INTRODUCTION — The polycystic ovary syndrome (PCOS) is an important cause of both menstrual irregularity and androgen excess in women. When fully expressed, the manifestations include irregular menstrual cycles, hirsutism, acne, and, frequently, obesity. The clinical manifestations of PCOS will be reviewed here. The epidemiology and pathogenesis of, diagnostic criteria for, and treatment of PCOS are described in detail separately. (See "Epidemiology, phenotype, and genetics of the polycystic ovary syndrome in adults" and "Diagnosis of polycystic ovary syndrome in adults" and "Treatment of polycystic ovary syndrome in adults".)
OVERVIEW — PCOS is one of the most common endocrinopathies in women of reproductive age, affecting between 6.5 and 10 percent of women overall [1,2]. In a meta-analysis of 55 population-based studies from Europe, Australia, Asia, and the United States, the rates of hirsutism, hyperandrogenemia, polycystic ovaries, and oligo-ovulation were 13, 11, 28, and 15 percent, respectively . The epidemiology of PCOS is reviewed in detail separately. (See "Epidemiology, phenotype, and genetics of the polycystic ovary syndrome in adults".)
It is important to appreciate that PCOS is a syndrome, reflecting multiple potential etiologies and variable clinical presentations. Its key features are oligo- or anovulation and hyperandrogenism. Other features are polycystic ovaries on pelvic ultrasonography, infertility due to oligo-ovulation, obesity, and insulin resistance.
Menstrual dysfunction — The menstrual dysfunction in PCOS is characterized by oligo- or amenorrhea, caused by infrequent or absent ovulation. The menstrual disturbances classically have a peripubertal onset. Affected women may have a normal or slightly delayed menarche followed by irregular cycles. Other women may apparently have regular cycles at first and subsequently develop menstrual irregularity in association with weight gain. Although the mechanism is not fully elucidated, many obese women with PCOS resume more regular menstrual cycles with even modest weight loss. (See "Treatment of polycystic ovary syndrome in adults", section on 'Weight reduction'.)
Gonadotropin dynamics — Many, but not all, women with PCOS have abnormal gonadotropin secretory dynamics. Most commonly, there is an increase in mean luteinizing hormone (LH) levels (figure 1) and in LH pulse frequency and amplitude when blood is sampled frequently (a minimum of every 10 minutes throughout the day) [4,5]. The likelihood of finding an elevation in serum LH depends upon the timing of the sample relative to the last menstrual period, the ovarian activity, the use of oral contraceptive (OC) pills, body mass index (BMI), and the frequency of LH sampling . Thus, the absence of an elevated serum LH level does not exclude the diagnosis of PCOS. (See "Diagnosis of polycystic ovary syndrome in adults", section on 'Diagnosis'.)
The serum concentration of follicle-stimulating hormone (FSH) may be normal or low in PCOS, leading to an elevated LH/FSH ratio compared with normally cycling, early follicular phase, young control women. However, neither an elevated serum LH concentration nor an increased LH/FSH ratio is part of the diagnostic criteria for PCOS. (See "Diagnosis of polycystic ovary syndrome in adults".)
It has been proposed that in utero exposure to androgens may program the female fetus to develop LH excess, ovarian and adrenal hyperandrogenism, amenorrhea, and insulin resistance at puberty [6-8].
Genetic analyses suggest that women with PCOS have an increased prevalence of allelic differences in FSH beta chain gene that are associated with increased LH concentration . (See "Epidemiology, phenotype, and genetics of the polycystic ovary syndrome in adults", section on 'Genetics'.)
Endometrial cancer risk — In PCOS, chronic stimulation of the endometrium by estrogen in the presence of chronically low progesterone levels associated with anovulation may result in an excess risk of endometrial hyperplasia and endometrial carcinoma. A national cohort study that included over 12,000 women with PCOS (with no information on treatment history) reported an increased risk of endometrial cancer . However, the excess absolute risk was very small (1.3 per 10,000 women per year [for women under age 50 years]). A meta-analysis of five studies including 138 women with PCOS and 5593 controls without PCOS reported an excess risk of endometrial cancer among women with PCOS (odds ratio [OR] 2.79, 95% CI 1.31-5.95) .
The reduction in ovulatory events in PCOS leads to deficient progesterone secretion and chronic exposure to estrogen. Thus, women with PCOS may have constant mitogenic stimulation of the endometrium (chronic estrogen stimulation, no progesterone for differentiation), leading to intermittent breakthrough bleeding and abnormal uterine bleeding (frequent or unusually heavy menstrual bleeding typically associated with anovulation).
Women with PCOS have other risk factors for endometrial cancer, including chronic hyperinsulinemia, increased serum insulin-like growth factor-1 (IGF-1) concentrations, hyperandrogenemia, and obesity .
Although there is no consensus on monitoring for endometrial hyperplasia in these patients, one study suggested that in oligo-ovulatory women with PCOS, an endometrial thickness <7 mm on transvaginal ultrasound was not associated with histologic evidence of endometrial hyperplasia .
Ovarian abnormalities — The key ovarian findings in PCOS include multiple, small, preantral and antral follicles in a peripheral location, with an increased volume of stroma. Histologically, there is a thickened and sclerotic cortex of the ovary, giving the appearance of a smooth white capsule on gross examination .
Ultrasound appearance — With new high-frequency transvaginal ultrasonography, the histologic findings can be corroborated noninvasively. A modified set of diagnostic criteria for PCOS (the Rotterdam criteria) has been published and is described in detail elsewhere. (See "Diagnosis of polycystic ovary syndrome in adults", section on 'Transvaginal ultrasound'.)
The Rotterdam ultrasound criteria include the presence of 12 or more follicles in each ovary measuring 2 to 9 mm in diameter and/or increased ovarian volume (>10 mL; calculated using the formula 0.5 x length x width x thickness). Ovarian volume and follicle number decrease with age in women with or without PCOS. Age-based criteria to define polycystic ovaries have therefore been proposed in women over age 40 years. The International PCOS Network has proposed revised criteria because of improvements in the resolution of pelvic ultrasound . They suggest a threshold for diagnosing a polycystic/multifollicular ovary be increased to ≥20 follicles per ovary. The group also confirmed that an ovarian volume >10 mL was consistent with PCOS. (See "Diagnosis of polycystic ovary syndrome in adults", section on 'Transvaginal ultrasound'.)
Using the original ultrasound criteria in combination with an ovarian volume greater than 10 mL (from revised criteria), nearly all women with irregular menses and hyperandrogenism have polycystic ovaries on ultrasound .
As a sole finding, sonographically detected polycystic ovaries are not sufficient to make the diagnosis of PCOS, although they may represent a mild form of ovarian hyperandrogenism and insulin resistance. This was illustrated in a study of 68 nonhirsute women with normal menstrual cycles, 39 of whom had polycystic morphology on ultrasound . Serum total and free testosterone and dehydroepiandrosterone sulfate (DHEAS) were higher in the early follicular phase in women with polycystic morphology compared with those with normal ovarian morphology. In addition, both fasting insulin and insulin resistance calculated from a homeostasis model assessment of insulin resistance (HOMA-IR or HOMA model: fasting glucose x fasting insulin) were higher in the women with polycystic morphology.
In a follow-up report from the same investigators, women with regular menstrual cycles and polycystic ovaries on ultrasound were not at increased risk for subsequent development of PCOS .
Follicular development — Follicular development and function are abnormal in PCOS ovaries, including abnormal patterns of follicular fluid hormone production (low follicular fluid estradiol concentrations and high levels of follicular fluid androgens) . There are also abnormalities in the dynamics of follicular development. Growth of later (antral) stages of follicles tends to be arrested at 5 to 8 mm in diameter, much smaller than a mature follicle destined to ovulate.
Although there is evidence for an abnormal ovarian endocrine environment, it is also possible that there is an intrinsic defect in ovarian folliculogenesis. As an example, in a histologic study of ovarian cortical biopsies in women with polycystic ovaries (either anovulatory or ovulatory) and normal controls, the density of small preantral follicles was sixfold greater in anovulatory women with polycystic ovaries compared with normals . Within the preantral follicular pool, the percentage of early growing (primary) follicles was significantly greater, the percentage of primordial (resting) follicles significantly lower, and there was a trend towards a greater percentage of atretic follicles in the anovulatory polycystic ovary patients compared with controls. These findings suggest that, although there might be a greater initial pool of follicles in women with PCOS, a higher percentage get recruited and then become atretic.
Serum AMH — Serum anti-müllerian hormone (AMH) is expressed by small (<8 mm) preantral and early antral follicles; serum concentrations reflect the size of the primordial follicle pool. In adult women, AMH levels gradually decline with age (as the primordial follicle pool decreases) and become undetectable at menopause . In women with PCOS, mean AMH concentrations are high but overlap with those of age-matched women without PCOS . In a meta-analysis of 10 observational studies of women with PCOS, a serum AMH concentration >4.7 ng/mL had a specificity and sensitivity for diagnosing PCOS of 79 and 83 percent, respectively . In one study, serum concentrations of AMH were two- to threefold higher in women with PCOS compared with normal ovulatory women . In addition, the number of small antral follicles detected on transvaginal imaging appears to be correlated with serum AMH concentrations . However, an elevated AMH is not currently considered to be a criterion for the diagnosis of PCOS, and available AMH assays are not yet well standardized .
Anovulatory infertility — Women with PCOS have infrequent ovulation and, therefore, often take longer to conceive. Many, if not most, women who have PCOS and oligo-ovulation and desire fertility eventually undergo ovulation induction therapies. Women who have PCOS may have other reasons for infertility as well since they have, in comparison with women with hypothalamic amenorrhea, a reduced rate of conception relative to the rate of ovulation after therapy with clomiphene citrate. Infertility was included in the original description of PCOS . (See "Ovulation induction with clomiphene citrate".)
Many studies have also described an increased rate of early pregnancy loss in PCOS, the mechanism of which is poorly understood , but may be related to obesity. (See "Recurrent pregnancy loss: Definition and etiology", section on 'Polycystic ovary syndrome'.)
Pregnancy complications — The risk of pregnancy complications is increased in women with PCOS. The spontaneous abortion rate in women with PCOS is 20 to 40 percent higher than the baseline in the general obstetric population . In addition, women with PCOS show higher risk of gestational complications, such as miscarriage, gestational diabetes mellitus (GDM), hypertension, and preeclampsia. These problems expose them to a higher risk of premature delivery and caesarean section .
In a meta-analysis of 27 studies involving 4982 women with PCOS, the ORs of developing GDM, pregnancy-induced hypertension, preeclampsia, and preterm birth were 3.4, 3.4, 2.2, and 1.9, respectively, when compared with the general obstetric population . In addition, their babies had a higher risk of admission to the neonatal intensive care unit (NICU; OR 2.3). Obesity, in the absence of PCOS, is also a risk factor for these complications. The risk of GDM is increased in women with PCOS independent of BMI . (See "Obesity in pregnancy: Complications and maternal management", section on 'Antepartum'.)
A prospective study of 150 pregnant women with PCOS suggests that the low-grade, chronic inflammation commonly seen in these patients, as evidenced by high serum concentrations of C-reactive protein (CRP), worsens during pregnancy and may be associated with excess risk of adverse pregnancy outcomes .
Clinical — Hyperandrogenism is the second defining characteristic of PCOS. This is manifested clinically by hirsutism, acne, and female pattern hair loss. Women with PCOS do not develop virilization (deepening of the voice or clitoromegaly). If virilization occurs, other causes of hyperandrogenism should be investigated, including ovarian hyperthecosis or an androgen-secreting neoplasm of the ovary or adrenal gland. (See "Ovarian hyperthecosis".)
Hirsutism is defined as excess terminal (thick, pigmented) body hair in a male distribution and is commonly noted on the upper lip, chin, around the nipples (periareolar), and along the linea alba of the lower abdomen (picture 1). The approach to evaluation and management of hirsutism is reviewed separately. (See "Evaluation of premenopausal women with hirsutism" and "Management of hirsutism in premenopausal women".)
Adolescent hyperandrogenemia may be a harbinger of adult PCOS, and clinical manifestations of PCOS often have a peripubertal onset. Two studies of peripubertal girls suggest that obesity contributes to the hyperandrogenemia, as increasing body mass index (BMI) was associated with increases in serum total testosterone, free testosterone, and dehydroepiandrosterone sulfate (DHEAS) concentrations [33,34]. (See "Definition, clinical features, and differential diagnosis of polycystic ovary syndrome in adolescents".)
Biochemical — Depending upon the androgen measured and the technique employed, between 50 and 90 percent of PCOS women have elevated serum androgen levels (figure 2) . In women who present with hyperandrogenic symptoms, we measure serum total testosterone concentrations because it provides the best overall estimate of androgen production in hirsute women . Although serum free testosterone may be the more sensitive test for the presence of hyperandrogenic disorders , currently available direct assays are inaccurate. If free testosterone is ordered, the method should be equilibrium dialysis. (See "Evaluation of premenopausal women with hirsutism", section on 'Biochemical testing'.)
In one report of 1000 consecutive women with androgen excess, most of whom had PCOS, 78 percent had high serum androgens . Total testosterone, free testosterone, and DHEAS concentrations were elevated in 38, 55.5, and 40 percent, respectively. Among women with PCOS, DHEAS is increased in approximately 16 percent of women who have normal total and free testosterone levels. A mildly elevated level in the setting of normal free testosterone is unlikely to affect management. (See "Steroid hormone metabolism in polycystic ovary syndrome".)
Serum androstenedione is sometimes elevated in women with PCOS. However, its role in the evaluation of PCOS and/or hirsutism is unclear . Its measurement may be important for documenting hyperandrogenism in some populations with PCOS, including Icelandic women. (See "Evaluation of premenopausal women with hirsutism", section on 'Hirsutism with oligomenorrhea/amenorrhea'.)
Some hyperandrogenic women have mildly elevated serum prolactin levels, but the etiology and clinical significance is uncertain . Levels of prolactin in excess of 40 mg/dL should prompt evaluation for other causes. (See "Clinical manifestations and evaluation of hyperprolactinemia".)
Obesity and insulin resistance — Although a controlled, systematic study has not been performed to determine the exact prevalence, most investigators find that at least one-half of women with PCOS are obese. Most women with PCOS are also hyperinsulinemic and insulin resistant, independent of obesity, compared with normal women [41,42]. In addition, the prevalence of the metabolic syndrome in women with PCOS appears to be increased. (See 'Metabolic syndrome' below.)
Hyperandrogenemia has a minor effect upon the insulin resistance of PCOS; however, hyperinsulinemia contributes to the hyperandrogenism both directly (through stimulation of androgen biosynthesis in the ovarian theca cell) and indirectly through its suppressive effects on sex hormone-binding globulin (SHBG) production by the liver. (See "Steroid hormone metabolism in polycystic ovary syndrome".)
We currently do not recommend routine assessment of insulin resistance in a clinical setting, since it is not possible to determine the extent to which PCOS contributes to insulin resistance, independent of body weight and adiposity. In addition, the magnitude of insulin resistance does not appear to predict the clinical response to insulin-lowering therapies. This issue is discussed separately. (See "Diagnosis of polycystic ovary syndrome in adults", section on 'Cardiometabolic risk assessment'.)
Nonalcoholic fatty liver disease — The prevalence of nonalcoholic fatty liver disease (NAFLD), including nonalcoholic steatohepatitis (NASH), may be increased in women with PCOS [43-45]. In one study, 21 of 70 women (30 percent) with PCOS had elevated serum alanine aminotransferase (ALT) concentrations . In contrast, in a population-based study of over 18,000 adults, an abnormal ALT was seen in only 2 percent of all women, 5 percent of women with type 2 diabetes, and 7 percent of obese women . (See "Epidemiology, clinical features, and diagnosis of nonalcoholic fatty liver disease in adults".)
Metabolic syndrome — In the most recent National Health and Nutrition Examination Survey (NHANES) report (1999 to 2000), the prevalence of the metabolic syndrome (as defined by the National Cholesterol Education Program/Adult Treatment Panel [ATP] III criteria) in normal women ages 20 to 39 years was approximately 18 to 19 percent . Using the same diagnostic criteria, the prevalence appears to be much higher in women with PCOS, as illustrated by the following findings:
●In one retrospective study, 43 percent of PCOS patients had the metabolic syndrome, roughly twofold higher than that of age-matched women in the general population, as reported by the NHANES III .
●In a second study, the prevalence of metabolic syndrome in women with PCOS was approximately 47 percent, compared with 4 percent in age-matched (but not weight-matched) controls with regular menses and no hirsutism .
●In the third study, a secondary analysis of 394 women with PCOS participating in a randomized trial (thiazolidinedione versus placebo), the metabolic syndrome was common (33.4 percent of subjects), particularly in those with the highest insulin levels and body mass index (BMI) . (See "Metabolic syndrome (insulin resistance syndrome or syndrome X)".)
Recommendations for metabolic evaluation of women with PCOS are reviewed separately. (See "Diagnosis of polycystic ovary syndrome in adults", section on 'Cardiometabolic risk assessment'.)
IGT/type 2 diabetes — The risk of type 2 diabetes is increased in PCOS, particularly in women with a first-degree relative with type 2 diabetes [30,51-55]. As an example, in a study of 122 obese women with PCOS, 45 percent had either impaired glucose tolerance (IGT; 35 percent) or type 2 diabetes mellitus (10 percent) by age 40 years . The women with diabetes had a 2.6-fold higher prevalence of first-degree relatives with type 2 diabetes. In a subset of 25 women who underwent repeat oral glucose tolerance testing (OGTT) after a mean of 34 months, 40 percent had a deterioration in glucose tolerance.
In a second study of 71 women with PCOS, the annual conversion rate from normal glucose tolerance to IGT was 17 percent . A retrospective study showed that prevalence of type 2 diabetes mellitus was 15 percent in PCOS patients and 2 percent in controls. It has also been suggested that up to 20 percent of PCOS patients have IGT or type 2 diabetes in the third decade [3,57].
Women with PCOS and a family history of type 2 diabetes may have an impairment in insulin secretion as well as insulin resistance [52,58]. In a study of 33 women with PCOS and 48 of their first-degree relatives who underwent a frequently sampled intravenous glucose tolerance test, there was a significant familial (sibling) correlation for the acute insulin response to intravenous glucose . This suggests that there is a heritable component to beta cell dysfunction in families of women with PCOS. (See "Epidemiology, phenotype, and genetics of the polycystic ovary syndrome in adults", section on 'Insulin secretion and action'.)
The frequency of diagnosis of type 2 diabetes may vary with the screening test used. This was illustrated in a report of 254 women with PCOS who underwent both a fasting blood glucose and a 75 g OGTT . The American Diabetes Association (ADA) criteria (based on fasting glucose) underestimated the prevalence of diabetes when compared with the World Health Organization (WHO) criteria (based on OGTT; 3.2 and 7.5 percent, respectively). Similar findings have been described in adults  and in adolescents  with PCOS, where two-hour post-OGTT blood glucose levels were abnormal in a greater percentage of subjects than were fasting glucose levels. (See "Diagnosis of polycystic ovary syndrome in adults", section on 'Cardiometabolic risk assessment'.)
The often familial nature of PCOS has led to examination for possible molecular linkages of this disorder to type 2 diabetes. As an example, a unique defect in serine phosphorylation of the insulin receptor that results in decreased activation of the receptor has been identified in approximately 50 percent of women with PCOS . Why this occurs is not clear, but serine phosphorylation of CYP17 may also be part of the mechanism of increased adrenal androgen synthesis . In addition, familial PCOS has been linked to an insulin regulatory locus on chromosome 11 . Whether this represents a common genetic defect in PCOS and diabetes or whether it reflects cosegregation of diabetes with PCOS in the tested families remains to be elucidated.
The evaluation of women with PCOS for glucose intolerance, including guidelines from a number of professional organizations, is reviewed elsewhere. (See "Diagnosis of polycystic ovary syndrome in adults", section on 'Cardiometabolic risk assessment'.)
The genetics of PCOS is also reviewed separately. (See "Epidemiology, phenotype, and genetics of the polycystic ovary syndrome in adults", section on 'Genetics'.)
Sleep apnea — Sleep apnea is common in women with PCOS ; women with PCOS should be questioned about signs and symptoms of sleep apnea and excessive daytime sleepiness.
●In a study of 53 women with PCOS compared with 452 premenopausal controls, obstructive sleep apnea (OSA) and excessive daytime sleepiness (diagnosed by an overnight sleep study or written questionnaire, respectively) were significantly more common in the PCOS group (odds ratio [OR] 30.6 and 9.0, respectively) . The differences remained significant, even when controlled for BMI. The strongest predictors for sleep apnea were fasting plasma insulin concentrations and glucose-to-insulin ratios. Similar results were seen in a second study .
●In women with PCOS, glucose tolerance appears to be directly related to the severity of the sleep-disordered breathing .
●OSA appears to be an important determinant of insulin resistance, glucose intolerance, and type 2 diabetes in PCOS. This was illustrated in a prospective study of 52 women with PCOS and 21 women without PCOS (of similar age and BMI) who underwent an overnight polysomnogram and a 75 g OGTT .
Dyslipidemia — Most studies of women with PCOS have demonstrated low high-density lipoprotein (HDL) cholesterol and high triglyceride concentrations, consistent with their insulin resistance , as well as an increase in low-density lipoprotein (LDL) cholesterol [55,71-73]. The approach to metabolic screening of women with PCOS is reviewed separately. (See "Diagnosis of polycystic ovary syndrome in adults", section on 'Cardiometabolic risk assessment'.)
In one review of 195 obese and nonobese women with PCOS and 65 weight-matched controls, serum LDL cholesterol was increased in both the obese and nonobese PCOS groups when compared with controls (mean differences of 16 and 32 mg/dL [0.41 and 0.82 mmol/L], respectively) . In addition, HDL cholesterol was modestly but significantly elevated (6 mg/dL [0.16 mmol/L]) in the obese women with PCOS, which may provide some degree of protection against cardiovascular disease. Although serum triglyceride concentrations appeared higher in the PCOS patients, it was not a statistically significant difference.
In a second study of 398 women with PCOS, the prevalence of abnormal lipid parameters was quite high :
●Total cholesterol ≥200 mg/dL (5.27 mmol/L): 35 percent
●LDL ≥130 mg/dL (3.36 mmol/L): 31 percent
●HDL <35 mg/dL (0.90 mmol/L): 15 percent
●Triglycerides >200 mg/dL (2.26 mmol/L): 16 percent
Women with PCOS are also more likely to have an increase in small, dense LDL particles when compared with women of similar BMI and insulin resistance without PCOS [75,76]. Small, dense LDL is strongly associated with an increased risk of coronary heart disease (CHD).
CORONARY HEART DISEASE — There have been concerns that women with PCOS are at increased risk for coronary heart disease (CHD) and other cardiovascular events, but these risks are not well established . Nevertheless, we recommend that all cardiovascular risk factors be considered for evaluation and treatment. The presence of obesity, insulin resistance, impaired glucose tolerance (IGT) or type 2 diabetes, and dyslipidemia may predispose women with PCOS to CHD . The following observations illustrate the range of findings that have been described.
Observational data — Data on long-term CHD morbidity and mortality in women with PCOS are inconclusive.
●In one 30-year follow-up study of women who had previously undergone wedge resection surgery (presumably for PCOS) [78,79], no increased mortality from cardiovascular disease was observed, in spite of an increased prevalence of cardiovascular risk factors, including diabetes.
●In contrast, in the Nurses' Health Study, a history of menstrual cycle irregularity was associated with an increased risk of nonfatal and fatal CHD (relative risk [RR] 1.25 and 1.67, respectively) . This might be explained by a high rate of PCOS with its associated metabolic disturbances in these women, although no clinical or biochemical androgen data were available for confirmation of the PCOS diagnosis.
●A similar increase in CHD mortality was noted in a second prospective cohort study . However, the magnitude of the effect was attenuated after adjusting for body mass index (BMI). In addition, a subgroup analysis from the Women's Ischemia Syndrome Evaluation (WISE) reported that among postmenopausal women with possible ischemia, features of PCOS (history of irregular menses and current hyperandrogenemia) were associated with angiographic evidence of CHD and lower event-free survival after cardiovascular events . The severity of the PCOS phenotype may correlate with cardiovascular risk .
C-reactive protein — Serum concentrations of C-reactive protein (CRP), a biochemical predictor of cardiovascular disease, appear to be commonly elevated in women with PCOS. As an example, in a retrospective analysis of 116 women with PCOS and 96 BMI-matched control women with regular menstrual cycles, serum CRP concentrations were high (>5 mg/L) in 37 and 10 percent of PCOS and control subjects, respectively . (See "C-reactive protein in cardiovascular disease".)
Endothelial function — Endothelial dysfunction has been thought to be a contributing factor to the development of atherosclerosis. Data on endothelial function in women with PCOS are conflicting, with some [85-88], but not all, studies  reporting evidence of endothelial dysfunction in women with PCOS. Insulin resistance [85,86]; high serum concentrations of testosterone , CRP , and total cholesterol ; or low serum adiponectin concentrations  were correlated with the observed endothelial dysfunction.
Functional and imaging studies
●Angiography – Women with PCOS may have more extensive coronary disease on angiography when compared with normal women. This was illustrated in a report of 143 women younger than age 60 years who were undergoing coronary angiography for assessment of chest pain or valvular disease . Ultrasound appearance of polycystic ovarian morphology was present in 42 percent of the women and was associated with hirsutism, lower levels of high-density lipoprotein (HDL) cholesterol, and higher concentrations of free testosterone, triglycerides, and C-peptide, when compared with women with normal-appearing ovaries. The women with polycystic ovaries had more extensive coronary disease on angiography than those with normal ovaries. However, this study did not distinguish between polycystic morphology and true PCOS; thus, the applicability of these findings to women with PCOS is uncertain.
●Carotid ultrasound – A tendency toward atherosclerosis was also suggested in an ultrasonographic study of 125 women with PCOS and 142 normal controls . Carotid artery intima-media thickness was significantly greater in women with PCOS who were ≥45 years old than in normal controls. However, the mean intima-media thickness in the PCOS group was still well below that seen in patients with significant carotid artery disease.
●EBCT – Electron beam computed tomography (EBCT) is a noninvasive measure of coronary artery calcium (CAC, a marker for atherosclerosis). In a study of 36 premenopausal women (mean age 38 years) with PCOS, the presence of CAC was more common in PCOS patients when compared with a group of age- and weight-matched controls (39 versus 21 percent, respectively; odds ratio [OR] 2.4) . However, after controlling for BMI, PCOS was no longer a predictor of CAC, suggesting that obese women with or without PCOS are at increased risk of atherosclerosis.
A higher prevalence of CAC was observed in PCOS women compared with controls in two additional reports [93,94]. In one, components of the metabolic syndrome (low HDL and insulin resistance) appeared to mediate the association between PCOS and CAC, independently of obesity . In the second, the increase in risk appeared to be independent of traditional cardiovascular risk factors and markers of inflammation .
VENOUS THROMBOEMBOLISM — Oral contraceptives (OCs), the mainstay of therapy for women with PCOS, are associated with an increased risk of venous thromboembolism (VTE) in all users but particularly in women over age 40 years and those with obesity .
Two studies based upon health insurance claims databases reported that PCOS itself appeared to be an additional risk factor for VTE [96,97]. However, both had important methodological limitations, and it cannot be determined whether the excess risk of VTE in this population was due to PCOS or the presence of obesity and other comorbidities. Neither study directly addressed the question of whether OC use disproportionately increases VTE risk in women with PCOS.
For most women with PCOS, the benefits of OCs still outweigh the potential risks of VTE. Thus, we still consider OCs to be first-line therapy for the management of hyperandrogenic symptoms, menstrual cycle control, and contraception. (See "Treatment of polycystic ovary syndrome in adults".)
Mood disorders — We agree with expert societies that women with PCOS should be screened for depression and anxiety at the time of diagnosis . There is evidence that women with PCOS may be more likely to have mood disorders (depression and anxiety) when compared with women without PCOS [57,99-105]:
●In a cross-sectional study of 117 women with PCOS, 75 (61 percent) had depression that could not be explained by obesity or hyperandrogenic symptoms, as mean body mass index (BMI) and presence of hirsutism or acne was similar in the women with or without depression .
●In a longitudinal cohort study of women with PCOS who were screened for mood disorders at ages 31 and 46 years, the prevalence of anxiety and/or depression symptoms was higher than in control women and was independent of obesity and hyperandrogenism . At age 46 years, 25 percent of women with PCOS had depression compared with 12 percent in the control group.
●In a retrospective cohort study of over 16,000 patients with PCOS and 16,000 controls (matched for age and obesity), the prevalence of depression and anxiety was significantly higher in the women with PCOS compared with controls (23 versus 19, 11.5 versus 9.3 percent, respectively) .
Eating disorders — Women with PCOS are also at risk for eating disorders, in particular, binge eating and bulimia nervosa [108-111]. In one report, bulimia nervosa, binge, or any eating disorder, but not anorexia nervosa were more common in women with than without PCOS (odds ratio [OR] for any eating disorder 3.68, 95% CI 1.38-9.81) .
Overall quality of life — In addition to eating and mood disorders, women with PCOS are at risk for sleep disorders and sexual dysfunction. A number of studies have reported decreased health-related quality of life in women with PCOS [107,112,113]. A meta-analysis of 36 studies reporting on 349,529 women reported that women with PCOS, when compared with those without PCOS, are more likely to have eating disorders as well as :
●Sleep disorders (hypersomnia [OR 4.39, 95% CI 1.07-18.07] and obstructive sleep apnea [OR 10.81, 95% CI 2.39-48.83])
●Sexual dysfunction (lower sexual satisfaction as measured on a visual analogue scale), but no difference in Total Female Sexual Function Index
In addition to screening for mood and eating disorders, we suggest evaluating for sleep disorders and sexual dysfunction. (See "Eating disorders: Overview of epidemiology, clinical features, and diagnosis" and "Overview of sexual dysfunction in females: Epidemiology, risk factors, and evaluation".)
Factors affecting phenotype — Ethnic, racial, and other cultural factors influence the phenotype of PCOS as illustrated by the following findings :
●Black and Hispanic women were more likely and Asian women less likely than White women to be obese . After adjusting for body mass index (BMI), Asian and Hispanic women were more likely to have diabetes, and Black women were more likely to have hypertension.
●Mexican American women were more obese and had higher serum fasting insulin concentrations than White women .
●Women in the United States, when compared with those in Italy, were more obese, more insulin resistant, and had lower serum high-density lipoprotein (HDL) concentrations . However, total calorie intake and dietary constituents were similar in the two groups, except that women in the United States ate more saturated fat. The authors hypothesized that diet alone did not explain the differences in body mass, and that genetic and lifestyle factors likely played a role.
In a study comparing the phenotype of PCOS in White women in Boston or Iceland (BMI-matched), serum androstenedione concentrations were higher and serum luteinizing hormone (LH) and testosterone concentrations lower in the Icelandic compared with Boston women . Ovarian volumes and Ferriman-Gallwey scores were also lower in the Icelandic women, but there were no differences in fasting glucose or insulin levels between the two groups.
In the same study, the phenotype of PCOS was compared among different ethnic groups in Boston. Serum insulin concentrations and homeostasis model assessment ([HOMA], a measure of insulin resistance) were higher in an African American subgroup in Boston compared with White and Asian women. However, these differences could be accounted for by BMI. There were no differences in sex steroid and gonadotropin levels among the different ethnic groups in Boston. These observations suggest that there are differences in the reproductive aspects of the PCOS phenotype in White Icelandic and White Boston women. In contrast, differences in insulin dynamics appear to be explained by differences in BMI and not country of origin or ethnic background.
Some of the clinical features of PCOS have a familial pattern, including the risk of type 2 diabetes [51-54], beta cell dysfunction , dyslipidemia (including high low-density lipoprotein [LDL] concentrations) [117,118], menstrual irregularity , and insulin resistance and hyperandrogenemia . Although a number of candidate genes have been proposed, none have been verified in large populations . (See "Epidemiology, phenotype, and genetics of the polycystic ovary syndrome in adults".)
Reproductive aging/menopause — Women with PCOS sometimes develop more regular menstrual cycles as they age [120-122]; this is thought to be related to the age-dependent decline in serum androgens that both women with and without PCOS experience [114,123]. Less is known about their menstrual patterns during the menopausal transition or their average age at menopause. Postmenopausal women with PCOS report more hirsutism symptoms, but fewer vasomotor symptoms than controls . Available data suggest that after menopause, clinical hyperandrogenism persists in spite of the eventual decline in serum androgens into the normal range.
In one study of 20 postmenopausal women with PCOS (mean age 54 years) compared with 20 age-matched controls, serum androgens (androstenedione, dehydroepiandrosterone sulfate [DHEAS], total testosterone, and free androgen index) were higher in the PCOS group, while sex hormone-binding globulin (SHBG) levels were lower .
In a 30-year longitudinal cohort study of 33 women with PCOS (mean age 50 years at baseline) and 118 age-matched controls, serum androgens were higher than controls until approximately age 70 years, but then declined into the normal range (similar to controls) by a mean age of 81 years .
Hirsutism was more common in PCOS patients at all time points, including the final evaluation when serum androgens were normal. The generalizability of these data are unclear as all of the women with PCOS had undergone wedge resection in their 20s. (See "Treatment of polycystic ovary syndrome in adults", section on 'Laparoscopic surgery'.)
Other observations in postmenopausal women with PCOS include higher C-reactive protein (CRP) concentrations and a greater insulin response to an oral glucose tolerance test (OGTT) compared with controls [127,128].
There are concerns that women with PCOS are at higher risk for coronary heart disease (CHD) after menopause, but data are limited. In a report from the longitudinal cohort study described above, hypertension and hypertriglyceridemia were more common in the PCOS group, while myocardial infarction, stroke, diabetes, cancer, and mortality prevalence was similar in the two cohorts with similar BMI .
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Polycystic ovary syndrome" and "Society guideline links: Hirsutism".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topics (see "Patient education: Polycystic ovary syndrome (The Basics)")
●Beyond the Basics topics (see "Patient education: Polycystic ovary syndrome (PCOS) (Beyond the Basics)")
●Common endocrinopathy – Polycystic ovary syndrome (PCOS) is thought to be one of the most common endocrinopathies in women, affecting between 6.5 and 8 percent of women overall. The syndrome is characterized clinically by oligomenorrhea and hyperandrogenism, as well as the frequent presence of associated risk factors for cardiovascular disease, including obesity, glucose intolerance, dyslipidemia, and obstructive sleep apnea (OSA).
•Menstrual dysfunction characterized by infrequent or absent menses. However, some women with PCOS have abnormal uterine bleeding as a result of their chronic anovulation. The ovulatory dysfunction typically results in infertility and the need for ovulation induction in those who wish to conceive. (See 'Menstrual dysfunction' above.)
•Typical polycystic appearance of the ovaries on transvaginal ultrasound in the majority of women with irregular menses and hyperandrogenism (using the original ultrasound criteria for polycystic ovaries) . However, this ultrasound appearance is nonspecific, as it may also be seen in normal-cycling women (see 'Ultrasound appearance' above). The ultrasound diagnostic criteria for PCOS are reviewed in detail elsewhere. (See "Diagnosis of polycystic ovary syndrome in adults".)
●Hyperandrogenism – Hyperandrogenism, which may include clinical signs (hirsutism, acne, alopecia) and/or elevated serum androgen concentrations. (See 'Hyperandrogenism' above.)
•A clustering of risk factors for diabetes and cardiovascular disease, including obesity (and insulin resistance), glucose intolerance, and dyslipidemia. (See 'Obesity and insulin resistance' above and 'Dyslipidemia' above.)
•Women with PCOS are at increased risk for type 2 diabetes, but an excess risk of cardiovascular disease has not yet been demonstrated definitively. (See 'IGT/type 2 diabetes' above and 'Coronary heart disease' above.)
•Women with PCOS may be more likely to have mood disorders (depression and anxiety). In addition, PCOS appears to be associated with an increased risk of eating disorders, in particular, binge eating. (See 'Psychosocial issues' above.)
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