 87% had elevated circulating testosterone (T) levels, while 32% of those with amenorrhea were also hyperandrogenemic. In 206 nonhirsute women, biochemical analysis revealed elevated androgens consistent with the diagnosis in 87% of those with oligomenorrhea and in 32% with amenorrhea. In contrast, most women with hirsutism alone have ultrasound findings of polycystic ovaries regardless of oligomenorrhea, amenorrhea, or regular cycles. ^,

Familial Occurrence

PCOS tends to aggregate within families, including among first-degree relatives. Based on hyperandrogenism, anovulation, and polycystic ovaries, the likelihood of PCOS in sisters and mothers of affected women is higher than that of normal controls. In a study of 115 sisters of 80 probands, PCOS occurred in 22% of reproductive-aged siblings, whereas hyperandrogenemia occurred in an additional 24%. Additional studies of families with PCOS have shown that 32% to 66% of sisters and 24% to 52% of mothers had the syndrome. ^, In contrast, a study of sisters and mothers of Turkish women with PCOS revealed rates of 16% and 8%, respectively.

Although a PCOS phenotype for brothers of affected women with PCOS is less clear, circulating dehydroepiandrosterone sulfate (DHEA-S) levels in first-degree male relatives are significantly higher than those of unrelated BMI-matched controls. Serum T, sex hormone binding globulin (SHBG), luteinizing hormone (LH), and follicle-stimulating hormone (FSH) were similar between groups. These collective results indicate that first-degree relatives of women with PCOS are at an increased risk of having PCOS. They support a genetic basis for hyperandrogenemia, which may contribute to the familial clustering of this disorder.

Hirsutism

The most distinctive clinical feature of PCOS is hirsutism, defined as excessive terminal hair in women that appears in a male pattern of distribution. The degree of hirsutism varies from mild to severe. Gradual and progressive growth usually indicates a functional etiology, whereas the rapid appearance of thick, pigmented hair often suggests a neoplastic source of androgen production. In PCOS, increased hair growth is commonly found on the side of the face, upper lip, and chin extending down into the neck ( Fig. 22.1 ). This pattern of hirsutism may be accompanied by an extension of pubic hair growth toward the umbilicus and inner thighs may include excess hair on the upper arms, abdominal flank, and back. More severe cases include the appearance of hair on the chest. Progressive hyperandrogenism may accompany temporal balding and male pattern baldness. The severity of hirsutism in PCOS correlates poorly with serum androgen concentrations, in part because the response of the hair follicle (pilosebaceous follicle) to androgen is also influenced by local steroid metabolism and other hormonal actions, including hyperinsulinemia from insulin resistance. ^, In addition, individual variation in hair growth may reflect ethnic differences, which may account for slight variations in the prevalence of PCOS in different parts of the world. ^{, ,}

Hirsutism is usually defined by a modified Ferriman-Gallwey (FG) score , which ranks each of nine body areas (i.e., upper lip, chin, chest, upper abdomen, lower abdomen, upper back, lower back, upper arms, thighs) from 0 to 4 (total range 0–36) to establish a score above the 95th percentile for the population. With this method, hirsutism is typically defined by a modified FG score of greater than or equal to 8 in black or white women of reproductive age. ^, However, different cutoffs apply to women of Mediterranean, Hispanic, Middle Eastern, South American, and Asian heritage. Limitations of the modified FG score are its subjective nature, poor correlation with hyperandrogenemia, failure to account for hair growth in other areas (i.e., sideburns, buttocks), different scores in various populations, and inability to assess the impact of hirsutism on a woman’s well-being. However, through history and exam, it is possible to identify selected hirsute women at risk for underlying disease that requires treatment, affects fertility, or has medical or genetic implications.

Several studies have examined androgen receptor (AR) activity in PCOS women with inconsistent results. The AR gene encodes variable length CAG repeat polymorphism in the transactivation domain of the X chromosome that affects the activity of the AR protein. Normal CAG numbers range from 8 to 35, with CAG repeat length and AR activity inversely correlated. ^, In a study of 330 women with PCOS and 289 controls, a shorter CAG repeat number was associated with PCOS. In this study, NIH criteria were used for the diagnosis of PCOS, ensuring evidence of hyperandrogenemia, whereas most prior studies utilized criteria that did not require hyperandrogenism. It is unclear whether altered AR activity accounts for the variability between hirsutism and serum androgen levels in some PCOS ethnic populations.

Hair growth may also vary according to the local activity of 5α-reductase, which can convert T to its more biologically active metabolite, dihydrotestosterone. There are two isoenzymes of 5α-reductase, type 1 and type 2. The type 2 isoenzyme predominates in hair follicles of the beard and genital hair as well as in the testes and prostate. Enhanced 5α-reductase activity in hirsutism likely involves both type 1 and type 2 isoforms of 5α-reductase. Examination of 5α-reduced metabolites has shown greater production among women with PCOS compared to controls. That 5α-reductase messenger ribonucleic acid (mRNA) expression in granulosa and theca cells of PCOS follicles is higher than that of cells of normal follicles agrees with the report that genetic polymorphisms of 5α-reductase isoforms correlate with increased risk for PCOS. ^,

Hypothyroidism and obesity may also promote excessive hair growth by lowering SHBG, which increases available free T levels. Of interest, sequence variations in the coding region of separate SHBG alleles were found in a heterozygous woman with severe hyperandrogenism during pregnancy, in whom barely detectable serum SHBG levels and elevated nonprotein bound T levels accompanied a SNP encoding a missense mutation that allowed normal steroid hormone binding, but caused abnormal glycosylation.

Acne

Acne is a complex, multifactorial inflammatory disease that involves excessive and altered sebum production, virulent subtypes of Cutibacterium acnes (C. acnes), and abnormal keratinocyte development and inflammation, all of which are influenced by hormonal and genetic factors. It can cause disfigurement, frustration, lower self-esteem, and body image distress. Hyperandrogenism occurs in about 50% of women with acne, in whom it increases sebum production and modifies its composition. In a recent meta-analysis of 60 studies, including 240,213 women with PCOS versus 1,902,022 controls, the pooled prevalence of acne among women with and without PCOS was 43% versus 21%, respectively. However, increased sensitivity of sebaceous glands to androgen accounts for acne in up to 60% of the remaining women with normal androgen levels. Therefore, acne as an isolated symptom should not be considered a sign of hyperandrogenism.

Female Pattern Hair Loss (FPHL)

FPHL, also called female androgenetic alopecia, refers to a common form of hair loss in women that differs from that of men. In FPHL, reduced hair density in the central portion of the scalp is due to a shortened anagen (growth) phase with miniaturization of the hair follicle that coexists with a conserved frontal hairline. Its two main patterns are (1) loss of hair density in the midscalp with a preserved frontal hairline (Ludwig pattern) and/or (2) accentuated midline frontal hair loss (i.e., a “Christmas tree” pattern [Olsen pattern]). Bitemporal recession can also occur (Hamilton pattern) ( Fig. 22.2 ).

FPHL occurs in 20% to 30% of women with PCOS. However, its relationship to androgen excess is unclear since FPHL can occur in women who have normal serum androgen levels or those who lack AR, suggesting complex causal mechanisms underlying this form of hair loss. ^, In addition to androgen excess and/or enhanced local androgen action, other suggested contributors to FPHL, although not necessarily causal factors, include polygenetic susceptibility, altered Wnt signaling, thyroid dysfunction, and nutrition (i.e., vitamin D, iron, and zinc).

Menstrual Irregularity

In PCOS, menstrual dysfunction, including irregular, infrequent, or absent menstrual bleeding, is often an extension of postmenarchal irregularity without the acquisition of monthly menstrual cyclicity. Irregular menses are not typically preceded by premenstrual symptomatology and are thus unpredictable. This clinical observation is highly suggestive of anovulation. In some women, the onset of chronic anovulation begins well after adolescence, but this is unusual. The 1991 National Institute of Child Health & Human Development (NICHD) Conference described oligoanovulation as fewer than six menses per year, whereas the recent international guidelines recommend fewer than eight menses per year. ^{, , ,} Although descriptions of anovulatory bleeding vary, prolonged heavy bleeding in PCOS women should raise concerns about abnormal endometrial hyperplasia and even endometrial adenocarcinoma.

Approximately 10% of women with PCOS have regular ovulatory cycles, ^, so a history of regular menstrual bleeding does not exclude the diagnosis (phenotype C). In late reproductive life, PCOS women can begin to experience regular ovulation due to a decrease in androgens and antimüllerian hormone (AMH). When compared to age-matched PCOS women with persistent anovulation, PCOS women in their fourth decade have regular menstrual cycles, a smaller follicle cohort, lower AMH levels, higher serum FSH levels, and lower androgen levels. ^, Whether changes in the follicle population or alterations in the ovarian endocrine milieu are responsible for the resumption of ovulation in late-age PCOS women remains to be determined.

Ovarian Morphology

In their classical description of the polycystic ovary, Stein and Leventhal noted at surgery that the ovarian cortex contained numerous peripheral antral follicles and the ovarian stroma was enlarged, comprising at least 25% of the medullary portion of the ovary. The hyperplastic medullary stroma appeared to be displacing cystic follicles toward the periphery ( Fig. 22.3 ). Subsequent introduction of ultrasound imaging facilitated the polycystic ovary, although morphological criteria were not uniform. ^,

At the 2003 Consensus Conference in Rotterdam, Netherlands, the polycystic ovary was ultrasonographically defined as having 12 or more follicles per ovary, irrespective of location or ovarian volume greater than 10 cm ( Fig. 22.4 ). ^, However, newer equipment and advanced technology have improved the precision of counting follicles. In this regard, recent evidence-based guidelines were published by the International PCOS Network that redefined polycystic ovarian morphology as >20 follicles per ovary or a volume greater than 10 cm ³ using a vaginal 8 MHz transducer.

As ovarian reserve declines in late reproductive age, cross-sectional studies have demonstrated that women with PCOS maintain a higher antral follicle number than women without PCOS of equivalent age. ^, However, a subsequent longitudinal analysis found that women with PCOS had a faster rate of follicle number decline over time than age-matched controls, even though rates of decreasing follicle numbers were similar between female groups after adjusting for baseline antral follicle count and female age.

This description of the polycystic ovary should not be confused with the ultrasound appearance of an ovary in women recovering from hypogonadotropic hypogonadism, in whom multiple small antral follicle growth often mimics a polycystic ovary. Similarly, during ovulation induction, multiple follicle formation may also accompany ovarian stimulation, so that the implication of a multifollicular ovary or polycystic ovary should be considered within the realm of the clinical setting.

In addition, polycystic ovary morphology can be found in normal ovulatory women without a history of hyperandrogenism. In a study of 104 young Danish women with polycystic ovaries, only 43 had other symptoms that fulfilled the criteria for PCOS. Thus, 58% of women with polycystic ovaries were essentially normal without menstrual abnormalities or evidence of hyperandrogenism. Similarly, polycystic ovaries have been shown to be a relatively common finding in a large series of well-characterized normal women between the ages of 25 and 45 years. Of 257 women, polycystic ovaries were identified in 32% overall, with the greatest percentage (62%) occurring in women 25 to 30 years old, followed by progressive decline in older groups ( Fig. 22.4 ). The physiological relevance of polycystic ovaries in normal women is unclear, but a longitudinal study suggests that such individuals are not at increased risk for PCOS. While the requisite identification of polycystic ovaries to define PCOS is clinically appropriate, the polycystic ovarian morphology may not be unique to the disorder.

Obesity

Almost two-thirds of women in the United States are overweight or obese, as are a little over half of Australian women. Similarly, increasing proportions of overweight and obese people have occurred in other countries. Obesity is a disease of excess body fat that is closely related to insulin resistance ; it increases the risks of hypertension, dyslipidemia, diabetes, and cardiovascular disease and elevates the overall mortality rate. However, obesity per se is not an intrinsic defect of PCOS, particularly since 40% to 50% of PCOS women are not obese. Rather, obesity interacts with hyperandrogenemia to worsen the PCOS phenotype and/or promote the development of PCOS in susceptible individuals. ^, Although postprandial thermogenesis is decreased in PCOS, the resting energy expenditure in PCOS appears equivalent to that of normal weight-matched controls. Interestingly, nonobese PCOS women show diminished use of lipid as a metabolic substrate during overnight fasting compared to normal women, suggesting that impaired conversion of lipid to carbohydrate/protein metabolism in PCOS women may enhance weight gain ( Fig. 22.5 ).

Women with NIH-defined PCOS preferentially accumulate abdominal fat with weight gain, ^, increasing their waist-to-hip ratio compared to BMI-matched normal women. ^, Preferential abdominal fat accumulation, also known as “android obesity,” promotes insulin resistance by increasing intraabdominal (visceral) fat and occurs in overweight or obese women with PCOS, increasing their risk for metabolic syndrome, a risk factor for cardiovascular disease. Although one study of PCOS and control women showed similar regional fat distribution between groups, more recent imaging in PCOS women has shown increased abdominal body fat underlying hyperinsulinemia from insulin resistance over a wide BMI range, accompanied by hyperandrogenism. This is consistent with normal-weight PCOS women with greater intraabdominal fat mass than age- and BMI-matched control women ( Table 22.2 ). In contrast, normal women with gynecoid obesity usually have enhanced fat accumulation in the hip, buttock, and thigh regions.

Insulin Resistance

Women with PCOS are insulin resistant and have compensatory hyperinsulinemia. ^{, ,} Depending on the population studied, the prevalence of glucose intolerance or type 2 diabetes in PCOS is about 40%. ^, That insulin resistance is common in obesity may account, in part, for the wide prevalence. Nevertheless, independent of obesity, a defect in insulin action in PCOS has been established. Generally, the degree of insulin resistance is mild. However, in healthy, normal-weight PCOS women by NIH criteria, hyperandrogenism accompanies preferential abdominal fat accumulation, increased intraabdominal fat mass, and adipose insulin resistance (adipose-IR) in vivo , defined by the product of fasting circulating free fatty acid (FFA) and insulin levels. ^{, ,} Nevertheless, the prevalence of glucose intolerance and subsequent diabetes over time in women with PCOS has been reported to be as high as 31% and 7.5%, respectively. In these individuals, progression to diabetes appears to be relatively rapid. ^{, ,} Commonly, fasting hyperglycemia is not evident; instead, a primary dysfunction of postprandial glucose uptake accompanies peripheral insulin resistance. ^,

First-degree relatives of PCOS women, including both sisters and brothers, also exhibit disordered glucose metabolism and insulin secretion. Aside from the increased risk of diabetes, insulin resistance may worsen the clinical manifestations of PCOS. Administration of insulin-lowering drugs can improve insulin sensitivity, reduce androgen levels, and restore ovulation in some—but not all—women with PCOS. Insulin resistance in women with PCOS can also increase the likelihood of lipid abnormalities. ^, The association of insulin resistance with visceral fat mass is underscored by the displacement of central fat to the peripheral compartment with improved insulin sensitivity following administration of insulin lowering drugs or weight reduction. ^,

Acanthosis Nigricans

Acanthosis nigricans is observed in 5% to 50% of hyperandrogenic women and is related to the presence and severity of hyperinsulinemia. It is characterized by symmetrical, darkened, velvety plaques that appear most commonly on the nape of the neck, in the intertriginous areas of the body such as skin folds, and on pressure-bearing surfaces such as knuckles and elbows ( Fig. 22.6 ). Acanthosis nigricans originates from epidermal hyperkeratosis and dermal fibroblast proliferation. There is not an increased number of melanocytes or melanin deposition despite apparent increased pigmentation. Acanthosis nigricans is considered a potential marker for insulin resistance and diabetes in adults. Reduction of hyperinsulinemia is associated with improvement in the darkened skin areas.

Mental Health

Studies from different world regions suggest that PCOS is associated with disturbances in mental health, including depression, anxiety, and eating disorders (ED). A meta-analysis reported the median prevalence of depression to be 36.6% in the PCOS group versus 14.2% in the control group. Women with PCOS were also four times as likely to have moderate to severe depressive symptoms. The prevalence of anxiety was 41.9% in women with PCOS and 8.5% among controls, and women with PCOS were six times more likely to have moderate and severe anxiety symptoms. These findings primarily included clinic-based patients and are similar to population-based studies and hospital datasets. ^, In addition to these cross-sectional studies, longitudinal studies have also demonstrated persistent depressive and anxiety symptoms over time. ^, Using an insurance claims dataset with 42,391 women with PCOS and 759,480 women without PCOS, the odds of both perinatal depression and postpartum depression were shown to be higher in women with PCOS. Although the precise etiology for increased anxiety and depressive symptoms is unclear, known risk factors for these conditions, such as insulin resistance, obesity, body image distress, and genetic associations, are significantly associated with PCOS.

There is also an association between PCOS and disordered eating; women with PCOS are more likely to have bulimia nervosa and binge ED but not anorexia nervosa. These findings are likely due to the high prevalence of risk factors for disordered eating behaviors, such as high BMI, early onset of overweight or obesity, and frequent dieting in this population. Further, health-related quality of life (HRQoL) is impaired due to increased anxiety and depressive symptoms, poor body image, delayed diagnosis, and inadequate education and information about PCOS. Lower composite HRQoL scores, using validated PCOS-specific tools for PCOS QoL, have been reported with maximum impact on hirsutism and menstrual domains. In adolescents and young adults, body weight issues had the strongest effect on HRQoL. The high disease burden of PCOS and mental illness led to the AE-PCOS Society position statement recommending screening for depression and anxiety in all women with PCOS at the time of diagnosis.

Infertility

PCOS is the leading cause of anovulatory infertility. ^, Approximately 75% to 85% of PCOS women have some degree of ovulatory dysfunction, although ovulation may occasionally occur in these individuals. Equally important, PCOS women with regular menstrual cycles can also be anovulatory, as shown in a study wherein 16% of 316 PCOS women with hyperandrogenism and oligoanovulation had normal-appearing menstrual cycles (i.e., 27–34 day intervals).

PCOS is often accompanied by obesity as an additional risk factor for anovulation, with normal-weight and obese PCOS patients representing different ends of a continuum of ovulatory dysfunction. In normal-weight PCOS patients, LH hypersecretion from increased hypothalamic gamma-aminobutyric acid, kisspeptin/neurokinin B, and perhaps AMH activities, as well as ovarian hyperandrogenism and AMH overproduction, appear to alter follicle development, with insulin also enhancing gonadotropin actions on ovarian steroidogenesis and granulosa cell differentiation. Hyperinsulinemia’s ability to induce premature follicle luteinization with early LH receptor expression and adipose-derived leptin’s ability to impair FSH-induced aromatase may be more important than LH in altering follicle development, explaining why weight loss restores anovulatory infertility in many obese PCOS patients but not in normal-weight PCOS patients who require ovulation induction.

Diagnostic Criteria

Diagnostic criteria for PCOS in adolescence have not been thoroughly established. While adolescent girls exhibit similar clinical features of the disorder adult women, the interpretation of significant symptomatology warrants further study.

Evidence of Androgen Excess. Perhaps the most reliable indicator of PCOS in adolescence is clinical hyperandrogenism, as evidenced by hirsutism. While quantification of excess hair growth in adult women has been determined by modified F-G scoring, there is little information about hirsutism in adolescent girls. In a study of 856 girls ages 9 and 10 who were followed for 9 years, upper lip hair was assessed by F-G scoring. In postmenarchal girls, the percent of those with grade 1 hair growth was 15.8%, 12.4% were grade 2, 2.1% were grade 3, and 0.6% were grade 4. This prevalence is similar to that reported in 430 consecutive women between the ages of 15 and 24 attending a general medical outpatient clinic, suggesting that F-G scoring may be used to quantify adolescent hair growth. Interestingly, in an analysis of hair growth in hirsute and nonhirsute adult Norwegian and Dutch women, the sum of scores from the lip, chin, and public regions could discriminate between those with and without hirsutism. ^, These body areas are easily accessible in the office setting and offer a convenient clinical assessment of hair growth in adolescent girls.

Although isolated mild hair growth in adolescence should not be considered as clinical evidence of hyperandrogenism, mild hirsutism accompanied by abnormalities of reproductive or metabolic function warrant further confirmation of androgen excess, including elevated serum total or free T levels. In early adolescence, circulating T gradually increases to achieve adult levels by 2 to 3 years after menarche. This pattern occurs in girls with regular and irregular menstrual cycles as well as those with oligomenorrhea. In those with obesity, both total and free T levels were markedly increased during puberty and early adolescence. Enhanced T secretion is associated with hyperinsulinemia that likely amplifies theca cell androgen production and lowers SHBG. Few studies have carefully examined changes in circulating T levels from early puberty through adolescence. Serum T levels, assessed by liquid chromatography-tandem mass spectrometry, have been reported for late-age adolescent women (median age of 17.5 years). Notably, the upper limit of values for T was comparable to those observed in normal adult women. These findings suggest that normative T values in adult women may be used to determine hyperandrogenemia in late-age adolescence, although discriminatory T values may be lower in early adolescent girls with suspected PCOS.

Acne can accompany hyperandrogenism in adolescent PCOS. However, acne is common in adolescent girls with a reported frequency of greater than 50%. Acne in normal puberty has been attributed to adrenal androgen production and is not included in the criteria for PCOS. However, with moderate to severe acne, assessment of serum androgen levels is reasonable.

Irregular Menstrual Bleeding. Adolescent girls frequently experience menstrual irregularity following menarche and during early adolescence, with highly variable patterns of menstrual bleeding and ovulation. During the first 2 years post-postmenarche, anovulation is common and marked by irregular bleeding. By the third year, regular cyclicity occurs in 95% of adolescents, with an average of 10 or more cycles per year. ^, Conversely, approximately 50% of 14- to 16-year-old girls with oligomenorrhea have persistent, irregular cycles at age 18. Similar findings were exhibited by young adolescent girls with oligomenorrhea who were followed for up to 6 to 8 years.

Consideration of PCOS is warranted in the adolescent who presents with irregular menstrual bleeding at least 2 years beyond menarche together with evidence of androgen excess.

Ovarian Morphology. In normal, healthy girls, the ovary may exhibit multiple follicles per ovary as determined by ultrasonography. The characteristic features of a polycystic ovary have not been established in adolescent girls with PCOS. This is due, in part, to developmental changes in the ovary during puberty. Thus, the antral follicle count appears to be an unreliable measure of PCOS in adolescence. Instead, most studies have shown that ovarian volume has a steady growth pattern throughout puberty and adolescence. ^, As a result, ovarian volume can be used to assess ovarian morphology. While most studies have used a value of greater than 10 cm ³ to detect polycystic ovary morphology, a recent report by the Pediatric Endocrine Society recommends a value of greater than 12 cm ³ for ovarian enlargement.

Magnetic resonance imaging (MRI) has also been used to image the ovary in adolescent girls with possible PCOS. Brown et al. described ovarian morphology in normal high school students and adolescents with PCOS based on the presence of hirsutism and oligomenorrhea. Using MRI, 17 of 21 normal individuals (81%) had 12 or more follicles per ovary. In 5 of 21 normal adolescents, ovarian volume was larger than 10 mL. Similar MRI findings were reported in 39 PCOS and 22 normal girls matched for age and BMI. Most of the subjects were obese. In the PCOS group, the median ovarian volume and follicle number per ovary were 11.8 cm ³ and 12, respectively, both of which were significantly greater than those of normal controls. Moreover, ovarian volume by MRI was significantly larger than that assessed by ultrasound, whereas comparison of follicle number was not possible due to unclear imaging by ultrasound. Therefore, MRI provides a clear depiction of the ovary unencumbered by obesity, although its cost and inconvenience combined with a lack of normative data in adolescents limits recommendation.

Serum AMH has been used as a surrogate measure for antral follicle number in adults. AMH levels are elevated in healthy girls with polycystic ovary morphology. ^, However, the utility of AMH among adolescents with PCOS has not been established. ^,

Clinical Presentation

During puberty or early adolescence, the symptoms of PCOS often emerge insidiously with changes accompanying normal pubertal development. The emergence of PCOS coincident with the events of puberty suggests that PCOS may be related to an abnormal expression of those factors that regulate puberty. Because the duration of menstrual irregularity accompanying normal puberty is variable, it is difficult to rely solely on this historical feature as a basis for diagnosis. Moreover, recognizing that some PCOS women exhibit normal ovulatory function, regular cyclic bleeding does not preclude the disorder in adolescence. Rather, early detection of PCOS in adolescent girls is predicated primarily on hyperandrogenic symptoms such as hirsutism and acne, acknowledging that adolescent acne alone does not necessarily reflect increased circulating testosterone levels. Nevertheless, when followed longitudinally, severe acne in this population has been associated with increased serum testosterone levels, although comparison to a corresponding nonacne, age-matched control group has not been reported.

In obese individual, associated reproductive-endocrine abnormalities may create uncertainty as to the mechanism of hyperandrogenism. Reduced SHBG is directly correlated to obesity, thus increasing free testosterone levels. In addition, obese adolescents, particularly those with acanthosis nigricans, are likely to have hyperinsulinemia from insulin resistance, which can suppress SHBG and promote excess ovarian androgen production. An ultrasound image of a polycystic ovary as determined by ovarian volume may be helpful, although established morphological criteria in adolescent girls is limited.

Abnormal Metabolic Function

Similar to adults, adolescent girls with hyperandrogenic PCOS exhibit abnormal insulin responses to glucose loading. The 24-hour pattern of insulin release is greater in hyperandrogenic girls than in normal girls, whereas a reciprocal relationship exists for IGFBP-1 secretion. Obesity worsens the likelihood of insulin resistance and PCOS is the most common endocrine obesity syndrome in adolescence. While obesity contributes to insulin resistance, obese, hyperandrogenemic PCOS girls have higher fasting serum insulin, less insulin sensitivity, and greater insulin secretion compared to obese girls without androgen excess. In adolescent PCOS, moreover, increased free T levels predict insulin resistance independent of BMI. The lipid profile in hyperandrogenic PCOS girls shows a higher low-density lipoprotein cholesterol (LDL-C) to high-density lipoprotein cholesterol (HDL-C) ratio in conjunction with lower SHBG levels. This adverse lipid profile is underscored by obesity. Associated comorbidities may vary among obese individuals, ^, since metabolically healthy, obese PCOS girls have a lower risk for type 2 diabetes, atherogenesis, inflammation, and hyperandrogenemia than obese adolescent PCOS with unhealthy metabolic profiles.

Obesity also increases the risk of nonalcoholic fatty liver disease (NAFLD), particularly in those with insulin resistance. In an early study of obese adolescents with PCOS, the prevalence of nonalcoholic steatohepatitis was based on elevated serum transaminase levels. Unfortunately, transaminases are not sensitive enough to identify adolescents with NAFLD. In a recent study, various metabolic measures were assessed in obese adolescents with PCOS in whom hepatic fat was quantified by MRI. The results revealed that the likelihood of hepatic steatosis could be determined based upon serum levels of ALT and SHBG, BMI percentile, and waist circumference. Early detection of hepatic steatosis and potential NAFLD in young women with PCOS represents a significant advance in the management of metabolic dysfunction in this population.

Prepubertal Disposition

It has been reported that girls with premature pubarche are at increased risk for functional ovarian hyperandrogenism and polycystic ovaries following puberty. Moreover, with the subsequent development of hyperandrogenism and hyperinsulinemia, there was a corresponding reduction in the birth weight of these individuals. The link between low birth weight and insulin resistance in children appears to persist throughout life as indicated by studies performed in early and late adulthood. ^, Low birth weight is commonly associated with hypoplasia of the fetal adrenal and correspondingly low serum DHEA-S levels as a marker for adrenarche, independent of and preceding gonadarche by several years. In pairs of siblings discordant at birth but of equivalent weight during childhood, DHEA-S levels are higher in those of low birth weight compared to those born with normal weight. Thus, if fetal growth modulates adrenarche, then increased DHEA-S may accompany exaggerated adrenarche in these children, with the resultant increased androgen pool promoting a cycle of altered physiology characteristic of PCOS. The presence of hyperinsulinemia from insulin resistance may further enhance androgen production in adolescent girls at risk for PCOS by suppressing SHBG, thereby increasing the availability of free T. Thus, the link between hyperinsulinemia and hyperandrogenism in postmenarchal girls, as it temporally relates to the onset of physiological insulin resistance during puberty, may be crucial in the genesis of PCOS.

While premature pubarche may increase the risk of PCOS after puberty, exposure to androgen prepubertally may also provoke PCOS-like features. In a nonhuman primate study, prepubertal female rhesus macaques at 1 year of age were administered Silastic T implants to cause a fourfold rise in circulating T levels that was maintained long-term throughout the course of study. At age 5, when the monkeys were in early adulthood, T-treated animals had significantly greater LH pulsatility during the early follicular phase compared with controls given cholesterol-filled implants. No differences were seen in insulin sensitivity, although there was a suggestion of multiple follicle formation in the ovaries as determined by magnetic resonance. Ovulation rates were similar in both groups. These results show that increased androgen exposure during pubertal development may enhance the neural drive to the reproductive axis that resembles that of obese hyperandrogenemic girls in early adulthood and is characteristic of PCOS. They further suggest that the prepubertal hypothalamic-pituitary-ovarian axis may be vulnerable to endocrinologic insult such as excess androgen production.