Infertility

2.2 Women with PCOS are at increased risk of anovulation and infertility; in the absence of anovulation, the risk of infertility is uncertain. We recommend screening ovulatory status using menstrual history in all women with PCOS seeking fertility. Some women with PCOS and a eumenorrheic menstrual history may still experience anovulation and a midluteal serum progesterone may be helpful as an additional screening test (1|⊕⊕○○).

2.3 We recommend excluding other causes of infertility, beyond anovulation, in couples where a woman has PCOS (1|⊕⊕○○).

Pregnancy complications

2.4 Because women with PCOS are at increased risk of pregnancy complications (gestational diabetes, preterm delivery, and pre-eclampsia) exacerbated by obesity, we recommend preconceptual assessment of body mass index (BMI), blood pressure, and oral glucose tolerance (1|⊕⊕⊕○).

Fetal origins

2.5 The evidence for intrauterine effects on development of PCOS is inconclusive. We suggest no specific interventions for prevention of PCOS in offspring of women with PCOS (2|⊕○○○).

Endometrial cancer

2.6 Women with PCOS share many of the risk factors associated with the development of endometrial cancer including obesity, hyperinsulinism, diabetes, and abnormal uterine bleeding. However, we suggest against routine ultrasound screening for endometrial thickness in women with PCOS (2|⊕⊕⊕○).

Obesity

2.7 Increased adiposity, particularly abdominal, is associated with hyperandrogenemia and increased metabolic risk (see cardiovascular disease prevention guidelines, Ref. 2). Therefore, we recommend screening adolescents and women with PCOS for increased adiposity, by BMI calculation and measurement of waist circumference (1|⊕⊕⊕○).

Depression

2.8 We suggest screening women and adolescents with PCOS for depression and anxiety by history and, if identified, providing appropriate referral and/or treatment (2|⊕⊕○○).

Sleep-disordered breathing/obstructive sleep apnea (OSA)

2.9 We suggest screening overweight/obese adolescents and women with PCOS for symptoms suggestive of OSA and, when identified, obtaining a definitive diagnosis using polysomnography. If OSA is diagnosed, patients should be referred for institution of appropriate treatment (2|⊕⊕○○).

Nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH)

2.10 We suggest awareness of the possibility of NAFLD and NASH but recommend against routine screening (2|⊕⊕○○).

Type 2 diabetes mellitus (T2DM)

2.11 We recommend the use of an oral glucose tolerance test (OGTT) (consisting of a fasting and 2-hour glucose level using a 75-g oral glucose load) to screen for impaired glucose tolerance (IGT) and T2DM in adolescents and adult women with PCOS because they are at high risk for such abnormalities (1|⊕⊕⊕○). A hemoglobin A1c (HgbA1c) test may be considered if a patient is unable or unwilling to complete an OGTT (2|⊕⊕○○). Rescreening is suggested every 3–5 years, or more frequently if clinical factors such as central adiposity, substantial weight gain, and/or symptoms of diabetes develop (2|⊕⊕○○).

1.1 Evidence

PCOS is a common disorder with systemic metabolic manifestations. Its etiology is complex, heterogeneous, and poorly understood. There are three definitions for PCOS currently in use that variably rely on androgen excess, chronic anovulation, and PCO to make the diagnosis (Table 1). However, all criteria are consistent in that PCOS is considered a diagnosis of exclusion. All three sets of diagnostic criteria include hyperandrogenism, either clinical or biochemical, and anovulation (6,–9). The Rotterdam criteria were the first to incorporate ovarian morphology on ultrasound as part of the diagnostic criteria (8, 9).

The panel from a recent National Institutes of Health (NIH)-sponsored Evidence-Based Methodology workshop on PCOS endorsed the Rotterdam criteria, although they identified the strengths and weaknesses of each of the three cardinal features (Table 2). These criteria allow the diagnosis to be made clinically (based upon a history of hyperandrogenic chronic anovulation) as well as biochemically with androgen assays or with ultrasound examination of the ovaries. We do not endorse the need for universal screening with androgen assays or ultrasound if patients already meet two of the three criteria clinically. It is recommended that the features leading to the diagnosis are documented. We recommend using the current definition of the Rotterdam criteria to document PCO morphology (at least one ovary with 12 follicles of 2–9 mm or a volume >10 mL in the absence of a dominant follicle >10 mm), in the absence of age-based criteria.

Disorders that mimic PCOS are comparatively easy to exclude; therefore, all women should be screened with a TSH, prolactin, and 17-OHP level (Table 3) (10,–12). Hyperprolactinemia can present with amenorrhea or hirsutism (13, 14). Thyroid disease may present with irregular menstrual cycles. In women with hyperandrogenism, nonclassic congenital adrenal hyperplasia should be excluded because it can be found in 1.5–6.8% of patients presenting with androgen excess (15, 16). In select women who present with amenorrhea, virilization, or physical findings not associated with PCOS, such as proximal muscle weakness (Cushing's syndrome) or frontal bossing (acromegaly), other diagnoses should be considered and excluded (Table 4).

1.1 Values and preferences

In the absence of evidence-based diagnostic criteria, we have relied on the recommendations of the NIH Panel as noted above. The presence of specific phenotypic features may result in different risk and comorbidity profiles. For example, hyperandrogenism may be more highly associated with metabolic abnormalities, whereas irregular menses and PCO morphology may be more highly associated with infertility. When interpreting published research, clinicians should note that criteria different from their own may be used when performing research. The committee notes that the diagnosis of PCOS is problematic in women who are perimenarchal or perimenopausal because amenorrhea and oligomenorrhea are natural stages in reproductive maturation and senescence, as are changes in circulating androgens and ovarian morphology. Therefore, we discuss the diagnosis of PCOS separately in these groups. Finally, because there is evidence of a genetic component to PCOS and familial clustering of reproductive and metabolic abnormalities in male and female relatives, a careful family history should be taken, and further screening of first-degree relatives is a consideration.

Diagnosis in adolescents

1.2 We suggest that the diagnosis of PCOS in an adolescent girl be made based on the presence of clinical and/or biochemical evidence of hyperandrogenism (after exclusion of other pathologies) in the presence of persistent oligomenorrhea. Anovulatory symptoms and PCO morphology are not sufficient to make a diagnosis in adolescents because they may be evident in normal stages in reproductive maturation (2|⊕⊕○○).

1.2 Evidence

All PCOS diagnostic criteria were derived for adults (Table 1), not adolescents. Furthermore, normal adolescent physiology may mimic symptoms of PCOS. Oligomenorrhea is common after menarche during normal puberty and is therefore not specific to adolescents with PCOS. Anovulatory cycles comprise 85% of menstrual cycles in the first year after menarche, 59% in the third year, and 25% by the sixth year. Anovulatory cycles are associated with higher serum androgen and LH levels (21). Approximately two-thirds of adolescents with PCOS will have menstrual symptoms, and for one-third it will be the presenting symptom, with the spectrum from primary amenorrhea to frequent dysfunctional bleeding (22). Therefore, it is appropriate to evaluate persistent oligomenorrhea or amenorrhea as an early clinical sign of PCOS, especially when it persists 2 years beyond menarche (23).

Acne is common although transitory during adolescence (24); thus, it should not be used in isolation to define hyperandrogenism in adolescents (25). Hirsutism may develop slowly and thus be less severe in adolescents than in adults due to the shorter exposure to hyperandrogenism (26). However, hirsutism was a major symptom in about 60% of adolescents in one study (27) and may be suggestive of PCOS in adolescents (28). The Ferriman-Gallwey hirsutism score was standardized only in adult Caucasians and may have a lower cut-point in adolescents (29). Androgenic alopecia has not been studied in adolescents and should be viewed cautiously in diagnosing PCOS (25).

There is a lack of well-defined cutoff points for androgen levels during normal pubertal maturation (30), as well as the lack of T assay standardization (31). Furthermore, hyperandrogenemia appears to be exacerbated by obesity because a significant proportion of obese girls have elevated androgen levels across puberty compared with normal-weight girls (32). Hyperandrogenemia during puberty may be associated with infertility in later life (33), and adult cutoffs should be used until appropriate pubertal levels are defined.

Lastly, the Rotterdam ultrasound PCO criteria were not validated for adolescents. Recommending a transvaginal ovarian ultrasound in this group raises practical and ethical concerns. Transabdominal ultrasound, already limited in evaluating the ovaries, is rendered even less technically adequate with obesity, common in adolescent PCOS (34). In addition, multifollicular ovaries are a feature of normal puberty that subsides with onset of regular menstrual cycling (35) and may be difficult to distinguish from PCO morphology (20). It is possible that elevated anti-Mullerian hormone levels may serve as a noninvasive screening or diagnostic test for PCO in this population, although there are no well-defined cutoffs (36, 37).

In summary, the diagnosis of PCOS in adolescents should be based on a complete picture that includes clinical signs and symptoms of androgen excess, increased androgen levels, and exclusion of other causes of hyperandrogenemia in the setting of oligomenorrhea.

1.2 Values and preferences

In making this recommendation, the committee acknowledges that the diagnosis of PCOS in adolescents is less straightforward than in adults. A high index of awareness is needed to initiate a thorough medical and laboratory evaluation of adolescent girls with signs and symptoms of PCOS, including a family history of PCOS. Until higher quality evidence becomes available, this recommendation places a higher value in making an early diagnosis of PCOS in adolescents for timely initiation of therapy, which outweighs harms and burdens of misdiagnosis.

Diagnosis in perimenopause and menopause

1.3 Although there are currently no diagnostic criteria for PCOS in perimenopausal and menopausal women, we suggest that a presumptive diagnosis of PCOS can be based upon a well-documented long-term history of oligomenorrhea and hyperandrogenism during the reproductive years. The presence of PCO morphology on ultrasound would provide additional supportive evidence, although this is less likely in a menopausal woman (2|⊕⊕○○).

1.3 Evidence

The natural history of PCOS through perimenopause into menopause is poorly studied, but many aspects of the syndrome appear to improve. Ovarian size, follicle count, and anti-Mullerian hormone levels (a marker of antral follicle count) decrease with normal aging in women with and without PCOS (38,–40). However, the decline in ovarian volume and follicle count may be less in women with PCOS than in normal women (39, 41, 42). Similarly, androgen levels decline with age in women with and without PCOS (serum T declines ∼50% between the ages of 20 and 40 y) (43,–45), with reports of improved menstrual frequency in PCOS (46, 47), although there is little evidence to support a decline in serum T associated with the menopause transition per se (43).

The diagnosis of PCOS in postmenopausal women is more problematic than in adolescents. There are no age-related T cutoffs for the diagnosis. Furthermore, T assays used to diagnose hyperandrogenemia in women are imprecise (31), even for assays utilizing tandem mass spectrometry technology (48). Nevertheless, supporting studies have shown that peri- and postmenopausal mothers of women with PCOS with a history of irregular menses tended to have features of PCOS as well as metabolic abnormalities, implying that aspects of the PCOS phenotype may persist with age (49). Very high T levels and/or virilization may suggest an androgen-producing tumor in postmenopausal women.

2.1 Evidence

The major clinical manifestations of hyperandrogenism include hirsutism, acne, and androgenic alopecia. The history of skin problems should assess the age at onset, the rate of progression, previous long-term treatments (including anabolic agents), any change with treatment or with fluctuations in body weight, and the nature of the skin complaint relative to those of other family members. In rare instances, male pattern balding, increased muscle mass, deepening of the voice, or clitoromegaly may occur, suggesting virilizing androgen levels and a possible underlying ovarian or adrenal neoplasm or severe insulin-resistant states (9, 50) (Table 4). Notably, in obese, insulin-resistant women with PCOS, acanthosis nigricans is often present, as are skin tags (51).

Hirsutism

The prevalence of hirsutism in the general population ranges from 5–15%, with relevant differences according to ethnicity and geographic location (9). In a large study of patients with clinical hyperandrogenism, 72.1% of 950 patients were diagnosed with PCOS (16). Therefore, PCOS represents the major cause of hirsutism, but the presence of hirsutism does not fully predict ovulatory dysfunction. Overall, hirsutism is present in approximately 65–75% of patients with PCOS (although lower in Asian populations) (15, 52). Hirsutism may predict the metabolic sequelae of PCOS (53) or failure to conceive with infertility treatment (54). Hirsutism often tends to be more severe in abdominally obese patients (9). The most common method of visually assessing hirsutism is still the modified Ferriman-Gallwey score (1, 55).

Acne and alopecia

Acne is common in women with PCOS, particularly in the teenage years, and the prevalence varies (14–25%), with some difference in relation to ethnicity and patient age (56). The combined prevalence of acne with hirsutism in PCOS is still poorly defined, although there is clinical evidence that the prevalence of each of these features is higher than the combination of the two (57). Androgenic alopecia may be graded by well-known subjective methods, such as the Ludwig score (58). Androgenic alopecia is less frequent and presents later, but it remains a distressing complaint with significant psychopathological comorbidities (9). It may be associated with hirsutism and acne, although there is a poor correlation with biochemical hyperandrogenism. Some studies have demonstrated an association between androgenic alopecia with metabolic syndrome (59) and insulin resistance (IR) (60, 61). Some studies found that acne and androgenic alopecia are not good markers for hyperandrogenism in PCOS, compared with hirsutism (53, 62).

2.1 Values and preferences

Evaluating hirsutism, acne, and alopecia in women with PCOS depends on careful grading, but is subjective. We place value on recognizing these particularly stressful symptoms, even if they do not correlate with objective findings. Alopecia and acne may be related to hyperandrogenism and are distressing; therefore, our preference is to document and consider consultation with a dermatologist and to determine whether they are related to other etiologies in the case of alopecia or in the case of acne if unresponsive to HCs. More research is needed to quantify the relationship between cutaneous signs of hyperandrogenism and cardiovascular disease.

Infertility

2.2 Women with PCOS are at increased risk of anovulation and infertility; in the absence of anovulation, the risk of infertility is uncertain. We recommend screening ovulatory status using menstrual history in all women with PCOS seeking fertility. Some women with PCOS and a eumenorrheic menstrual history may still experience anovulation and a midluteal serum progesterone may be helpful as an additional screening test (1|⊕⊕○○).

2.3 We recommend excluding other causes of infertility, beyond anovulation, in couples where a woman has PCOS (1|⊕⊕○○).

2.2–2.3 Evidence

Infertility was one of the original symptoms of PCOS described by Stein and Leventhal (63) and is a common presenting complaint (64). Among a large series of women presenting with PCOS, close to 50% reported primary infertility, and 25% reported secondary infertility (65). Population-based studies of infertility have suggested that anovulatory infertility (encompassing PCOS) is common, accounting for 25–40% of cases (65, 66). Furthermore, PCOS is estimated to be the most common cause of ovulatory dysfunction, accounting for 70–90% of ovulatory disorders (67). Prolonged periods of anovulation are likely associated with increased infertility (68). Women with PCOS had a monthly spontaneous ovulation rate of 32% on placebo in a multicenter trial that randomly assigned subjects to placebo or troglitazone (69). Nevertheless, lifetime fecundity in Swedish women with PCOS was similar to controls, and almost three-fourths of women with PCOS conceived spontaneously (70).

Some women with PCOS and a eumenorrheic menstrual history may still experience anovulation, and a midluteal serum progesterone may be helpful as an additional screening test. Although the primary mechanism of infertility is presumed to be oligo- or anovulation, there are other potential factors including diminished oocyte competence (71, 72) and endometrial changes discouraging implantation (73, 74). Other factors associated with PCOS, such as obesity, have also been associated with subfertility and delayed conception (75). Male factor infertility or tubal occlusion must also be considered (one study in PCOS found a nearly 10% rate of severe oligospermia and a 5% rate of bilateral tubal occlusion) (76).

2.2–2.3 Values and preferences

In making this recommendation, we emphasize the overall increased infertility burden among women with PCOS and ovulatory dysfunction, although there are spontaneous conceptions, which may increase with improved menstrual frequency and aging. The natural history of fertility in women with PCOS and the influence of milder phenotypes lacking ovulatory dysfunction are not well understood or described.

Pregnancy complications

2.4 Because women with PCOS are at increased risk of pregnancy complications (gestational diabetes, preterm delivery, and pre-eclampsia) exacerbated by obesity, we recommend preconceptual assessment of BMI, blood pressure, and oral glucose tolerance (1|⊕⊕⊕○).

2.4 Evidence

There is a growing body of evidence that PCOS has implications for adverse pregnancy outcomes. Confounders include iatrogenic multiple pregnancy due to ovulation induction, higher complications in pregnancies resulting from infertility treatment per se, and higher rates of obesity in women with PCOS. Some studies have suggested increased early pregnancy loss in women with PCOS (77, 78). A meta-analysis of studies comparing IVF outcomes in women with and without PCOS demonstrated no significant difference in miscarriage rates between the two groups (odds ratio [OR], 1.0; 95% confidence interval [CI], 0.5–1.8) (79).

The link between PCOS and gestational diabetes was initially suggested by retrospective data (80). A study of 99 women with PCOS and 737 controls noted a higher rate of gestational diabetes, but it was largely explained by a higher prevalence of obesity in the PCOS group (81, 82). In contrast, a meta-analysis in which confounding factors such as BMI were taken into account demonstrated that PCOS was independently associated with an increased risk for gestational diabetes and hypertension (83). This meta-analysis demonstrated a small but significant association between premature singleton births (<37 wk gestation) and PCOS (OR, 1.75; 95% CI, 1.16–2.62), and between PCOS and pre-eclampsia (OR, 3.47; 95% CI, 1.95–6.17). Most studies reporting an association between hypertension or pre-eclampsia and pregnancy in PCOS are small and poorly controlled and show mixed results (82). In one of the largest studies, PCOS (n = 99) was not a significant predictor of pre-eclampsia compared with control pregnancies (n = 737), when controlled for nulliparity (more common in PCOS) (81). Although only a small absolute difference in gestational age was noted between cases and controls, increased neonatal morbidity was present (83).

2.4 Values and preferences

In making this recommendation, we believe that a priority should be placed on reducing the overall increased morbidity from pregnancy complications such as gestational diabetes, pre-eclampsia, and preterm delivery in women with PCOS. Whether these increased risks are due to PCOS itself or the features associated with PCOS such as IR or obesity requires further study.

Fetal origins

2.5 The evidence for intrauterine effects on development of PCOS is inconclusive. We suggest no specific interventions for prevention of PCOS in offspring of women with PCOS (2|⊕○○○).

2.5 Evidence

Nonhuman primate models and sheep models suggest that androgen exposure in utero may program the fetus to express features characteristic of PCOS in adult life (84,–86). Human data are limited, but there is evidence of fetal programming by androgens in girls with classic adrenal hyperplasia or with a mother with a virilizing tumor (87, 88). Androgen levels may be increased in pregnant women with PCOS (89). Nevertheless, an Australian study of 2900 pregnant women demonstrated no relationship between T levels at 18 and 34 weeks gestation and the presence of PCOS in 244 female offspring aged 14–17 years (90). The relationship between T levels during pregnancy in women with PCOS to outcomes remains to be determined using accurate assay methodology.

There is evidence that cardiovascular disease in humans is related to intrauterine events. Intrauterine growth restriction has been associated with increased rates of coronary heart disease, hypertension, and T2DM, providing evidence for fetal programming of adult diseases (91). There are limited data to suggest that intrauterine growth restriction may be associated with subsequent development of PCOS in some populations (92). In addition, a subset of girls born small for gestational age are at risk for developing premature adrenarche, IR, or PCOS (93, 94), although this has not been confirmed in longitudinal, population-based studies in northern Europe (95). Available data support the concept that rapid postnatal weight gain and subsequent adiposity can exacerbate metabolic abnormalities and PCOS symptoms (94, 96,–98).

Endometrial cancer

2.6 Women with PCOS share many of the risk factors associated with the development of endometrial cancer including obesity, hyperinsulinism, diabetes, and abnormal uterine bleeding. However, we suggest against routine ultrasound screening for endometrial thickness in women with PCOS (2|⊕⊕⊕○).

2.6 Evidence

An association between PCOS and endometrial cancer was first described in 1949 (99). There have been few studies with cohorts large enough to adequately assess the risk of endometrial cancer in women with PCOS. In a long-term follow-up of women with PCOS in the United Kingdom, morbidity data over 31 years were available on 319 compared with 1060 control women. Women with PCOS did not have a higher all-cause mortality but did show a 3.5 increased relative risk (RR) of development of endometrial cancer (100). A more recent meta-analysis assessing the association between PCOS and endometrial cancer suggested that women with PCOS had an increased risk of developing endometrial cancer (RR = 2.7; 95% CI, 1.0–7.29) (101), confirmed by a subsequent systematic review with a 3-fold increased risk (102).

Several factors in the epidemiology of endometrial cancer suggest a link to PCOS. Young women with endometrial cancer are more likely to be nulliparous and infertile, have higher rates of hirsutism, and have a slightly higher chance for oligomenorrhea (103). Obesity and T2DM, common in women with PCOS, are also endometrial cancer risk factors (104,–107). In a woman with these risk factors, low physical activity scores further elevated the cancer risk (108).

There currently are no data supporting routine endometrial biopsy of asymptomatic women (109) or ultrasound screening of the endometrium (110). Ultrasound screening in women without abnormal bleeding shows poor diagnostic accuracy for diagnosing intrauterine pathology (110, 111). The American Cancer Society recommends against routine cancer screening for endometrial cancer in women at average or increased risk (with the exception of Lynch syndrome), but women should be counseled to report unexpected bleeding and spotting (112).

2.6 Values and preferences

In making this recommendation for increased awareness of endometrial cancer risk in women with PCOS, particularly those with abnormal uterine bleeding, prolonged amenorrhea, diabetes, and/or obesity, we believe that a priority should be placed on the consequences of development of endometrial cancer, and this priority offsets the limited data available for independent association with PCOS.

Obesity

2.7 Increased adiposity, particularly abdominal, is associated with hyperandrogenemia and increased metabolic risk (see cardiovascular disease prevention guidelines, Ref. 2). Therefore, we recommend screening adolescents and women with PCOS for increased adiposity by BMI calculation and measurement of waist circumference (1|⊕⊕⊕○).

2.7 Evidence

Prevalence of obesity in PCOS

The prevalence of obesity varies greatly across the world; however, studies in different countries with significantly different background rates of obesity (30–70%) have yielded similar rates for the prevalence of PCOS (52, 113). Whether the incidence of PCOS may parallel the growing epidemic of obesity is unknown, although a modest but nonsignificant trend in the prevalence of PCOS with increasing BMI has been reported (114). Obesity may also cluster in PCOS families (97, 115), and referral bias to specialty clinics may also elevate the association of PCOS with obesity (116).

Impact of obesity on the phenotype of PCOS

Obesity in general and abdominal obesity in particular cause relative hyperandrogenemia, characterized by reduced levels of SHBG and increased bioavailable androgens delivered to target tissues (117, 118). Abdominal obesity is also associated with an increased T production rate and a non-SHBG-bound androgen production rate of dehydroepiandrosterone and androstenedione (119). Estrogen levels, particularly estrone, may also be higher in PCOS (120).

Menstrual disorders are frequent when the onset of excess weight occurs during puberty rather than during infancy (121). In adult overweight and obese women with PCOS, menstrual abnormalities and chronic oligoanovulation are more frequent than in normal-weight women (118). Obese women with PCOS exhibit a blunted responsiveness and lower pregnancy rates to pharmacological treatments for ovulation induction, such as clomiphene citrate, gonadotropins, or pulsatile GnRH (54, 68, 122).

Obesity increases the risk of the metabolic syndrome, IGT/diabetes mellitus (DM), dyslipidemia, and IR (118, 119, 123,–128). Longitudinal studies have shown that IR may worsen over time (125). Consequently, obesity has a negative impact that may exceed that of the PCOS status per se.

2.7 Values and preferences

In making this recommendation, the committee believes that excess weight and obesity may have an important impact on the early development of PCOS and on the clinical presentation (93, 129, 130). Obesity may change in degree and possibly in distribution from adolescence to postmenopausal age, and these changes should be monitored.

Depression

2.8 We suggest screening women and adolescents with PCOS for depression and anxiety by history and, if identified, providing appropriate referral and/or treatment (2|⊕⊕○○).

2.8 Evidence

Small observational community- and patient-based case control studies consistently demonstrate an increased prevalence of depression in women with PCOS. In women with PCOS compared with non-BMI-matched controls, self-rated questionnaires demonstrate an increased rate of depressive symptoms (131,–133). Similarly, in studies with direct psychiatric interviews, there was a higher lifetime incidence of a major depression episode and recurrent depression (OR, 3.8; 95% CI, 1.5–8.7; P = .001) and a history of suicide attempts that was seven times higher in PCOS cases vs controls (134). In a longitudinal study examining changes in depression scores, the incidence of depression was 19% in 1–2 years of follow-up (135). The increased prevalence of depression and depressive symptoms in women with PCOS appears to be independent of obesity, androgen levels, hirsutism, acne, and infertility (131,–133, 135,–137). Thus, studies of depression using different patient groups and methods of identification demonstrate an increased prevalence of depression in women with PCOS (138).

Community- and clinic-based case-control studies and studies using psychiatric interviews demonstrate higher rates of anxiety and panic disorders in women with PCOS (134, 137, 139). In addition, eating disorders are more common in women with PCOS (OR, 6.4; 95% CI, 1.3–31; P = .01) (132) and include binge-eating disorder (12.6 vs 1.9%; P < .01) (133). Although a history of depression or anxiety may be present in many women and adolescents with PCOS, for those without a prior diagnosis, a simple office screen using a two-item questionnaire such as the PHQ-2 may be helpful (140). Those identified with depression or anxiety should be referred for further therapy.

Sleep-disordered breathing/OSA

2.9 We suggest screening overweight/obese adolescents and women with PCOS for symptoms suggestive of OSA, and when identified, obtaining a definitive diagnosis using polysomnography. If OSA is diagnosed, patients should be referred for institution of appropriate treatment (2|⊕⊕○○).

2.9 Evidence

Women with PCOS develop OSA at rates that equal or exceed those in men. The high prevalence of OSA is thought to be a function of hyperandrogenism (a defining feature of PCOS) as well as obesity (common in PCOS) (141, 142), although these factors alone do not fully account for the finding. Even after controlling for BMI, women with PCOS were 30 times more likely to have sleep-disordered breathing and nine times more likely than controls to have daytime sleepiness (141). It also appeared that women with PCOS taking oral contraceptives were less likely to have sleep-disordered breathing (141), consistent with the lower likelihood of sleep-disordered breathing in postmenopausal women treated with hormone replacement therapy (143). Finally, women with PCOS had a significantly higher mean apnea-hypopnea index compared with weight-matched controls (22.5 ± 6.0 vs 6.7 ± 1.7; P < .01), with the difference most pronounced in rapid eye movement sleep (41.3 ± 7.5 vs 13.5 ± 3.3; P < .01) (143). Thus, the risk imparted by obesity is not sufficient to account for the high prevalence of sleep-disordered breathing in PCOS, suggesting that additional factors must be involved.

Continuous positive airway pressure treatment of OSA in patients with PCOS demonstrated modestly improved IR after controlling for BMI (P = .013) (144). In young obese women with PCOS, successful treatment of OSA improves insulin sensitivity, decreases sympathetic output, and reduces diastolic blood pressure. The magnitude of these beneficial effects is modulated by the hours of continuous positive airway pressure use and the degree of obesity.

2.9 Values and preferences

It is difficult to diagnose sleep abnormalities on the basis of a history and physical or by questionnaire. Polysomnography, when performed, should occur in a certified sleep laboratory with proper accreditation. The interpretation and recommendation(s) for treatment of sleep-disordered breathing/OSA should be made by a board-certified expert in sleep medicine.

NAFLD and NASH

2.10 We suggest awareness of the possibility of NAFLD and NASH but recommend against routine screening (2|⊕⊕○○).

2.10 Evidence

NAFLD is characterized by excessive fat accumulation in the liver (steatosis), whereas NASH defines a subgroup of NAFLD in which steatosis coexists with liver cell injury and inflammation (after exclusion of other causes of liver disease (viral, autoimmune, genetic, alcohol consumption, etc). Primary NAFLD/NASH is most commonly associated with IR and its phenotypic manifestations (145). The prevalence of ultrasound-documented NAFLD in the general population is 15–30% (146). Risk factors pertinent to PCOS include increasing age, ethnicity, and metabolic dysfunction (obesity, hypertension, dyslipidemia, diabetes). Because many women with PCOS have metabolic dysfunction, the association of PCOS with NAFLD is not surprising, but the available literature, especially in reference to the risk of NASH, is incomplete (147). Clinical studies report a 15–60% prevalence of NAFLD in the population, depending on the index used to define liver damage (increased serum alanine aminotransferase or ultrasound), the presence of obesity, and ethnicity (147,–153). Whether androgen excess may be involved in the pathophysiology of NAFLD in women with PCOS is still unclear (153,–155). Thus, women with PCOS and metabolic risk factors and/or IR may be screened using serum markers of liver dysfunction. If serum markers are elevated, noninvasive quantification of fibrosis by ultrasound and liver biopsy may be considered (156).

2.10 Values and preferences

In making this recommendation we believe that a priority should be placed on identifying this potentially major complication in women with PCOS with IR and/or metabolic syndrome. However, there is currently no simple and reliable screening test for NAFLD because elevated serum transaminases have low sensitivity and specificity. We also believe that investigating the true prevalence of NAFLD in collaboration with gastroenterologists and hepatologists who can identify and apply reliable markers of NASH should be a research priority for future recommendations. Finally, there is no approved drug to treat NAFLD, although lifestyle therapy, insulin sensitizers, and antioxidants are thought to be beneficial.

Type 2 diabetes mellitus

2.11 We recommend the use of an OGTT (consisting of a fasting and a 2-hour glucose level using a 75-g oral glucose load) to screen for IGT and T2DM in adolescents and adult women with PCOS because they are at high risk for such abnormalities (1|⊕⊕⊕○). An HgbA1c may be considered if a patient is unable or unwilling to complete an OGTT (2|⊕⊕○○). Rescreening is suggested every 3–5 years, or more frequently if clinical factors such as central adiposity, substantial weight gain, and/or symptoms of diabetes develop (2|⊕⊕○○).

2.11 Evidence

Adolescents and adult women with PCOS are at increased risk for IGT and T2DM (125, 126, 157). A diagnosis of PCOS confers a 5- to 10-fold increased risk of developing T2DM (125, 126, 157). The overall prevalence of glucose intolerance among US women and adolescents with PCOS was 30–35%, and 3–10% had T2DM. Nonobese women with PCOS had a 10–15% prevalence of IGT and a 1–2% prevalence of T2DM (125, 126, 157). Limited studies have shown poor sensitivity of glycohemoglobin measure for detecting IGT (158, 159). Those with T2DM had a significantly higher prevalence of first-degree relatives with T2DM, confirming family history as an important risk factor. Multiple studies have also shown deterioration in glucose tolerance with follow-up (126, 158, 160).

Because of the high risk of IGT and T2DM in PCOS, periodic screening of patients to detect early abnormalities in glucose tolerance is recommended by several scientific organizations, although an interval for screening has not been specified (161,–163).

2.11 Values and preferences

In making this recommendation, the committee believes in the strength of the evidence for a tight link between PCOS and diabetes and believes that reducing morbidity of IGT/diabetes through early diagnosis and treatment outweighs any unforeseen harm or burdens resulting from the screening. We have recommended an OGTT over an HgbA1c because of the potential increased association between IGT and cardiovascular disease in women (164, 165) and the potential to identify women at risk for gestational DM before pregnancy. Women with PCOS and IGT early in pregnancy are at greater risk for developing gestational DM (166), but there are currently insufficient data to recommend earlier screening for gestational DM in women with PCOS. Given the lack of evidence of the ideal period for rescreening, we have arbitrarily recommended a period of 3–5 years.

Cardiovascular risk

2.12 We recommend that adolescents and women with PCOS be screened for the following cardiovascular disease risk factors (Table 5): family history of early cardiovascular disease, cigarette smoking, IGT/T2DM, hypertension, dyslipidemia, OSA, and obesity (especially increased abdominal adiposity) (1|⊕⊕○○).

2.12 Evidence

Members of the Androgen Excess and Polycystic Ovary Syndrome Society conducted a systematic analysis and published a consensus statement regarding assessment of cardiovascular risk and prevention of cardiovascular disease in women with PCOS (167) (Table 5). In addition to elevations in triglycerides and decreases in high-density lipoprotein (HDL)-cholesterol, women with PCOS have higher low-density lipoprotein (LDL)-cholesterol and non-HDL-cholesterol, regardless of BMI (117, 167). Women with PCOS should have BMI and blood pressure measured at each clinic visit (and consider waist circumference if nonobese; ≥ 36 inches is abnormal), and upon diagnosis of PCOS, additional testing should include a complete fasting lipid profile (total cholesterol, LDL-cholesterol, non-HDL-cholesterol, HDL-cholesterol, and triglycerides).

Although hypertension has been an inconsistent finding, women with PCOS appear to be at risk, at least later in life (168,–170). Although in many studies both systolic and diastolic blood pressures are normal (168,–171), in others, mean arterial pressures and ambulatory systolic pressures are elevated in women with PCOS compared with controls (172). In addition, the nocturnal drop in mean arterial blood pressure is lower, a finding that has also been demonstrated in obese adolescents with PCOS (171, 173).

Anatomic evidence of early coronary and other vascular disease in PCOS has been documented using varied techniques. Increased carotid artery intima-media thickness, an independent predictor of stroke and myocardial infarction, has been noted in PCOS compared with age-matched control women (174). Another marker of atherosclerosis, coronary artery calcification, is more common in women with PCOS than in controls, even after adjusting for the effects of age and BMI (175,–177). Echocardiography revealed both anatomic and functional differences between women with PCOS and controls including an increased left atrial size, increased left ventricular mass index, lower left ventricular ejection fraction (178), and diastolic dysfunction (179, 180). Of note, the left ventricular mass index was linearly related to the degree of IR (178).

Some, but not all, studies (181,–183) demonstrate impaired endothelial function in women with PCOS, as reflected in reduced brachial artery reactivity to hyperemia (184, 185) and reduced vascular compliance, independent of obesity, IR, total T, or total cholesterol (186). Improved endothelial function has been documented when IR is attenuated with insulin-lowering medication or through weight loss (187,–190). Discrepant findings between studies may be the result of the heterogeneous nature of the populations studied.

Despite the increased prevalence of cardiovascular risk factors in women with PCOS, there are limited longitudinal studies, and those are too small to detect differences in event rates (191). Nevertheless, epidemiological data consistently point to increased cardiovascular risk in women with stigmata of PCOS. The Nurses' Health Study noted an adjusted RR of 1.53 (95% CI, 1.24–1.90) for coronary heart disease in women with a history of irregular menstrual cycles (192). In addition, a case-control study based on data in the Women's Health Study database found that women who developed cardiovascular events had lower SHBG and higher calculated free androgen index (193). Among postmenopausal women evaluated for suspected ischemia, clinical features of PCOS were associated with more angiographic coronary artery disease and worsening cardiovascular event-free survival (194).