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 comor-
bidities, 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/16110-
fertility-and-sterility/posts/36446-26627

P
olycystic ovary syndrome (PCOS) PCOS has primarily been regarded ovarian morphology, improve with age
is a common but complex endo- as a disease of reproductive-age women, (16, 17). In this review we examine
crine disorder affecting 6%–10% predominantly associated with infertility whether the above-mentioned comor-
of reproductive-age women worldwide (6). The focus on symptom management bidities persist beyond the premeno-
(1, 2). Despite its high prevalence, (irregular menses and hirsutism) is short- pausal years, because it is important for
heterogeneous presentations, ethnic sighted, because there is compelling physicians and patients alike to be well
variations, and different phenotypes global data linking PCOS to a number versed in these risks.
make timely diagnosis a challenge for of metabolic and nonmetabolic morbid-
both patients and physicians (3–5). In ities, such as type 2 diabetes (DM),
addition, given the multitude of dyslipidemia, hypertension, obesity, METHODS
comorbidities associated with PCOS, it metabolic syndrome (MetS), depression, Our review compares the risk of health
is common for care to be fractured, anxiety, obstructive sleep apnea (OSA), complications, specifically DM, dyslipi-
with individual symptoms managed by pregnancy complications, nonalcoholic demia, obesity, hypertension, MetS,
different providers, such as reproductive fatty liver disease (NAFLD), endometrial depression, anxiety, OSA, pregnancy
endocrinologists, gynecologists, cancer, and possibly cardiovascular dis- complications, NAFLD, endometrial
medical endocrinologists, primary ease (CVD) (7–15) indicating the need for cancer, and CVD, in women with
care physicians, psychologists, screening, counseling, and management PCOS versus women without PCOS.
dermatologists, and nutritionists. It is of these risks during the reproductive There is a large amount of primary
not clear who offers counseling years. Most diagnostic features of data available for each of these topics,
regarding long-term complications to PCOS, such as menstrual irregularity, including multiple well designed,
these women. biochemical hyperandrogenism, and recently published systematic reviews
(SRs) and meta-analyses (MAs). We
Received July 11, 2018; revised and accepted August 8, 2018. therefore initially searched for SRs
L.G.C. has nothing to disclose. A.D. has nothing to disclose. and MAs on each of these comorbid-
Reprint requests: Anuja Dokras, M.D., Ph.D., 3701 Market St., Suite 800, Philadelphia, Pennsylva-
nia 19104 (E-mail: Adokras@obgyn.upenn.edu). ities. Because most studies included in
the SRs and MAs had a mean age of
Fertility and Sterility® Vol. 110, No. 5, October 2018 0015-0282/$36.00
Copyright ©2018 American Society for Reproductive Medicine, Published by Elsevier Inc.
20–30 years, we considered this group
https://doi.org/10.1016/j.fertnstert.2018.08.021 to represent ‘‘risk in reproductive-age

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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 interna-
tional guidelines recommend that diagnosis of PCOS can be
made in perimenopausal and menopausal women based on
documented long-term history of oligomenorrhea and hyper-
androgenism during the reproductive years (18). We therefore
included prospective cohort, retrospective cohort, and cross-
sectional 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 follow-
up 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 Rot-
terdam 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 Interna-
tional 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 4.4-
fold increase in women with PCOS residing in Asia and a 4.7-
fold increase in those residing in the Americas. Although
there were no significant differences in the risk of DM in sub-
groups matched by BMI (odds ratio [OR] 1.13, 95% confidence
interval [CI] 0.83–1.54, 7 studies), this may be a result of rela-
tively 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
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not be surprising to see a stronger BMI-independent associa-
tion 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 exam-
ined 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 high-
est tertile of total testosterone levels and history of oligome-
norrhea 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 normal-
weight 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 devel-
oping DM (95% CI 1.1–46.5) (30). In the CARDIA cohort,
although subjects were enrolled prospectively, history of oli-
gomenorrhea and hirsutism was obtained at year 16 which,
similarly to the SWAN study, is subject to recall bias. Howev-
er, testosterone levels were measured with the use of serum
banked at the year 2 visit to define biochemical hyperandro-
genism, 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 En-
gland, 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 sub-
jects in the older age groups were small. In the Northern
Finland birth cohort 1966 dataset, women with presumed
795
VIEWS AND REVIEWS

TABLE 1

Recent published meta-analyses of PCOS-related morbidities in reproductive-age women.

No. of studies: overall/ Risk (95% CI), BMI-
Outcome BMI-matched Total n/PCOS Risk (95% CI) matched studies
Impaired glucose 15/10 1,828/914 OR 3.26 (2.17–4.90)* OR 2.13 (1.39, 3.25)*
tolerance, Kakoly
et al., 2018
Type 2 diabetes, Kakoly 12/7 2,038/3,118 OR 2.87 (1.44–5.72)* OR 1.13 (0.83, 1.54)
et al., 2018
Dyslipidemia, Wild et al., LDL-C: 27/13 1,612/2,760 SMD 12 mg/dL (10, 16)* SMD 9 mg/dL (6–12)*
2011 NonHDL-C: 30/15 1,716/2,787 SMD 19 mg/dL (16, 22)* SMD 16 mg/dL (14–19)*
Triglycerides: 26/16 1,657/2,710 SMD 26 mg/dL (17, 35)* Reported as NS
HDL-C: 30/15 1,544/2,872 SMD 6 mg/dL (4, 9)* Reported as NS
Overweight/obesity, Lim Overweight and obesity: 3,132/4,502 RR 1.95 (1.52–2.50) NR
et al., 2012 21/NR
Obesity: 18/NR 4,160/4,885 RR 2.77 (1.88–4.10)
Central obesity: 6/NR 1,191/2,396 RR 1.73 (1.31–2.30)
Hypertension No meta-analysis
Metabolic syndrome, 41/11 11,245/11,129 OR 2.5 (2.0–3.2)* OR 2.6 (1.3–5.5)*
Behboudi-Gandevani
et al., 2018
Obstetrical Gestational DM: 28 /NR For total MA: 17,816/ RR 2.78 (2.27–3.40)* ppBMI <25: RR:3.03
complications, Yu 123,756 (1.99–4.62)*
et al., 2016 ppBMI >25: RR:2.44
(1.53–3.88)*
Pregnancy-induced RR 2.46 (1.95–3.09)* ppBMI <25: RR:3.20
hypertension: 25/NR (2.16–4.74)*
ppBMI >25: RR:2.25
(1.67–3.02)*
Preeclampsia: 25/NR RR 2.79 (2.29–3.38)* ppBMI <25: RR:2.57
(1.78–3.69)*
ppBMI >25: RR:2.57
(1.56–4.24)*
Obstructive sleep apnea, 8/NR 141/518 OR 9.7 (2.76–34.41)* NR
Helvaci et al., 2017
Depression and anxiety, Depression: 18/4 1,917/2,346 OR 3.78 (3.03–4.72)* OR 3.25 (1.73–6.09)*
Cooney et al., 2017 Anxiety: 9/4 1,409/1,236 OR 5.62 (3.22–9.80)* OR 6.30 (1.88–21.09)*
Nonalcoholic fatty liver 17/subgroup analysis 2,715/2,619 OR 2.54 (2.19–2.95)* Obese only: OR 3.01
disease, Wu et al., obese: 5, (significant (1.88–4.82)
2018 nonobese: 3 heterogeneity) Nonobese: OR 2.07
(1.12–3.85)
Cancer, Barry et al., 2014 Endometrial cancer: 138/5,593 OR 2.79 (1.31–5.95)* NR
5/NR (significant
heterogeneity)
Breast cancer: 3/NR 529/39,795 OR 0.95 (0.64–1.39) NR
Ovarian cancer: 3/NR 111/18,378 OR 1.41 (0.93–2.15) NR
Carotid IMT, Meyer et al., 19/NR 1,123/923 SMD 0.072 mm (0.040– NR
2012 0.105)*
Endothelial dysfunction 21/7 98/566 Pooled mean: 3.4% Pooled mean: 4.1%
by FMD, Sprung (1.9 to 94.9)* (2.7 to 5.5)*
et al., 2013
Coronary artery disease, Myocardial infarction: 472/1,162 OR 1.21 (0.68–2.14); NR
Technical bulletin 3/NR P¼ .5
Stroke: 4/NR 791/2,221 OR 1.64 (0.92–2.93); NR
P¼ .1
CVD-related death: 2/NR 341/438 OR 1.81 (0.55–5.88); NR
P¼ .3
Coronary artery disease/ 340/1,812 OR 2.44 (0.88–6.74); NR
coronary heart P¼ .09
disease: 2/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.

796 VOL. 110 NO. 5 / OCTOBER 2018

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VOL. 110 NO. 5 / OCTOBER 2018

TABLE 2

Longitudinal and cross-sectional studies examining morbidities in women with PCOS with mean ages >40 years.
Study Study design PCOS definition and n Age (y) and BMI (kg/m2) Outcomes (measured at follow-up) Results
Calderon-Margalit PC, CARDIA Woman's NIH (recall of Starting cohort age: 20– Carotid intima media thickness BMI-adjusted mean, PCOS vs.
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et al., 2014, U.S. Study, a population- oligomenorrhea at 32; age at follow- (C-IMT) control: internal C-IMTc::
based multicenter age 20–30, up: 38–50 (mean þ0.07 mm*;
cohort of young biochemical 45). bulb C-IMTc: þ0.096 mm*;
common C-IMTc:: 0.02 mm (above
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adults hyperandrogenism); BMI at age 38–50:

Chang et al., 2011, U.S.
Cibula et al., 2000,
Czech Republic
PCOS: n ¼ 55; PCOS: 29.3  6.50; values are b from multivariable
Control: n ¼ 668 Control: 29.9  7.47 model, SDs not reported)
Coronary artery calcification (CAC) CAC: aORa 2.7 (1.31–5.60)
CS, nested cohort from Rotterdam (recall of Age 35–49; Prevalence of DM (fasting glucose DM: reported as not significant.
the Dallas Heart oligomenorrhea at PCOS: 40 (IQR 37–42)*; R126 mg/dL or use of glucose- Both groups 9%–10% per
Study (2000–2002), age 20–30, tT Control: 42 (IQR 39– lowering medication) figure
a population-based defined as upper 45). Prevalence of hypertriglyceridemia TG: PCOS 15.3% vs. control 14.1%
multiethnic cohort quartile); control BMI: (TG R150 mg/dL)
subjects all had tT PCOS: 31.7 (26.5–38.1) Prevalence of low HDL-C HDL: PCOS 44.4% vs. control
<80 mg/dL; *; 53.5%
PCOS: n ¼ 144; Control: 28.7 (2.5.5– Prevalence of HTN (systolic BP HTN: PCOS 29.2% vs. control
Control: n ¼ 170 33.9) R140 mm Hg or diastolic BP 18.8%*; higher prevalence
R90 mm Hg or use of persisted after comparing PCOS
antihypertensive medication) with age-, BMI-, and ethnicity-
matched control group (data not
reported)
Prevalence of MetS (ATPIII criteria) MetS: reported as not significant.
PCOS 38%–40%, control
33%–35% per figure
Prevalence of CAC >10 Agataston CAC: PCOS 5.4% vs. control 6.3%
units aORa 0.65 (0.36–1.13)
RC, women with history NIH plus infertility; Starting age: NR; Prevalence of type2 DM (fasting DM: PCOS 32% vs. control 8%*
of wedge resection PCOS: n ¼ 28; Age at follow-up: 45– glucose R126 mg/dL or use of
in 1960–1981, Control: n ¼ 752 59. medication)
control women BMI (age 45–59): PCOS: Prevalence of dyslipidemia
from random 28.0  4.2; Control: Cholesterol R190 mg/dL PCOS 71% vs. control 71%
population sample 28.2  5.2 LDL R140 mg/dL PCOS 57% vs. control 44%
in same age range HDL %40 mg/dL PCOS 7% vs. control 7%
TG R170 mg/dL) PCOS 25% vs. control 28%
Prevalence of HTN (BP R140/ PCOS 50% vs. control 39%
90 mm Hg or use of medication)
CAD: chest pain evaluated as CAD: PCOS 21% vs. control 5%*
definite or possible angina, a
history of definite or possible MI,

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a history of transluminal
percutaneous coronary
angioplasty or coronary artery
bypass grafting
Gottschau et al., 2015, PC, Danish National ICD codes; Starting age: 9–49; Diagnosis by Danish Cancer Registry
Denmark Patient Registry, SIRs PCOS: n ¼ 12,070 median age range: Endometrial cancer SIR 1.19 (1.06–1.34)*;
calculated by Control: NA 25–29; Age R50: 2.0 (0.5–5.1)
Cooney. PCOS and long-term health. Fertil Steril 2018.
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VIEWS AND REVIEWS

TABLE 2

Continued.
Study Study design PCOS definition and n Age (y) and BMI (kg/m2) Outcomes (measured at follow-up) Results
comparing cancer median follow-up: 5.7 y Breast cancer SIR 1.1 (0.8–1.4);
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rates in women with (IQR 1–16 y); Age R50: 1.4 (0.9–2.2)
PCOS vs. the BMI: NR Ovarian cancer SIR 1.8 (0.8–3.2);
general Danish Age R50: 1.3 (0.1–4.6)
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female population
Hudecova et al., 2011, RC, outpatient registry Rotterdam; Age at start: NR; Mean values of TG and HDL-C TG: 125.7  82.3 vs. 90.3 
Sweden to identify all PCOS: n ¼ 87; Age at follow-up: 43. 42.5 mg/dL* (P< .001 after
women with Control: n ¼ 87 BMI (at age 43): PCOS: adjusting for BMI and other
diagnosis of PCOS 28.3  6.0; Control: confounders);
from 1987 to 1995, 25.7  4.4* HDL-C: 61.8  19.3 vs. 65.6
age-matched 15.4 mg/dL
control women MetS: R3 of 5 NCEP/ATPIII criteria MetS: 23.8% vs. 8.0%*
from population
registry
Karjula et al., 2017, PC, northern Finland NIH; Age at start: 31; Prevalence of depression and Depression:
Finland birth cohort 1966 PCOS: n ¼ 125 at start/ Age at follow-up: 46. anxiety (self-report of diagnosis Age 31: 9.6% vs. 5.3%*;
85 at follow up BMI: NR or treatment) Age 46: 25.9% vs. 14%.*
Control: n ¼ 2,188 Anxiety: data not presented,
at start/1,576 at reported as not significant
follow up Depression or anxiety score R1.75 Depression:
at age 46 PCOS 17.4% vs. control 15.2%;
Anxiety:
PCOS 12.8% vs. control 8.3%
Lin et al., 2017, Taiwan RC, Taiwan National ICD-9 codes for PCOS; Starting cohort age: Diagnosis by ICD-9 codes
Health Insurance PCOS: 4,595 28.00  6.79; Prevalence of type 2 DM DM: PCOS 2.4% vs. control 1.4%*
Research Database, Control: 4,595 follow-up range: Prevalence of dyslipidemia Dyslipidemia: PCOS 3.1% vs.
control subjects age 2–13 y. control 2.4%*
matched BMI: NR. Prevalence of HTN HTN: PCOS 3.9% vs. control 3.7%
Baseline prevalence of Incident obstructive sleep apnea OSA: PCOS 1.7% vs. control 0.6%
obesity: 1.1% vs. (OSA) aHRa 2.63 (1.57–4.04)
0.9%.
Mani et al., 2013, U.K. RC, endocrinology clinic PCOS diagnosis noted Mean starting age: DM: ICD-9 or ICD-10 codes DM:
in Leichestershire, in chart (73% met 29.6; mean age at Overall: OR 2.0 (1.7–2.4)*;
U.K., control Rotterdam criteria); follow-up: 36.3. Age 15–44: OR 6.0 (4.9–8.3)*;
subjects age PCOS: n ¼ 2,301 BMI (age 36): 30.1  Age 45–54: OR 3.8 (2.6–5.4)*;
matched from the Control: n ¼ 2,301. 7.6/NR Age 55–64: OR 2.9 (1.6–5.3)*;
Health Survey for Analysis stratified by Age R65: OR 7.1 (2.2–23.4)*
England age: Age-stratified prevalence of MI in Age 16–44: 0.1% (0.0–1.2);
VOL. 110 NO. 5 / OCTOBER 2018

16–44 y: n ¼ 185; PCOS: ICD-9 or ICD-10 codes Age 45–54: 1.9% (0.5–3.4);
45–54 y: n ¼ 352; Age 55–64: 6.0% (0.9–11.1);
55–64 y: n ¼ 83; Age R65: 27.3% (1.0–53.6)
R65 y: n ¼ 11. (control prevalence not reported)
Odds of MI in women with PCOS MI:
compared with control 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)*
Cooney. PCOS and long-term health. Fertil Steril 2018.
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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) Results
Meun et al., 2018, The PC, Rotterdam Study, a NIH (recall of Mean starting age: Prevalence of type 2 DM (FBG DM: PCOS 18.9% vs. control 7.0%*
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Netherlands prospective oligomenorrhea at PCOS: 69.6  8.7; R126 mg/dL or use of

population-based age 25 and highest Control: 69.2  8.6; medication)
study of subjects quartile of median follow-up: Carotid intima media thickness C-IMT: mean difference 0.010 mm
R55 years old in
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testosterone 11 y. (C-IMT) (0.007 to 0.026)

Rotterdam, The [>34.3 ng/dL]); BMI (age 70): Peripheral arterial disease (PAD; PAD: OR 0.66 (0.28–1.51)
Netherlands, all PCOS: n ¼ 106; PCOS: 27.9  4.5; ankle brachial index values of
women Control: n ¼ 171 Control: 26.8  3.8* %0.9.)
postmenopausal Coronary heart disease (CHD): fatal CHD: PCOS 11.3% vs. control 8.2%
and >55 years old at or nonfatal MI (diagnosed by
study start physician, confirmed with
documented symptoms and
elevated enzymes or ECG
abnormalities)
Stroke: diagnosed when a patient Stroke: PCOS 12.3% vs. control
had typical neurologic 15.2%
symptoms confirmed by CT or
MRI
CVD: either stroke or MI Composite CVD: PCOS 25.5% vs.
control 20.5%
Ollila et al., 2017, PC, northern Finland Self-report of Starting age: 31; age at Prevalence of type 2 DM (FBG DM:
Finland birth cohort, oligomenorrhea and follow-up: 46. R126 mg/dL and/or 2-h OGTT PCOS 12.4% vs. control 4.3%*;
longitudinal data set hirsutism at age 31 BMI (age 46): R200 mg/dL) overweight/obese women (BMI
comprising follow- or self-report of PCOS: 28.60  6.3; R25 kg/m2): PCOS 17.4% vs.
up of all individuals polycystic ovaries or Control: 26.34  5.3* control 6.6%*;
with expected birth PCOS at age 46; lean women (BMI <25 kg/m2):
in 1966 PCOS: n ¼ 279; PCOS 1.8% vs. control 0%
Control: n ¼ 1,577
Pinola et al., 2017, CS, secondary analysis Rotterdam, subdivided PCOS age: 30.0  7.2 Prevalence of hypertriglyceridemia TG age >39:
Finland, Sweden, of subjects from 8 into HA and NA (range 14–49); (TG R150 mg/dL) HA-PCOS 32.6%*;
Norway, Denmark studies in Nordic phenotypes. Control age: 33.5  9.9 NA-PCOS 17.4%; control 13.2%
countries, PCOS Overall: (range 18–62)*; Prevalence of low HDL (%50 mg/dL) HDL age >39:
subjects recruited PCOS: n ¼ 1,550 (analysis stratified by HA-PCOS 30.2%*;
from clinics and Control: n ¼ 447. age: <30, 30–39, NA-PCOS 21.7%; control 21.3%
community Age >39: and >39). Prevalence of HTN: systolic BP HTN age >39:
advertisements, HA-PCOS: n ¼ 45; BMI (overall group): R130 mm Hg or diastolic BP HA-PCOS 62.5%y;
control subjects NA-PCOS: n ¼ 50; 29.2  6.9/25.9  R85 mm Hg NA-PCOS 50%; control 40.5%
from community Control: n ¼ 90. 5.4.* Prevalence of Met-S Met-S age >39:
BMI (age >39 y): HA-PCOS 42.4%y;

Fertility and Sterility®

PCOS: 29.2  5.5*; NA-PCOS 19.5%; control 18.2%
Control: 25.4  3.7
Polotsky et al., 2012, CS, baseline data from NIH (recall of Age: 45.8  2.7 (range Prevalence of IGT (FBG R110 mg/ IGT: PCOS 25%vs. control 9.2%*
U.S. SWAN study, a oligomenorrhea 42–52). dL)
multiethnic plus highest tertile Median BMI (age 45): Prevalence of hypertriglyceridemia TG: PCOS 31.3% vs. control
longitudinal study of of tT (R50 ng/dL); PCOS: 30.9 (IQR 29.4– (fasting TG R150 mg/dL); 16.2%*
women as they go 32.6)*;
Cooney. PCOS and long-term health. Fertil Steril 2018.
799
 800

VIEWS AND REVIEWS

TABLE 2

Continued.
Study Study design PCOS definition and n Age (y) and BMI (kg/m2) Outcomes (measured at follow-up) Results
from premenopause PCOS: n ¼ 117; Control: 26.6 (IQR HDL-C <50 mg/dL HDL: PCOS 52.1% vs. control
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to postmenopause Control: n ¼ 487 26.3–26.9) 33.3%*

MetS (NCEP/ATPIII criteria) Met-S: PCOS 41.0% vs. control
17.0%*
For personal use only. No other uses without permission. Copyright ©2018. Elsevier Inc. All rights reserved.

Elevated depression scores (CESD Depression: PCOS 29.9% vs. control

R16) 23.9%
Polotsky et al., 2014, PC, longitudinal follow- NIH (OAa and HAb Starting cohort age: 42– Incidence rate of MetS compared Unadjusted RR, PCOS compared
U.S. up of SWAN cohort evaluated together 52; follow-up for with control with control: 3.57 (2.14–5.00)*;
and separately); 12 y; aRR,a PCOS compared with
At baseline: those with baseline control: 1.4 (0.9–2.2)
PCOS: n ¼ 66; MetS excluded for
Control: n ¼ 1,186 this analysis.
Baseline BMI:
PCOS: 27.1 (IQR 25.4–
28.8)*;
Control: 25.1 (IQR
24.8–25.4)
Schmidt et al., 2011, PC, women with a Rotterdam; Starting age: 40–59; Prevalence of conditions by ICD
Sweden history of a wedge PCOS: n ¼ 32; age at follow-up: code or use of medication
resection and age- Control: n ¼ 95. 61–79 (mean 70). DM PCOS 22% vs. control 14%
matched control Hyperlipidemia BMI (at age 70): PCOS: Dyslipidemia PCOS 24% vs. control 27%
women (latter from analysisc: 27.1  5.0; Control: Hypertension Age 40–59: PCOS 39% vs. control
WHO MONICA PCOS: n ¼ 25; 26.4  4.8 11%*; age 61–79: PCOS 69%
study (ratio 1:4), Control: n ¼ 68. vs. control 41%*
control women MI PCOS 9.4% vs. control 7.4%
reported as Stroke PCOS 18.8% vs. control 10.5%
comparable in terms
of BMI but unclear if
they were BMI
matched
Wang et al., 2011, U.S. PC, CARDIA Woman's NIH (recall of Starting cohort age: 20– Prevalence of DM PCOS 23.1% vs. control 13.1%*;
Study, a population- oligomenorrhea at 32; age at follow- aORa 2.6 (1.3–5.2)*
based multicenter age 20–30, up: 38–50. Prevalence of dyslipidemia PCOS 41.9% vs. control 27.7%*;
cohort of young biochemical BMI (age 20–32; aORa 2.0 (1.0–3.9)
adults hyperandrogenism); normal/overweight/ Prevalence of HTN PCOS 26.9% vs. control 26.3%
PCOS: n ¼ 53; obese): aORa: 1.8 (0.9–3.6)
Control: n ¼ 1,074 PCOS: 58.5%/18.9%/
22.6%;
VOL. 110 NO. 5 / OCTOBER 2018

Control: 58.2%/
22.1%/19.7%
Wild et al., 2000 (two RC, women with PCOS Hospital records, 62% Starting cohort age: NR; Prevalence of conditions identified
publications of same and age- and had data to confirm mean follow-up: by physician documentation in
cohort), U.K. neighborhood- by Rotterdam 31 y (range 14–47); chart
matched control criteria; age at follow-up: mean Type 2 DM PCOS 6.9% vs. control 3.0%*;
women PCOS: n ¼ 319; 56.7 (range 38–98). aORb 2.2 (0.9–5.2)
Control: n ¼ 1,060 BMI (age 38–50):
Cooney. PCOS and long-term health. Fertil Steril 2018.
VOL. 110 NO. 5 / OCTOBER 2018

TABLE 2

Continued.
Study Study design PCOS definition and n Age (y) and BMI (kg/m2) Outcomes (measured at follow-up) Results
PCOS: 27.1*; High cholesterol PCOS 30% vs. control 17%*; aORb
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Control: 26.2. 3.2 (1.7–6.0)*

Prevalence of obesity:
PCOS: 26%*; HTN PCOS 23% vs. control 19%*; aORb
For personal use only. No other uses without permission. Copyright ©2018. Elsevier Inc. All rights reserved.

Control: 18% 1.4 (0.9–2.0)

Endometrial cancer PCOS 2.2% vs. control 0.4%*;
aORb 6.0 (1.0–36.9)*
Breast cancer PCOS 4.1% vs. control 3.4%; aORb
1.3 (0.6–2.8)
Coronary heart disease (including PCOS 4.7% vs. control 4.0%; aORb
MI, angina, coronary 1.2 (0.5–2.6)
revascularization procedure or
positive treadmill test)
Stroke/TIA 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 retro-
spective 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.

Fertility and Sterility®

801
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 subse-
quent assessment at age 46.
Another large longitudinal study, using the Taiwan Na-
tional 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 highest-
quartile 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 differ-
ences 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 peri-
menopause 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 recom-
mend screening all women with PCOS at their initial visit
(18). Subsequent screening can be performed at 1–3-year in-
tervals 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)
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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 over-
weight/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 hyperan-
drogenic PCOS group after adjusting for BMI (Table 2). Hu-
decova 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 dyslipide-
mia 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 ‘‘diffi-
culty losing weight’’ is cited by patients as the most concern-
ing 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

Long-Term Risk: Studies in Women >40 Years of
Age
Despite the importance of obesity, it is not typically the pri-
mary 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. There-
fore, 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 usu-
ally 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 self-
reported PCOS (n ¼ 183) had a higher prevalence of hyper-
tension 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 as-
sociation 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 hyper-
tension than control women (29.2% vs. 18.8%; P¼ .03)
which persisted in age-, BMI-, and ethnicity-matched anal-
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Fertility and Sterility®
ysis (24) (Table 2). In the CARDIA cohort, the rates of hyper-
tension 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 BMI-
adjusted 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 age-
and 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 (1.7-
fold) or Androgen Excess and PCOS Society criteria (2.1-
fold), 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 dif-
ference 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 devel-
oped MetS in their premenopausal years may represent a
lower-risk group.
803
VIEWS AND REVIEWS
OBSTETRICAL COMPLICATIONS:
GESTATIONAL DIABETES, PREGNANCY-
INDUCED HYPERTENSION, AND
PREECLAMPSIA
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 diag-
nostic 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 devel-
oping 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.
OBSTRUCTIVE SLEEP APNEA
Meta-analysis of Studies in Reproductive-Age
Women
Obstructive sleep apnea is a chronic sleep disorder character-
ized by recurrent complete or partial upper airway obstruc-
tions 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 hy-
pertension (53), DM (54), and coronary artery disease (55) in
804
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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.
METABOLIC RISKS IN RELATIVES OF WOMEN
WITH PCOS
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 preva-
lences of MetS in fathers and sisters, of hypertension in fa-
thers, 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 pre-
sumed 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 associa-
tions 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

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 Asia-
Pacific region (2.3-fold), and America (3.0-fold) (67). Find-
ings 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 endome-
trial 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), case-
control 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 endo-
metrial 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 con-
trol 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).
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Fertility and Sterility®
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 to-
tal 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 can-
cer. 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). Cor-
onary artery calcium (CAC) scores as measured with the use
of cardiac computerized tomography or magnetic reso-
nance 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 atheroscle-
rosis 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 associa-
tion 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 2.7-
fold 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 Leices-
806
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For personal use only. No other uses without permission. Copyright ©2018. Elsevier Inc. All rights reserved.
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 cor-
onary 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 diag-
nostic 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, pul-
monary 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) af-
ter adjusting for confounders, including obesity and diabetes.
Unfortunately, the PCOS group included those with a diag-
nosis 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 evi-
dence 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 preva-
lence of DM may vary depending on ethnicity and environ-
mental 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 path-
ogenesis 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 dif-
ferences in risk based on PCOS phenotype, namely, the
VOL. 110 NO. 5 / OCTOBER 2018

hyperandrogenic phenotype. Currently, screening for all
components of MetS at the time of diagnosis has been recom-
mended in women with PCOS (91). Our review provides evi-
dence for continued screening at frequent intervals beyond
reproductive age.
Although there is evidence of increased risks of obstruc-
tive sleep apnea, depression, anxiety, NAFLD, and endome-
trial 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 long-
term health in women with PCOS. Although there is good ev-
idence 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 sub-
jects 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 fac-
tors. 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 bet-
ter 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 diag-
nosis visit (18). Women should also be counseled about the
increased risk of diabetes and hypertension during preg-
nancy. Future studies should focus on the prevalence of mor-
bidities in older women to determine frequency of screening
recommendations and appropriate counseling and manage-
ment strategies.
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Fertility and Sterility®
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