Beyond fertility: polycystic ovary syndrome and long-term health

Beyond fertility: polycystic ovary syndrome and long-term health Laura G. Cooney, M.D.a and Anuja Dokras, M.D., Ph.D.b a Department of Obstetrics and Gynecology, University of Wisconsin, Madison, Wisconsin; and b Department of Obstetrics and Gynecology, University of Pennsylvania, Philadelphia, Pennsylvania

Polycystic ovary syndrome (PCOS) is a reproductive, endocrine, and metabolic disorder affecting millions of women worldwide. Women with PCOS are often identified in adolescence or early adulthood with symptoms of oligomenorrhea or hirsutism or when presenting for infertility care. The health risks associated out of PCOS, however, go far beyond management of these common presenting symptoms or fertility treatment and likely extend past the reproductive years through and beyond menopause. International surveys suggest that most patients are dissatisfied with long-term counseling related to medical and psychologic issues. We performed a review of comorbidities, including diabetes mellitus, dyslipidemia, obesity, hypertension, metabolic syndrome, depression, anxiety, obstructive sleep apnea, nonalcoholic fatty liver disease, endometrial cancer, and cardiovascular disease, in both reproductive-age and older women with PCOS. Most meta-analyses in reproductive-age women demonstrate increased risks independent from obesity. Longitudinal and cross-sectional studies including women with PCOS >40 years of age are limited in number and design, but many demonstrate that some of these comorbidities persist. All providers involved in the multidimensional care of women with PCOS should be aware of these long-term health risks to provide appropriate counseling, screening, and management options. We identify limitations that should be the focus of future studies designed to study health outcomes in postmenopausal women with PCOS. (Fertil SterilÒ 2018;110:794–809. Ó2018 by American Society for Reproductive Medicine.) Key Words: PCOS, menopause, aging, diabetes, cardiovascular disease Discuss: You can discuss this article with its authors and with other ASRM members at https://www.fertstertdialog.com/users/16110fertility-and-sterility/posts/36446-26627

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olycystic ovary syndrome (PCOS) is a common but complex endocrine disorder affecting 6%–10% of reproductive-age women worldwide (1, 2). Despite its high prevalence, heterogeneous presentations, ethnic variations, and different phenotypes make timely diagnosis a challenge for both patients and physicians (3–5). In addition, given the multitude of comorbidities associated with PCOS, it is common for care to be fractured, with individual symptoms managed by different providers, such as reproductive endocrinologists, gynecologists, medical endocrinologists, primary care physicians, psychologists, dermatologists, and nutritionists. It is not clear who offers counseling regarding long-term complications to these women.

PCOS has primarily been regarded as a disease of reproductive-age women, predominantly associated with infertility (6). The focus on symptom management (irregular menses and hirsutism) is shortsighted, because there is compelling global data linking PCOS to a number of metabolic and nonmetabolic morbidities, such as type 2 diabetes (DM), dyslipidemia, hypertension, obesity, metabolic syndrome (MetS), depression, anxiety, obstructive sleep apnea (OSA), pregnancy complications, nonalcoholic fatty liver disease (NAFLD), endometrial cancer, and possibly cardiovascular disease (CVD) (7–15) indicating the need for screening, counseling, and management of these risks during the reproductive years. Most diagnostic features of PCOS, such as menstrual irregularity, biochemical hyperandrogenism, and

Received July 11, 2018; revised and accepted August 8, 2018. L.G.C. has nothing to disclose. A.D. has nothing to disclose. Reprint requests: Anuja Dokras, M.D., Ph.D., 3701 Market St., Suite 800, Philadelphia, Pennsylvania 19104 (E-mail: [email protected]). Fertility and Sterility® Vol. 110, No. 5, October 2018 0015-0282/$36.00 Copyright ©2018 American Society for Reproductive Medicine, Published by Elsevier Inc. https://doi.org/10.1016/j.fertnstert.2018.08.021 794

ovarian morphology, improve with age (16, 17). In this review we examine whether the above-mentioned comorbidities persist beyond the premenopausal years, because it is important for physicians and patients alike to be well versed in these risks.

METHODS Our review compares the risk of health complications, specifically DM, dyslipidemia, obesity, hypertension, MetS, depression, anxiety, OSA, pregnancy complications, NAFLD, endometrial cancer, and CVD, in women with PCOS versus women without PCOS. There is a large amount of primary data available for each of these topics, including multiple well designed, recently published systematic reviews (SRs) and meta-analyses (MAs). We therefore initially searched for SRs and MAs on each of these comorbidities. Because most studies included in the SRs and MAs had a mean age of 20–30 years, we considered this group to represent ‘‘risk in reproductive-age VOL. 110 NO. 5 / OCTOBER 2018

Fertility and Sterility® women’’ (Table 1). Because the goal of the present review was to evaluate ‘‘long-term risk,’’ we then searched for studies that evaluated the selected comorbidities specifically in women with PCOS over the age 40 years (Table 2). These studies were identified from the SRs and MAs described in Table 1 and from new literature queries performed to include studies published after the search periods described for each SR and MA. There are limited longitudinal studies of women with a prospectively confirmed diagnosis of PCOS. Recent international guidelines recommend that diagnosis of PCOS can be made in perimenopausal and menopausal women based on documented long-term history of oligomenorrhea and hyperandrogenism during the reproductive years (18). We therefore included prospective cohort, retrospective cohort, and crosssectional studies that reported confirmed or presumed PCOS diagnosis with a mean age >40 years (Table 2). Studies that did not report mean age at follow-up but reported followup time such that the estimated age could be calculated to be >40 years were also included. We excluded studies that did not use either National Institutes of Health (NIH) or Rotterdam diagnostic criteria (19, 20) (e.g., LH-FSH ratio, wedge resection of ovary). Given that studies with a large number of subjects are needed to evaluate risk of rare events such as CVD, we included administrative databases that used International Classification of Disease (ICD), 9th Edition, codes for PCOS diagnosis. For each comorbidity we have summarized published SRs/MAs in young women (Table 1) and then described the results of our SR for women >40 years of age (Table 2).

IMPAIRED GLUCOSE TOLERANCE AND TYPE 2 DIABETES MELLITUS Meta-Analyses of Studies in Reproductive-Age Women Over the past decade, the associations between PCOS and impaired glucose tolerance (IGT) and DM have been clearly defined. Two MAs have shown higher rates of both IGT and DM in women with PCOS (7, 21). The recent MA reported threefold increased odds of IGT in women with PCOS, with minimal statistical heterogeneity (Table 1). This association was highest in women from the Asian subcontinent and North/South Americans (5.2-fold and 4.4-fold, respectively) and moderate in studies from Europe (2.6-fold). In addition, an increased prevalence of IGT was noted in body mass index (BMI)–matched (2.1-fold), non–BMI-matched (4.8-fold), lean-matched (4.4-fold), and overweight or obese–matched groups (2.5-fold) (7). In the same MA, the risk of DM was increased with a 4.4fold increase in women with PCOS residing in Asia and a 4.7fold increase in those residing in the Americas. Although there were no significant differences in the risk of DM in subgroups matched by BMI (odds ratio [OR] 1.13, 95% confidence interval [CI] 0.83–1.54, 7 studies), this may be a result of relatively small numbers in this subanalysis (PCOS: n ¼ 73/1,023; control: n ¼ 259/2,098; 7 studies). Because the mean age was 30 years in most studies included in this MA, no sensitivity analyses based on age were conducted (7). Therefore, it may VOL. 110 NO. 5 / OCTOBER 2018

not be surprising to see a stronger BMI-independent association with IGT at these young ages, but not with DM.

Long-Term Risk of Impaired Glucose Tolerance: Studies in Women Above 40 Years The association between PCOS symptoms and IGT was examined in the Study of Women's Health Across the Nation (SWAN), a longitudinal study of women in the United States as they went through menopause (22). Women with PCOS (mean age 45.8 years; n ¼ 117) had higher prevalence of IGT compared with control women (25% vs. 9.2%; P< .001; Table 2). The presumed diagnosis of PCOS was based on highest tertile of total testosterone levels and history of oligomenorrhea in the reproductive years (22). In the general population, those with IGT at baseline develop DM at a yearly rate of 5.7% (23), suggesting that women with PCOS are a high-risk group.

Long-Term Risk of Type 2 Diabetes Mellitus: Studies in Women Above 40 Years of Age Several prospective and retrospective cohort studies have evaluated the association between PCOS and DM in older women (5, 9, 24–30) (Table 2). In the CARDIA (Coronary Artery Risk Development in Young Adults) Woman's Study (CWS) (30), women with PCOS (n ¼ 53) did not have a higher prevalence of DM at study entry, but had a higher risk of DM by age 38–50 years (23% vs. 13%; P< .05; Table 2). In adjusted analysis, normal-weight women with PCOS (n ¼ 31) had a greater than threefold increased odds (95% CI 1.2–8.0) of developing DM compared with normalweight control subjects (n ¼ 610), supporting a role for PCOS in the development of DM beyond the contribution of BMI alone. Women who had ‘‘persistent PCOS,’’ defined as meeting NIH criteria both at baseline and at follow-up (n ¼ 15), had a greater than sevenfold increased odds of developing DM (95% CI 1.1–46.5) (30). In the CARDIA cohort, although subjects were enrolled prospectively, history of oligomenorrhea and hirsutism was obtained at year 16 which, similarly to the SWAN study, is subject to recall bias. However, testosterone levels were measured with the use of serum banked at the year 2 visit to define biochemical hyperandrogenism, suggesting better confirmation of the PCOS diagnosis. In a retrospective cohort study of women with PCOS attending an endocrinology clinic in Leichestershire, United Kingdom, the prevalence of DM increased with age: 16– 44 y: 4.4% (n ¼ 1,855); 45–54 y: 11.1% (n ¼ 352); 55–64 y: 15.7% (n ¼ 83); and R65 y: 45.5% (n ¼ 11). Compared with age-matched women from the Health Survey for England, odds of DM in PCOS was higher in all age groups (27) (Table 2). Main limitations of this study included lack of adjustment for BMI and the use of chart abstraction for PCOS diagnosis; however, 73% of women had enough data to confirm Rotterdam criteria. Although the large sample size allowed stratification by age groups, the number of subjects in the older age groups were small. In the Northern Finland birth cohort 1966 dataset, women with presumed 795

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TABLE 1 Recent published meta-analyses of PCOS-related morbidities in reproductive-age women. Outcome Impaired glucose tolerance, Kakoly et al., 2018 Type 2 diabetes, Kakoly et al., 2018 Dyslipidemia, Wild et al., 2011 Overweight/obesity, Lim et al., 2012 Hypertension Metabolic syndrome, Behboudi-Gandevani et al., 2018 Obstetrical complications, Yu et al., 2016

Obstructive sleep apnea, Helvaci et al., 2017 Depression and anxiety, Cooney et al., 2017 Nonalcoholic fatty liver disease, Wu et al., 2018 Cancer, Barry et al., 2014

Carotid IMT, Meyer et al., 2012 Endothelial dysfunction by FMD, Sprung et al., 2013 Coronary artery disease, Technical bulletin

No. of studies: overall/ BMI-matched

Total n/PCOS

Risk (95% CI)

Risk (95% CI), BMImatched studies

15/10

1,828/914

OR 3.26 (2.17–4.90)*

OR 2.13 (1.39, 3.25)*

12/7

2,038/3,118

OR 2.87 (1.44–5.72)*

OR 1.13 (0.83, 1.54)

LDL-C: 27/13 NonHDL-C: 30/15 Triglycerides: 26/16 HDL-C: 30/15 Overweight and obesity: 21/NR Obesity: 18/NR Central obesity: 6/NR No meta-analysis 41/11

1,612/2,760 1,716/2,787 1,657/2,710 1,544/2,872 3,132/4,502

SMD 12 mg/dL (10, 16)* SMD 19 mg/dL (16, 22)* SMD 26 mg/dL (17, 35)* SMD 6 mg/dL (4, 9)* RR 1.95 (1.52–2.50)

SMD 9 mg/dL (6–12)* SMD 16 mg/dL (14–19)* Reported as NS Reported as NS NR

4,160/4,885 1,191/2,396

RR 2.77 (1.88–4.10) RR 1.73 (1.31–2.30)

11,245/11,129

OR 2.5 (2.0–3.2)*

OR 2.6 (1.3–5.5)*

For total MA: 17,816/ 123,756

RR 2.78 (2.27–3.40)*

ppBMI <25: RR:3.03 (1.99–4.62)* ppBMI >25: RR:2.44 (1.53–3.88)* ppBMI <25: RR:3.20 (2.16–4.74)* ppBMI >25: RR:2.25 (1.67–3.02)* ppBMI <25: RR:2.57 (1.78–3.69)* ppBMI >25: RR:2.57 (1.56–4.24)* NR

Gestational DM: 28 /NR

Pregnancy-induced hypertension: 25/NR

RR 2.46 (1.95–3.09)*

Preeclampsia: 25/NR

RR 2.79 (2.29–3.38)*

8/NR

141/518

OR 9.7 (2.76–34.41)*

Depression: 18/4 Anxiety: 9/4 17/subgroup analysis obese: 5, nonobese: 3

1,917/2,346 1,409/1,236 2,715/2,619

OR 3.78 (3.03–4.72)* OR 5.62 (3.22–9.80)* OR 2.54 (2.19–2.95)* (significant heterogeneity)

Endometrial cancer: 5/NR

138/5,593

Breast cancer: 3/NR Ovarian cancer: 3/NR 19/NR

529/39,795 111/18,378 1,123/923

21/7

98/566

OR 2.79 (1.31–5.95)* (significant heterogeneity) OR 0.95 (0.64–1.39) OR 1.41 (0.93–2.15) SMD 0.072 mm (0.040– 0.105)* Pooled mean: 3.4% (1.9 to 94.9)*

Myocardial infarction: 3/NR Stroke: 4/NR

472/1,162 791/2,221

CVD-related death: 2/NR

341/438

Coronary artery disease/ coronary heart disease: 2/NR

340/1,812

OR 1.21 (0.68–2.14); P¼ .5 OR 1.64 (0.92–2.93); P¼ .1 OR 1.81 (0.55–5.88); P¼ .3 OR 2.44 (0.88–6.74); P¼ .09

OR 3.25 (1.73–6.09)* OR 6.30 (1.88–21.09)* Obese only: OR 3.01 (1.88–4.82) Nonobese: OR 2.07 (1.12–3.85) NR NR NR NR Pooled mean: 4.1% (2.7 to 5.5)* NR NR NR NR

Note: BMI ¼ body mass index; CI ¼ confidence interval; DM ¼ diabetes mellitus; FMD ¼ flow-mediated dilation; HDL-C ¼ high-density lipoprotein cholesterol; IMT ¼ intima media thickness; LDL-C ¼ low-density lipoprotein cholesterol; NR ¼ not reported; NS ¼ not significant; OR ¼ odds ratio; ppBMI ¼ prepregnancy body mass index (kg/m2); RR ¼ relative risk; SMD ¼ standardized mean difference. * P< .05 compared with control. Cooney. PCOS and long-term health. Fertil Steril 2018.

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TABLE 2 Longitudinal and cross-sectional studies examining morbidities in women with PCOS with mean ages >40 years. Study design

PCOS definition and n

Age (y) and BMI (kg/m2)

Outcomes (measured at follow-up)

Calderon-Margalit et al., 2014, U.S.

PC, CARDIA Woman's Study, a populationbased multicenter cohort of young adults

NIH (recall of oligomenorrhea at age 20–30, biochemical hyperandrogenism); PCOS: n ¼ 55; Control: n ¼ 668

Starting cohort age: 20– 32; age at followup: 38–50 (mean 45). BMI at age 38–50: PCOS: 29.3  6.50; Control: 29.9  7.47

Carotid intima media thickness (C-IMT)

Chang et al., 2011, U.S.

CS, nested cohort from the Dallas Heart Study (2000–2002), a population-based multiethnic cohort

Rotterdam (recall of oligomenorrhea at age 20–30, tT defined as upper quartile); control subjects all had tT <80 mg/dL; PCOS: n ¼ 144; Control: n ¼ 170

Age 35–49; PCOS: 40 (IQR 37–42)*; Control: 42 (IQR 39– 45). BMI: PCOS: 31.7 (26.5–38.1) *; Control: 28.7 (2.5.5– 33.9)

Study

Coronary artery calcification (CAC) Prevalence of DM (fasting glucose R126 mg/dL or use of glucoselowering medication) Prevalence of hypertriglyceridemia (TG R150 mg/dL) Prevalence of low HDL-C Prevalence of HTN (systolic BP R140 mm Hg or diastolic BP R90 mm Hg or use of antihypertensive medication) Prevalence of MetS (ATPIII criteria)

Cibula et al., 2000, Czech Republic

PC, Danish National Patient Registry, SIRs calculated by

797

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NIH plus infertility; PCOS: n ¼ 28; Control: n ¼ 752

ICD codes; PCOS: n ¼ 12,070 Control: NA

Starting age: NR; Age at follow-up: 45– 59. BMI (age 45–59): PCOS: 28.0  4.2; Control: 28.2  5.2

Starting age: 9–49; median age range: 25–29;

BMI-adjusted mean, PCOS vs. control: internal C-IMTc:: þ0.07 mm*; bulb C-IMTc: þ0.096 mm*; common C-IMTc:: 0.02 mm (above values are b from multivariable model, SDs not reported) CAC: aORa 2.7 (1.31–5.60) DM: reported as not significant. Both groups 9%–10% per figure TG: PCOS 15.3% vs. control 14.1% HDL: PCOS 44.4% vs. control 53.5% HTN: PCOS 29.2% vs. control 18.8%*; higher prevalence persisted after comparing PCOS with age-, BMI-, and ethnicitymatched control group (data not reported) MetS: reported as not significant. PCOS 38%–40%, control 33%–35% per figure CAC: PCOS 5.4% vs. control 6.3% aORa 0.65 (0.36–1.13) DM: PCOS 32% vs. control 8%*

PCOS 71% vs. control 71% PCOS 57% vs. control 44% PCOS 7% vs. control 7% PCOS 25% vs. control 28% PCOS 50% vs. control 39% CAD: PCOS 21% vs. control 5%*

SIR 1.19 (1.06–1.34)*; Age R50: 2.0 (0.5–5.1)

Fertility and Sterility®

Gottschau et al., 2015, Denmark

RC, women with history of wedge resection in 1960–1981, control women from random population sample in same age range

Prevalence of CAC >10 Agataston units Prevalence of type2 DM (fasting glucose R126 mg/dL or use of medication) Prevalence of dyslipidemia Cholesterol R190 mg/dL LDL R140 mg/dL HDL %40 mg/dL TG R170 mg/dL) Prevalence of HTN (BP R140/ 90 mm Hg or use of medication) CAD: chest pain evaluated as definite or possible angina, a history of definite or possible MI, a history of transluminal percutaneous coronary angioplasty or coronary artery bypass grafting Diagnosis by Danish Cancer Registry Endometrial cancer

Results

Continued. Study

Hudecova et al., 2011, Sweden

Karjula et al., 2017, Finland

Lin et al., 2017, Taiwan

Mani et al., 2013, U.K.

Study design comparing cancer rates in women with PCOS vs. the general Danish female population RC, outpatient registry to identify all women with diagnosis of PCOS from 1987 to 1995, age-matched control women from population registry PC, northern Finland birth cohort 1966

PCOS definition and n

Rotterdam; PCOS: n ¼ 87; Control: n ¼ 87

Age (y) and BMI (kg/m2)

Outcomes (measured at follow-up)

median follow-up: 5.7 y (IQR 1–16 y); BMI: NR

Breast cancer

Age at start: NR; Age at follow-up: 43. BMI (at age 43): PCOS: 28.3  6.0; Control: 25.7  4.4*

Ovarian cancer Mean values of TG and HDL-C

MetS: R3 of 5 NCEP/ATPIII criteria

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NIH; PCOS: n ¼ 125 at start/ 85 at follow up Control: n ¼ 2,188 at start/1,576 at follow up

Age at start: 31; Age at follow-up: 46. BMI: NR

RC, Taiwan National Health Insurance Research Database, control subjects age matched

ICD-9 codes for PCOS; PCOS: 4,595 Control: 4,595

RC, endocrinology clinic in Leichestershire, U.K., control subjects age matched from the Health Survey for England

PCOS diagnosis noted in chart (73% met Rotterdam criteria); PCOS: n ¼ 2,301 Control: n ¼ 2,301. Analysis stratified by age: 16–44 y: n ¼ 185; 45–54 y: n ¼ 352; 55–64 y: n ¼ 83; R65 y: n ¼ 11.

Starting cohort age: 28.00  6.79; follow-up range: 2–13 y. BMI: NR. Baseline prevalence of obesity: 1.1% vs. 0.9%. Mean starting age: 29.6; mean age at follow-up: 36.3. BMI (age 36): 30.1  7.6/NR

Prevalence of depression and anxiety (self-report of diagnosis or treatment) Depression or anxiety score R1.75 at age 46 Diagnosis by ICD-9 codes Prevalence of type 2 DM Prevalence of dyslipidemia Prevalence of HTN Incident obstructive sleep apnea (OSA) DM: ICD-9 or ICD-10 codes

Age-stratified prevalence of MI in PCOS: ICD-9 or ICD-10 codes

Odds of MI in women with PCOS compared with control

Cooney. PCOS and long-term health. Fertil Steril 2018.

Results SIR 1.1 (0.8–1.4); Age R50: 1.4 (0.9–2.2) SIR 1.8 (0.8–3.2); Age R50: 1.3 (0.1–4.6) TG: 125.7  82.3 vs. 90.3  42.5 mg/dL* (P< .001 after adjusting for BMI and other confounders); HDL-C: 61.8  19.3 vs. 65.6 15.4 mg/dL MetS: 23.8% vs. 8.0%* Depression: Age 31: 9.6% vs. 5.3%*; Age 46: 25.9% vs. 14%.* Anxiety: data not presented, reported as not significant Depression: PCOS 17.4% vs. control 15.2%; Anxiety: PCOS 12.8% vs. control 8.3% DM: PCOS 2.4% vs. control 1.4%* Dyslipidemia: PCOS 3.1% vs. control 2.4%* HTN: PCOS 3.9% vs. control 3.7% OSA: PCOS 1.7% vs. control 0.6% aHRa 2.63 (1.57–4.04) DM: Overall: OR 2.0 (1.7–2.4)*; Age 15–44: OR 6.0 (4.9–8.3)*; Age 45–54: OR 3.8 (2.6–5.4)*; Age 55–64: OR 2.9 (1.6–5.3)*; Age R65: OR 7.1 (2.2–23.4)* Age 16–44: 0.1% (0.0–1.2); Age 45–54: 1.9% (0.5–3.4); Age 55–64: 6.0% (0.9–11.1); Age R65: 27.3% (1.0–53.6) (control prevalence not reported) MI: Overall: OR 0.8 (0.4–2.4); Age 15–44: OR 1.2 (0.1–15.5); Age 45–54: OR 10.6 (4.4–22.9)*; Age 55–64: OR 9.3 (3.7–23.0)*; Age R65: OR 12.9 (3.4–48.6)*

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TABLE 2

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TABLE 2 Continued. Study Meun et al., 2018, The Netherlands

Study design

PCOS definition and n

Age (y) and BMI (kg/m2)

Outcomes (measured at follow-up)

Results

PC, Rotterdam Study, a prospective population-based study of subjects R55 years old in Rotterdam, The Netherlands, all women postmenopausal and >55 years old at study start

NIH (recall of oligomenorrhea at age 25 and highest quartile of testosterone [>34.3 ng/dL]); PCOS: n ¼ 106; Control: n ¼ 171

Mean starting age: PCOS: 69.6  8.7; Control: 69.2  8.6; median follow-up: 11 y. BMI (age 70): PCOS: 27.9  4.5; Control: 26.8  3.8*

Prevalence of type 2 DM (FBG R126 mg/dL or use of medication) Carotid intima media thickness (C-IMT) Peripheral arterial disease (PAD; ankle brachial index values of %0.9.) Coronary heart disease (CHD): fatal or nonfatal MI (diagnosed by physician, confirmed with documented symptoms and elevated enzymes or ECG abnormalities) Stroke: diagnosed when a patient had typical neurologic symptoms confirmed by CT or MRI CVD: either stroke or MI

DM: PCOS 18.9% vs. control 7.0%*

Ollila et al., 2017, Finland

PC, northern Finland birth cohort, longitudinal data set comprising followup of all individuals with expected birth in 1966

Pinola et al., 2017, Finland, Sweden, Norway, Denmark

CS, secondary analysis of subjects from 8 studies in Nordic countries, PCOS subjects recruited from clinics and community advertisements, control subjects from community

CS, baseline data from SWAN study, a multiethnic longitudinal study of women as they go

799

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NIH (recall of oligomenorrhea plus highest tertile of tT (R50 ng/dL);

Starting age: 31; age at follow-up: 46. BMI (age 46): PCOS: 28.60  6.3; Control: 26.34  5.3*

Prevalence of type 2 DM (FBG R126 mg/dL and/or 2-h OGTT R200 mg/dL)

PCOS age: 30.0  7.2 (range 14–49); Control age: 33.5  9.9 (range 18–62)*; (analysis stratified by age: <30, 30–39, and >39). BMI (overall group): 29.2  6.9/25.9  5.4.* BMI (age >39 y): PCOS: 29.2  5.5*; Control: 25.4  3.7 Age: 45.8  2.7 (range 42–52). Median BMI (age 45): PCOS: 30.9 (IQR 29.4– 32.6)*;

Prevalence of hypertriglyceridemia (TG R150 mg/dL) Prevalence of low HDL (%50 mg/dL) Prevalence of HTN: systolic BP R130 mm Hg or diastolic BP R85 mm Hg Prevalence of Met-S

Prevalence of IGT (FBG R110 mg/ dL) Prevalence of hypertriglyceridemia (fasting TG R150 mg/dL);

CHD: PCOS 11.3% vs. control 8.2%

Stroke: PCOS 12.3% vs. control 15.2% Composite CVD: PCOS 25.5% vs. control 20.5% DM: PCOS 12.4% vs. control 4.3%*; overweight/obese women (BMI R25 kg/m2): PCOS 17.4% vs. control 6.6%*; lean women (BMI <25 kg/m2): PCOS 1.8% vs. control 0% TG age >39: HA-PCOS 32.6%*; NA-PCOS 17.4%; control 13.2% HDL age >39: HA-PCOS 30.2%*; NA-PCOS 21.7%; control 21.3% HTN age >39: HA-PCOS 62.5%y; NA-PCOS 50%; control 40.5% Met-S age >39: HA-PCOS 42.4%y; NA-PCOS 19.5%; control 18.2% IGT: PCOS 25%vs. control 9.2%* TG: PCOS 31.3% vs. control 16.2%*

Fertility and Sterility®

Polotsky et al., 2012, U.S.

Self-report of oligomenorrhea and hirsutism at age 31 or self-report of polycystic ovaries or PCOS at age 46; PCOS: n ¼ 279; Control: n ¼ 1,577 Rotterdam, subdivided into HA and NA phenotypes. Overall: PCOS: n ¼ 1,550 Control: n ¼ 447. Age >39: HA-PCOS: n ¼ 45; NA-PCOS: n ¼ 50; Control: n ¼ 90.

C-IMT: mean difference 0.010 mm (0.007 to 0.026) PAD: OR 0.66 (0.28–1.51)

Continued. Study

Study design from premenopause to postmenopause

PCOS definition and n

Age (y) and BMI (kg/m2)

Outcomes (measured at follow-up)

PCOS: n ¼ 117; Control: n ¼ 487

Control: 26.6 (IQR 26.3–26.9)

HDL-C <50 mg/dL MetS (NCEP/ATPIII criteria)

Polotsky et al., 2014, U.S.

PC, longitudinal followup of SWAN cohort

NIH (OAa and HAb evaluated together and separately); At baseline: PCOS: n ¼ 66; Control: n ¼ 1,186

Schmidt et al., 2011, Sweden

PC, women with a history of a wedge resection and agematched control women (latter from WHO MONICA study (ratio 1:4), control women reported as comparable in terms of BMI but unclear if they were BMI matched PC, CARDIA Woman's Study, a populationbased multicenter cohort of young adults

Rotterdam; PCOS: n ¼ 32; Control: n ¼ 95. Hyperlipidemia analysisc: PCOS: n ¼ 25; Control: n ¼ 68.

RC, women with PCOS and age- and neighborhoodmatched control women

Hospital records, 62% had data to confirm by Rotterdam criteria; PCOS: n ¼ 319; Control: n ¼ 1,060

Wang et al., 2011, U.S.

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Wild et al., 2000 (two publications of same cohort), U.K.

Cooney. PCOS and long-term health. Fertil Steril 2018.

Starting cohort age: 42– 52; follow-up for 12 y; those with baseline MetS excluded for this analysis. Baseline BMI: PCOS: 27.1 (IQR 25.4– 28.8)*; Control: 25.1 (IQR 24.8–25.4) Starting age: 40–59; age at follow-up: 61–79 (mean 70). BMI (at age 70): PCOS: 27.1  5.0; Control: 26.4  4.8

Elevated depression scores (CESD R16) Incidence rate of MetS compared with control

Prevalence of conditions by ICD code or use of medication DM Dyslipidemia Hypertension MI Stroke

NIH (recall of oligomenorrhea at age 20–30, biochemical hyperandrogenism); PCOS: n ¼ 53; Control: n ¼ 1,074

Starting cohort age: 20– 32; age at followup: 38–50. BMI (age 20–32; normal/overweight/ obese): PCOS: 58.5%/18.9%/ 22.6%; Control: 58.2%/ 22.1%/19.7% Starting cohort age: NR; mean follow-up: 31 y (range 14–47); age at follow-up: mean 56.7 (range 38–98). BMI (age 38–50):

Prevalence of DM Prevalence of dyslipidemia Prevalence of HTN

Prevalence of conditions identified by physician documentation in chart Type 2 DM

Results HDL: PCOS 52.1% vs. control 33.3%* Met-S: PCOS 41.0% vs. control 17.0%* Depression: PCOS 29.9% vs. control 23.9% Unadjusted RR, PCOS compared with control: 3.57 (2.14–5.00)*; aRR,a PCOS compared with control: 1.4 (0.9–2.2)

PCOS 22% vs. control 14% PCOS 24% vs. control 27% Age 40–59: PCOS 39% vs. control 11%*; age 61–79: PCOS 69% vs. control 41%* PCOS 9.4% vs. control 7.4% PCOS 18.8% vs. control 10.5%

PCOS 23.1% vs. control 13.1%*; aORa 2.6 (1.3–5.2)* PCOS 41.9% vs. control 27.7%*; aORa 2.0 (1.0–3.9) PCOS 26.9% vs. control 26.3% aORa: 1.8 (0.9–3.6)

PCOS 6.9% vs. control 3.0%*; aORb 2.2 (0.9–5.2)

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TABLE 2

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TABLE 2 Continued. Study

Study design

PCOS definition and n

Age (y) and BMI (kg/m2)

Outcomes (measured at follow-up)

PCOS: 27.1*; Control: 26.2. Prevalence of obesity: PCOS: 26%*; Control: 18%

High cholesterol

PCOS 30% vs. control 17%*; aORb 3.2 (1.7–6.0)*

HTN

PCOS 23% vs. control 19%*; aORb 1.4 (0.9–2.0) PCOS 2.2% vs. control 0.4%*; aORb 6.0 (1.0–36.9)* PCOS 4.1% vs. control 3.4%; aORb 1.3 (0.6–2.8) PCOS 4.7% vs. control 4.0%; aORb 1.2 (0.5–2.6)

Endometrial cancer Breast cancer Coronary heart disease (including MI, angina, coronary revascularization procedure or positive treadmill test) Stroke/TIA

Results

PCOS 3.1% vs. control 1.2%*; aORb 3.4 (1.2–9.6)

Note: aOR ¼ adjusted odds ratio (95% confidence interval); BMI ¼ body mass index; BP ¼ blood pressure; CAD ¼ coronary artery disease; CARDIA ¼ Coronary Artery Risk Development in Young Adults; CESD ¼ Center for Epidemiological Studies Depression Scale; CS ¼ cross-sectional; CT ¼ computerized tomography; CVD ¼ cardiovascular disease; DM ¼ diabetes mellitus; ECG ¼ electrocardiography; FBG ¼ fasting blood glucose; H ¼ hirsutism; HA ¼ hyperandrogenism (clinical or biochemical); HTN ¼ hypertension; ICD ¼ International Classification of Disease; IQR ¼ interquartile range; MetS ¼ metabolic syndrome; MI ¼ myocardial infarction; MRI ¼ magnetic resonance imaging; NA ¼ normoandrogenic; NCEP/ATPIII ¼ American Heart Association and U.S. National Cholesterol Education Program/Adult Treatment Panel III; NIH ¼ National Institutes of Health; NR ¼ not reported; OA ¼ oligoanovulation; OGTT ¼ oral glucose tolerance test; PC ¼ prospective cohort; PCOM ¼ polycystic ovarian morphology on ultrasound; PCOS ¼ polycystic ovary syndrome; RC ¼ retrospective cohort; SIR ¼ standardized incidence ratio; SWAN ¼ Study of Women's Health Across the Nation; TG ¼ triglycerides; THIN ¼ The Health Improvement Network; TIA ¼ transient ischemic attack; tT ¼ total testosterone. *P< .05 compared with control yP< .05 compared with both NA-PCOS and control. a Adjusted for multiple confounders, including age and BMI. b Adjusted for BMI. c Different number than in analysis of other conditions in the same study owing to missing data for this outcome. Cooney. PCOS and long-term health. Fertil Steril 2018.

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VIEWS AND REVIEWS PCOS were more likely to have DM at the age of 46 years compared with control women (12.4% vs. 4.3%; P< .001) (Table 2) (29). In a multivariate model, overweight/obese women (BMI R25 kg/m2) with PCOS had an increased risk of DM at age 46 compared with overweight/obese control women (OR 2.45, 95% CI 1.28–4.67), but lean women did not. In this study, PCOS diagnosis was based on self-report of oligomenorrhea and hirsutism at initial assessment (age 31) or by self-report of polycystic ovaries or PCOS at subsequent assessment at age 46. Another large longitudinal study, using the Taiwan National Health Insurance Research Database, found a higher prevalence of DM in 4,595 women with PCOS compared with age-matched control women (2.4% vs. 1.4%; P¼ .001) (26). A small retrospective cohort in the Czech Republic of 28 women with PCOS (age 45–59 y) found higher rates of DM than in local control women (32% vs. 8%; P< .001) (25). In the Rotterdam study, a higher prevalence of DM was reported in a cohort of women with presumed PCOS (mean age 70 y; n ¼ 106) compared with control women (n ¼ 171; 18.9% vs. 7.0%; P< .01) (28). PCOS was defined as highestquartile testosterone (>34.3 ng/dL) and a history of irregular cycles at age 25. Three studies did not show an increased risk of DM in older women with PCOS (9, 24, 31) (Table 2). In a study from the United Kingdom, prevalence of DM was higher in women with PCOS compared with age-matched control women (6.9% vs. 3.0%, mean age 56.7 y); however, this risk was not significant after adjustment for BMI (adjusted OR [aOR] 1.4, 95% CI 0.9–2.0). On retrospective chart review, 67% of women in the study met Rotterdam criteria (31). In a Swedish study (9), prospectively defined women with PCOS according to the Rotterdam criteria and age-matched control women showed no difference in prevalence of DM at ages 61–79, potentially related to small numbers of subjects (PCOS: n ¼ 32; control: n ¼ 95) (9). In a cross-sectional cohort of the Dallas Heart Study (mean age 40), no differences in percentage of women with DM were noted (24) (Table 2). These studies across different populations and countries collectively demonstrate that the risk of IGT is increased in the reproductive years and the risk of DM is increased in perimenopause and beyond in women with PCOS. Although risk of IGT and DM are compounded by obesity, studies suggest an obesity-independent association between PCOS and IGT/DM. It is imperative that all providers are aware of these increased risks and follow current guidelines that recommend screening all women with PCOS at their initial visit (18). Subsequent screening can be performed at 1–3-year intervals based on the presence of other risk factors for diabetes.

DYSLIPIDEMIA Meta-Analysis of Studies in Reproductive-Age Women An MA of 30 studies with the mean age of subjects <45 years found higher mean serum low-density lipoprotein (LDL) cholesterol (LDL-C), non–high-density lipoprotein (HDL) 802

cholesterol (nonHDL-C), and triglyceride (TG) levels and lower HDL-C levels in women with PCOS (n > 2,000) compared with control women (n > 2,000; Table 1) (8). The association with LDL-C and nonHDL-C persisted when matched on BMI (mean difference: LDL-C: 9 mg/dL, 95% CI 6–12; nonHDL-C: 16 mg/dL, 95% CI 14–19). Of note, the absolute values for components of the lipid panel were often within the normal ranges; for example, in the above MA only three studies had mean TG levels R150 mg/dL in women with PCOS. One of the largest studies in this MA included 557 women with PCOS (mean age 32.4 y) and 295 control women from the Netherlands (32). When stratified by BMI, LDL-C levels were higher in both lean and overweight/obese women with PCOS compared with control women, whereas significant differences in TG and HDL-C were seen only in the overweight/obese group, suggesting that PCOS compounds the increased risk of dyslipidemia associated with obesity.

Long-Term Risk: Studies in Women >40 Years of Age The aforementioned CARDIA and SWAN studies showed a higher prevalence of dyslipidemia in women with PCOS (22, 30) (Table 2). A cross-sectional study combining eight cohorts from the Nordic countries compared women with PCOS (n ¼ 1,500) and control women (n ¼ 447), including women >39 years of age (n ¼ 95; maximum ages 59 y in PCOS group and 62 y in control group) (33) and reported a higher prevalence of dyslipidemia only in the hyperandrogenic PCOS group after adjusting for BMI (Table 2). Hudecova et al. also reported higher TG levels in women with PCOS (mean age 43  5.8 y) after controlling for BMI (34), although the mean values for both groups were in the normal range (Table 2). No difference in rates of dyslipidemia were reported by Chang et al., Cibula et al., or Schmidt et al., although the latter two studies included few women with PCOS (32 and 35, respectively; Table 2) (9, 25). In summary, although there are fewer studies examining the prevalence of dyslipidemia in older women with PCOS, the current data suggest that dyslipidemia is common in young women with PCOS and likely persists beyond menopause.

OVERWEIGHT/OBESITY Meta-analysis of Studies in Reproductive-Age Women Obesity is one of the most common comorbidities, and ‘‘difficulty losing weight’’ is cited by patients as the most concerning feature of PCOS (3–5). In a large MA (Table 1), the pooled estimated prevalence of obesity in women with PCOS (mean ages predominantly late 20s) was 61% (95% CI 54%–68%; 101 studies), with an increase in prevalence of overweight and central obesity (35). The risk of obesity was even higher in high-quality studies (relative risk [RR] 4.68, 95% CI 2.52– 8.70), and subgroup analysis showed that white women had a higher relative risk of obesity compared with Asians (10.8-fold vs. 2.3-fold; P< .001) (35). VOL. 110 NO. 5 / OCTOBER 2018

Fertility and Sterility® Long-Term Risk: Studies in Women >40 Years of Age Despite the importance of obesity, it is not typically the primary outcome in longitudinal studies looking at other long-term health outcomes in PCOS. Moreover, BMI is a confounder of cardiometabolic outcomes, and many studies match PCOS and control subjects on BMI. Therefore, it can be hard to determine the true prevalence of overweight/obesity in non–population-based studies. Of the 18 studies included in our longitudinal review (Table 2), three did not report BMI for the full cohort (27, 36, 37), one did not indicate if BMI matching occurred (9), two did not report BMI at follow-up (26, 30), and two reported data on the same cohort of patients as another included study (38, 39) so only the original study was evaluated. Of the remaining ten studies, seven reported a higher BMI in women with PCOS (22, 24, 28, 29, 31, 33, 40). In these studies, mean BMI in control women ranged from 25 to 29 kg/m2 and mean BMI in women with PCOS ranged from 27 to 32 kg/m2. Five of the six studies that were population based and thus at a lower risk for bias reported higher BMI in women with POCS compared with control women (22, 24, 28, 29, 40). Thus, most evidence supports the findings that women with PCOS continue to be more overweight/obese than control women even in older years.

HYPERTENSION Meta-analysis of Studies in Reproductive-Age Women Elevations in blood pressure in women with PCOS has usually been reported in the context of MetS (10), with few studies examining prevalence of hypertension as a primary outcome. In the Australian Longitudinal Study on Women's Health, a community-based cohort, women with selfreported PCOS (n ¼ 183) had a higher prevalence of hypertension than 4,638 control women (ages 28–33 years; 5.1% vs. 1.0%; P< .001). However, in a multivariable model including BMI and DM, there was only a trend toward an association between PCOS and hypertension (OR 1.6, 95% CI 0.9–2.6; P¼ .09) (41). Hillman et al. evaluated the association between race and hypertension in 20–34-year-old women with PCOS (white: n ¼ 244; black: n ¼ 67) compared with age- and race-matched control women in the National Health and Nutrition Examination Survey (NHANES). They found that black women with PCOS had a higher prevalence of hypertension than black control women (45.5% vs. 10.6%; P< .001) and white women with PCOS had higher rates of hypertension than white control women (31.9% vs. 3.3%; P< .001) (42).

Long-Term Risk: Studies in Women >40 Years of Age In a cross-sectional analysis of the Dallas Heart Study, women with PCOS (mean age 40 y) had higher rates of hypertension than control women (29.2% vs. 18.8%; P¼ .03) which persisted in age-, BMI-, and ethnicity-matched analVOL. 110 NO. 5 / OCTOBER 2018

ysis (24) (Table 2). In the CARDIA cohort, the rates of hypertension were similar in women with PCOS compared with control women both at baseline (2.9% vs. 1.9%; P>.05) and at 38–50 years (26.9% vs. 26.3%; aOR 1.8, 95% CI 0.9–3.6; Table 2) (30). In the combined analysis of eight Nordic studies, hyperandrogenic PCOS women >39 years of age had higher rates of hypertension and higher BMIadjusted systolic blood pressure, but mean values for both groups were in the normal range (33) (Table 2). Wild et al. also described higher rates of hypertension in women with PCOS but not after controlling for BMI (aOR 2.2, 95% CI 0.9–5.2; Table 1) (31). In the small study by Schmidt et al., higher rates of hypertension were noted in women with PCOS at follow-up (Table 2), but 36% of the control women (vs. 22% of the PCOS women) were lost to follow-up (9). In summary, the reported prevalence of hypertension varies considerably, with most studies not showing a continued risk of hypertension, independent from BMI, after menopause.

METABOLIC SYNDROME Meta-analysis of Studies of Reproductive-Age Women Metabolic syndrome is a cluster of metabolic disturbances including central obesity, hyperglycemia/insulin resistance, dyslipidemia, and hypertension. Given the association of PCOS with many of these individual components, it is not surprising that MAs have shown a greater than twofold increased risk of MetS in women with PCOS (10, 21). In a recent analysis of 41 studies, mean agse 20–30 years, the increased risk of MetS persisted in studies that were ageand BMI-matched or adjusted for age and BMI (aOR 2.6, 95% CI 1.3–5.5; 11 studies; PCOS: n ¼ 2,033; Table 1) (10). The association was higher in studies that used NIH criteria (6.0-fold) compared with those that used Rotterdam (1.7fold) or Androgen Excess and PCOS Society criteria (2.1fold), suggesting that PCOS phenotype may modulate the risk.

Long-Term Risk: Studies in Women >40 Years of Age Several studies have shown a higher prevalence of MetS in older women with presumed PCOS diagnosis compared with control women (22, 24, 33, 40) (Table 2). Some of these studies also showed a higher prevalence of MetS in the hyperandrogenic PCOS phenotype compared with the nonhyperandrogenic phenotype (33). In the SWAN study, women with presumed PCOS who did not have MetS at baseline (n ¼ 1,929) had higher rates of MetS during follow-up of 12 years (incidence rates: PCOS: 3.57, 95% CI 2.14–5.0; control: 2.26, 95% CI 2.0–2.52; P¼ .011). This difference was not significant after adjustment for confounders including BMI (hazard ratio [HR] 1.4, 95% CI 0.9–22; Table 2) (38) suggesting that women with PCOS who have not developed MetS in their premenopausal years may represent a lower-risk group. 803

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OBSTETRICAL COMPLICATIONS: GESTATIONAL DIABETES, PREGNANCYINDUCED HYPERTENSION, AND PREECLAMPSIA

the general population, thereby likely increasing the risk for long-term negative health effects in PCOS. Larger prospective studies on the risk of OSA in women with PCOS are needed.

Although pregnancy complications are inherently seen only in reproductive-age women, it is pertinent to highlight these associations, given that gestational diabetes (GDM), pregnancy-induced hypertension (PIH), and preeclampsia are associated with long-term cardiometabolic risks. Numerous MAs have evaluated the associations between PCOS and pregnancy complications (11, 43–46). The most recent MA found higher rates of GDM in PCOS (RR 2.78, 95% CI 2.27–3.40; P< .001), which remained significant after stratification by age and BMI (11) (Table 1). One of the largest prospective studies on this topic used the Taiwan National Health Insurance Research Database for 1998– 2012 and reported a higher prevalence of GDM in women with PCOS (n ¼ 3,109) compared with age-matched control women (n ¼ 31,090; 20.5% vs. 10.5%; P< .0001) (47). PCOS and GDM were diagnosed with ICD-9 codes and patients were subsequently excluded if they did not also have a diagnostic code for PCOS-associated blood tests (testosterone, FSH, LH) or ultrasonography. Women with PCOS also have over a greater than twofold increased risk of PIH (RR 2.46, 95% CI 1.95–3.09; P¼ .001) and preeclampsia (RR 2.79, 95% CI 2.29–3.38; P< .001), which remained significant after stratification by age and mean BMI (11) (Table 2). In the general population, women with GDM have a higher risk of developing diabetes (48) and women with preeclampsia have a higher risk of developing hypertension and CVD (49, 50). Although there are no longitudinal studies of women with PCOS with a history of pregnancy complications, collectively these findings highlight a subset of women with PCOS who have a higher overall risk of DM and hypertension.

METABOLIC RISKS IN RELATIVES OF WOMEN WITH PCOS

OBSTRUCTIVE SLEEP APNEA Meta-analysis of Studies in Reproductive-Age Women Obstructive sleep apnea is a chronic sleep disorder characterized by recurrent complete or partial upper airway obstructions during sleep leading to intermittent hypoxia, and it affects 2%–5% of adult women (51). In a recent MA, women with PCOS (mean age <35 y) had a pooled prevalence of OSA of 32% (95% CI 13%–55%; 8 studies; Table 1) (52); however, not all studies controlled for BMI, a known risk factor for the development of OSA (51) and the overall quality of the included studies was low.

Long-Term Risk: Studies in Women >40 Years of Age Only one study (Taiwan National Health Insurance Database) has examined the risk of OSA in older women with PCOS and reported a higher risk (HR 2.63, 95% CI 1.57–4.04) in women with PCOS after adjusting for demographic data and medical comorbities (26) (Table 2). OSA has been associated with hypertension (53), DM (54), and coronary artery disease (55) in 804

Family history of cardiometabolic risk factors increases the risk in the proband. A recent MA of 14 studies demonstrated that mothers of women with PCOS (‘‘PCOS mothers’’) had a higher prevalence of MetS (RR 1.78, 95% CI 1.37, 2.30; P< .0001) and dyslipidemia (RR 1.16, 95% CI 1.02–1.31; P¼ .02) than mothers of control women (56). PCOS mothers also had significantly higher systolic BP than control mothers. Interestingly, this MA also showed increased prevalences of MetS in fathers and sisters, of hypertension in fathers, sisters, and brothers, and of dyslipidemia in fathers of women with PCOS. This suggests a clustering of metabolic risk in families of women with PCOS, thereby increasing their risk for long-term adverse impact.

DEPRESSION AND ANXIETY Meta-analysis of Studies in Reproductive-Age Women There are several MAs examining the risk of depressive and anxiety symptoms in women with PCOS (13, 57–61). We recently reported a median prevalence of 36.6% (interquartile range [IQR] 22.3%–50.0%) for depressive symptoms and 41.9% (IQR 13.6%–52.0%) for anxiety symptoms in women with PCOS (13) (Table 1), with an increased odds when evaluating BMI-matched studies: depressive symptoms: OR 3.25, 95% CI 1.73–6.09 (4 studies); anxiety symptoms: OR 6.30, 95% CI 1.88–21.09 (3 studies). In the majority of studies in this MA, the mean age was <30 years. Longitudinal studies support the association with increased incident depression or anxiety (62–64), although again, mean age at last follow-up was <35 years in these studies.

Long-Term Risk: Studies in Women >40 Years of Age Few studies have examined the prevalence of depression and anxiety in older women with PCOS. In the previously described Northern Finland birth cohort, women with presumed PCOS had higher self-report of being diagnosed or treated for depressive symptoms than control women at both age 31 (9.6% vs. 5.3%; P¼ .003) and age 46 (25.9% vs. 14%; P¼ .003), but there were no significant associations with self-reported anxiety (36) (Table 2). Analysis of data from the SWAN study (mean age 45 y) did not find an increased prevalence of elevated depression scores in women with presumed PCOS compared with control women (29.9% vs. 23.9%; P¼ .14) (22). More studies are needed to evaluate the risk of persistent depressive and anxiety symptoms in peri- and postmenopausal women with PCOS. VOL. 110 NO. 5 / OCTOBER 2018

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NONALCOHOLIC FATTY LIVER DISEASE Meta-analysis of Studies in Reproductive-Age Women Nonalcoholic fatty liver disease refers to the accumulation of fat in the liver, ranging from simple hepatic steatosis to the stage of nonalcoholic steatohepatitis (NASH) and potentially leading to cirrhosis. The median worldwide prevalence of NAFLD (mean age in 50s) is 20% (65). Three MAs have shown an increased prevalence of NAFLD in women with PCOS (15, 66, 67). BMI-stratified subgroup analysis showed higher odds in both obese (3.0-fold) and nonobese (2.1-fold) subjects (Table 1) and an increased risk in women residing in Europe (2.0-fold), the AsiaPacific region (2.3-fold), and America (3.0-fold) (67). Findings from these MAs are further supported by a recent large population-based study in the United Kingdom using The Health Improvement Network (THIN) database, which showed that young women with PCOS (median age 30 y) have a twofold increased risk of developing NAFLD compared with age- and BMI-matched control women. In fact, the impact of PCOS on NAFLD rates was similar to the impact of DM and IGT on rates of NAFDL (68).

Long-Term Risk: Studies in Women >40 Years of Age Despite data that NAFLD increases with age (65), there are no studies in older women with PCOS.

CANCER Meta-analysis of Studies in Reproductive-Age Women Given long periods of anovulation and a high prevalence of obesity, it is not surprising that women with PCOS have higher rates of endometrial cancer, as reported by multiple MAs (14, 69, 70). Most recently, Barry et al. reported that women with PCOS had a 2.8-fold increased odds of endometrial cancer compared with control women (Table 1). When analysis was restricted to studies with mean ages <54 years, heterogeneity was eliminated (I2 ¼ 0) and the strength of the association increased (OR 4.05, 95% CI 2.42– 6.76, 4 studies). No association between PCOS and either breast or ovarian cancer was reported (14) (Table 1). Studies included in this MA were limited by small number of events (<30 cancers in women with PCOS for all studies), casecontrol rather than prospective cohort design, self-report of PCOS diagnosis, and lack of controlling for BMI. Of the included studies, only one (71) reported BMI-adjusted ORs, and in that analysis the association between PCOS and endometrial cancer was no longer significant. A population-based retrospective cohort study (mean age 35 y) of 2,566 women with PCOS reported higher rates of endometrial cancer in women with PCOS compared with control women (0.4% vs. <0.01%; P< .001; age-adjusted HR 22.5, 95% CI 6.94–73.14), but not of breast or skin cancer. Cervical cancer was noted to be lower in women with PCOS (2.6% vs. 3.8%; age-adjusted HR 0.69, 95% CI 0.54–0.88) (63). VOL. 110 NO. 5 / OCTOBER 2018

Long-Term Risk: Studies in Women >40 Years of Age All five of the case-control studies in the above MA (14) had a mean age >40 years. In the prospective cohort by Wild et al., women with PCOS (mean age 56 y) had a higher prevalence of endometrial cancer than control women (2.2% vs. 0.4%; P¼ .001; BMI-adjusted OR 6.0, 95% CI 1.0–36.9), but not of breast cancer (39) (Table 2). In a large registry-based Danish cohort, when the analysis was restricted to women >50 years of age, the risk of endometrial cancer was no longer significantly increased in women with PCOS (standardized incident ratio 2.0, 95% CI 0.5–5.1; Table 2) (37). Again, the total number of events were small (four endometrial cancers), thereby decreasing power for this analysis. Studies support the evidence of an increased risk of endometrial cancer in younger women with PCOS, but not of breast or ovarian cancer. This risk likely persists but may be attenuated after menopause.

CARDIOVASCULAR DISEASE: SUBCLINICAL ATHEROSCLEROSIS Current studies suggest that women with PCOS have a high prevalence of DM, IGT, dyslipidemia, and obesity during the reproductive years, and most of these risks persist beyond this time period. In addition to these traditional CVD risk factors, there is evidence of increased subclinical atherosclerosis.

Meta-analysis of Studies in Reproductive-Age Women An increase in carotid artery intima media thickness (C-IMT) has been associated with increased risk of CVD events, including stroke and myocardial infarction (MI) (72, 73). An MA (19 studies; PCOS: n ¼ 1,123) showed that women with PCOS have a higher C-IMT compared with control women (P< .0001; Table 1) (74). In the general population, for every 0.1 mm incremental increase in mean C-IMT, the hazard of stroke increases by 18% and the hazard of MI increases by 15% (73). Mean age in most of the studies in this MA (74) was late 20s, suggesting that evidence for subclinical atherosclerosis may be detected at a young age. Endothelial dysfunction, another marker of subclinical atherosclerosis, is measured by comparing changes in arterial flow-mediated dilation (FMD). Lower FMD predicts CVD events in the general population (75). In an MA, women with PCOS (age range 22–34 y) had a 3.4% lower pooled mean FMD (95% CI 1.9–4.9, 21 studies) than control women, with significant findings after matching on age and BMI (76) (Table 1). Coronary artery calcium (CAC) scores as measured with the use of cardiac computerized tomography or magnetic resonance imaging have also been reported to be higher in some small cohorts of young women with PCOS (77, 78) but not in others (79). Collectively these studies support increased evidence of subclinical atherosclerosis in young women with PCOS. 805

VIEWS AND REVIEWS Long-Term Risk: Studies in Women >40 Years of Age Few studies have examined markers of subclinical atherosclerosis in older women with PCOS (24, 28, 80). In the CARDIA cohort, women with PCOS assessed at the age of 45 years had higher mean internal carotid IMT (P¼ .02) and bulb mean carotid IMT (P¼ .003) than control women (80) (Table 2). In contrast, in the Rotterdam Study (mean age 70 y, follow-up 12 y; PCOS: n ¼ 106), there was no association between presumed PCOS diagnosis and either increased C-IMT or peripheral artery disease (28) (Table 2). In the CARDIA cohort, women with PCOS were also 2.7fold more likely to have presence of CAC (aOR 2.7, 95% CI 1.31–5.60) compared with control women (80) (Table 2). In contrast, women with PCOS in the Dallas Heart Study (mean age 40 y) showed no difference in rates of CAC score >0 compared with control women (5.4% vs. 6.3%, age- and BMI-adjusted OR 0.63, 95% CI 0.36–1.11) (24). Another study reported higher prevalence of CAC in both black and white women with PCOS, but generalizability may be low because LH-FSH ratio was included for PCOS diagnosis (81). Overall, the studies examining subclinical atherosclerosis in older women with PCOS are few in numbers and show mixed results.

CARDIOVASCULAR DISEASE EVENTS: MYOCARDIAL INFARCTION OR STROKE Meta-analysis of Studies in Reproductive-Age Women Although there are sufficient data supporting increased risk of subclinical atherosclerosis in reproductive age, the prevalence of CVD events needs to be assessed to counsel women and implement prevention strategies. There are several MAs examining the association between PCOS and risk of MI or stroke (82–84), although they included studies with significant limitations, e.g., PCOS diagnosis presumed on menstrual irregularity only (84) or inclusion of a study that was subsequently retracted (85). When these MAs were redone for recent international guidelines including only quality studies (18, 86), there was no difference in risk of MI (OR 1.21, 95% CI 0.68–2.14; P¼ .5; 3 studies, 1,633 participants), stroke (OR 1.64, 95% CI 0.92–2.93, P¼ .1; 4 studies), CVD-related death (OR 1.81, 95% CI 0.55, 5.88, P¼ .3; 2 studies), or coronary artery/heart disease (OR 2.44, 95% CI 0.88, 6.74, P¼ .09; 2 studies; Table 1) (87). The mean ages of women in the two largest studies included in this analysis were <40 years at follow-up. Given the small numbers of subjects and relative youth, and the absolute risk of a CVD event being very low, it is likely that these studies were underpowered (27, 88).

Long-Term Risk: Studies in Women >40 Years of Age Few studies have examined the prevalence of CVD events in older women with PCOS. Mani et al. showed that women with PCOS diagnosed in an endocrinology clinic had higher odds of MI than age-matched control women from the Leices806

tershire National Health Service Health Informatics Services database and the Health Survey for England in all age groups >45 years (27) (Table 2). Of note, there were 94 women with PCOS >55 years of age. In contrast, the Rotterdam Study showed that women with presumed PCOS (n ¼ 106; mean age of cohort 70 y) did not have higher rates of incident coronary heart disease, stroke, or composite CVD over 11 years of follow-up (28). The retrospective diagnosis of PCOS based on upper quartile of testosterone and history of oligomenorrhea at age 25 is a significant limitation, and small numbers of CVD events in each group make interpretation of these results difficult. Other studies that have evaluated the risk of CVD in women with PCOS have been limited by incomplete diagnostic criteria. One study reported similar prevalence of stroke and MI in women with PCOS and control women (PCOS: n ¼ 136; age >45 y); however, generalizability is limited because PCOS diagnostic criteria included obesity and infertility (89). Another recent study (90) used a national registry in Denmark to compare rates of CVD (ICD-10 codes for angina, MI, pulmonary embolism, deep vein thrombosis, or CVD medication) in women with presumed PCOS (n ¼ 18,122) versus control women (n ¼ 52,769). Median age at inclusion was 27 years (IQR 23–35) and follow-up was 11.1 years (IQR 6.9–16.0). They found a higher risk of CVD (aHR 1.3, 95% CI 1.2–1.4) after adjusting for confounders, including obesity and diabetes. Unfortunately, the PCOS group included those with a diagnosis code of either PCOS or hirsutism, again potentially limiting generalizability. Given the low numbers of women included in some of these studies and the retrospective or incomplete diagnosis of PCOS, future studies should include larger cohorts of well defined women with PCOS to determine the precise risk of CVD events in this population.

DISCUSSION Our review of the literature suggests that there is good evidence to support an increased risk of IGT and DM in both reproductive-age and older women with PCOS. Although, this evidence comes from different world regions, the prevalence of DM may vary depending on ethnicity and environmental influences. Screening for diabetes is currently recommended at the diagnosis visit in all women with PCOS regardless of age and BMI (18). Our SR of longitudinal studies examining the increased risk of DM in older women with PCOS suggests the continued need for frequent screening beyond menopause. Several studies also support an increased risk of dyslipidemia and MetS in young women with PCOS. The association between PCOS and MetS could be due to both the inherent insulin resistance, which is part of the pathogenesis of PCOS, or lifestyle-associated insulin resistance related to the increased risk of overweight/obesity in PCOS. Compared with IGT and DM, there are fewer studies that have examined the prevalence of dyslipidemia and MetS in older women with PCOS. Nonetheless these studies, from different regions of the world, show an increased prevalence of dyslipidemia and MetS. Future studies should address differences in risk based on PCOS phenotype, namely, the VOL. 110 NO. 5 / OCTOBER 2018

Fertility and Sterility® hyperandrogenic phenotype. Currently, screening for all components of MetS at the time of diagnosis has been recommended in women with PCOS (91). Our review provides evidence for continued screening at frequent intervals beyond reproductive age. Although there is evidence of increased risks of obstructive sleep apnea, depression, anxiety, NAFLD, and endometrial cancer in younger women with PCOS, it is not yet clear whether these risks continue into the postmenopausal years, clearly highlighting the need for further research in older women with PCOS. DM, MetS, depression, and OSA are associated with CVD and therefore may affect longterm health in women with PCOS. Although there is good evidence to suggest an increased prevalence of abnormal markers of subclinical atherosclerosis in young women with PCOS, data in the older age group are very limited. In addition, published studies do not clearly indicate an increased risk of CV events associated with PCOS. These negative studies may be the result of small number of subjects in individual studies (9, 25), presumed retrospective diagnosis of PCOS (25, 28), inclusion of mild phenotypes in the control group, high prevalence of obesity in PCOS, inclusion of primarily premenopausal women, and recall bias for diagnosis of both PCOS and CV events (28, 30). The lack of high-quality studies used to answer questions of long-term health risk are well recognized. The ideal study should include a large cohort of reproductive-age women whose PCOS phenotype is prospectively characterized (19) and followed for several decades, because the prevalence of CVD increases with age and premenopausal women have a low risk of CV events. We recognize that such a study may be difficult to conduct because a very large number of subjects would be needed to monitor the end points, given the heterogeneity of PCOS and influence of factors such as ethnicity and BMI on the prevalence of associated risk factors. A potential protective effect of PCOS as women age, secondary to a later age of menopause, has been suggested (91, 92). However, based on the published literature, it is currently unclear if the risk of CVD is increased in older women with PCOS, and long-term studies are needed to better counsel our patients. In conclusion, counseling of women with PCOS needs to be expanded beyond discussions regarding management of menstrual irregularity, hirsutism, and fertility. In addition to cardiometabolic risk, other comorbidities associated with PCOS also contribute to overall health burden. Young women with PCOS have an increased risk of depressive symptoms, OSA, and NAFLD, although very few studies have assessed continued risk in older women with PCOS. Current guidelines suggest that screening for depressive and anxiety symptoms should also be offered at the diagnosis visit (18). Women should also be counseled about the increased risk of diabetes and hypertension during pregnancy. Future studies should focus on the prevalence of morbidities in older women to determine frequency of screening recommendations and appropriate counseling and management strategies.

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