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Polycystic ovary syndrome

is the cardiometabolic risk increased after menopause?

Alur-Gupta, Snigdha, MD; Dokras, Anuja, MD, PhD

doi: 10.1097/GME.0000000000001286
Clinical Corner: NAMS Practice Pearl

Although more commonly known for its fertility sequelae, dermatologic, metabolic, and psychological morbidities associated with polycystic ovary syndrome (PCOS) are not well recognized. This Practice Pearl reviews the effect of PCOS on cardiometabolic risk during the reproductive years and the consequence of these findings in middle-aged women. Current screening and management recommendations are reviewed.

Department of Obstetrics and Gynecology, Perelman School of Medicine, University of Pennsylvania.

Received 11 October, 2018

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder affecting reproductive-aged women.1 Two of these three criteria are needed to make the diagnosis: oligomenorrhea, clinical or biochemical hyperandrogenism, and polycystic-appearing ovaries on ultrasound, resulting in different phenotypes—hyperandrogenic and nonhyperandrogenic.

Women with PCOS typically have resumption of menstrual regularity and normalization of serum androgen levels and ovarian morphology by the fourth decade of life. Hence, it is recommended that diagnosis of PCOS in the perimenopausal or postmenopausal periods be made by well-documented history.1 Although many clinicians are aware of the effects of PCOS on fertility, the complex array of associated metabolic, dermatologic, and psychological challenges and their implications on a woman's health beyond the initial childbearing years are less well recognized. In reproductive-aged women with PCOS, type 2 diabetes mellitus (DM) and other cardiovascular disease (CVD) risk factors such as dyslipidemia, hypertension, and obesity are increased in prevalence. However, the persistence of these risk factors and their effect on cardiovascular (CV) events after menopause is less clear.

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Young women with PCOS have an increased risk of type 2 DM (odds ratio [OR], 4.00; 95% confidence interval [CI], 1.97-8.10), independent of age and body mass index,2 with a prevalence of 2% to 10%, depending on the population studied. These women also have a higher likelihood of developing metabolic syndrome, an aggregation of risk factors including obesity, dyslipidemia, hypertension, and glucose intolerance that increases the risk of DM and CVD. These risk factors are especially elevated in young women with the hyperandrogenic phenotype, suggesting a potential deleterious role for androgens.

A few small longitudinal studies have examined the persistence of CVD risk before menopause. In the Coronary Artery Risk Development in Young Adults study, the increased risk of DM and dyslipidemia persisted over 2 decades, with age at follow-up ranging from 38 to 50 years.3 A meta-analyses of several small studies also showed that parameters of subclinical atherosclerosis, identified as impaired flow-mediated dilation and increased carotid intima-media thickness, are worse in women with PCOS.4 However, the mean age of participants in most of the studies ranged from 20 to 30 years, with very few longitudinal studies assessing the prevalence of subclinical CVD in older women with PCOS.

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There are mixed reports in the literature, given the low prevalence of CVD in premenopausal women. A large national registry-based longitudinal study in Denmark found that young women with PCOS (median age, 29 y; follow-up, 11 y) were more likely to have CVD risk factors, including hypertension and dyslipidemia, and CVD compared with women without PCOS.5 Similarly, in a large Australian hospital database (median age of patients, 35.8 y), an increased risk of hypertensive disorder, ischemic heart disease, cerebrovascular disease, and arterial and venous disease was reported in women with PCOS compared with those without PCOS.6 However, limitations of these studies include the diagnostic criteria used; inclusion of young, relatively lean participants; and use of ICD codes to identify composite outcomes. Therefore, it is critical to follow a large cohort of women diagnosed using contemporary criteria over several decades to clearly understand the persistence of CVD risk factors and effect on CV events in all PCOS phenotypes.

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Although most symptoms of PCOS improve by the fourth decade, age at menopause may be delayed because of the higher number of antral follicles present during the reproductive years.7 How do these changes affect CVD risk in the menopause transition and beyond?

In the Study of Women's Health Across the Nation, a history of oligomenorrhea and serum testosterone levels in the highest tertile (presumed diagnosis of PCOS) conferred an increased risk of metabolic syndrome (mean age, 45.8 y), as did elevated serum testosterone alone, suggesting that hyperandrogenism may be a contributor to cardiometabolic risk. In the same cohort, those women with PCOS but without metabolic syndrome at baseline developed incident metabolic syndrome at a comparable rate to controls after a 12-year period. Further, there were no differences in the self-reported risk of myocardial infarction and stroke between the two groups.8 These findings suggest that women with history suggestive of PCOS who have no evidence of increased cardiometabolic risk factors by the perimenopause years may have a similar risk of CVD to that of controls.

A few other studies have examined the rate of CVD events in postmenopausal women with PCOS with conflicting results. In a meta-analysis including five studies (mean age, > 45 y), the risk of nonfatal stroke (OR, 1.94; 95% CI, 1.19-3.17) and coronary heart disease (OR, 1.70; 95% CI, 0.92-3.11) was increased in women with PCOS compared with controls.9 The recent Rotterdam study, a prospective cohort study of menopausal women with presumed diagnosis of PCOS (mean age, 70 y), found no association between high androgen levels and incident CVD.10 Most of these studies, however, had several limitations, including the presumed diagnosis of PCOS, assessment of serum androgens in the perimenopause period, and small study sizes. Other proposed explanations for not identifying a consistent increase in postmenopausal CV events despite high prevalence of CVD risk factors include later onset of menopause, possibly conferring a protective effect for CVD, and diminishing differences compared with controls with an increase in age in the general population.

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Postmenopausal persistence of PCOS could be considered likely with continuing evidence of hyperandrogenism or a long-term history of irregular menstrual cycles and hyperandrogenism in the reproductive years. On the basis of evidence of increased CVD risk factors in young women with PCOS, recently published international guidelines for PCOS recommend assessment of individual CVD risk factors and global CVD risk to stratify long-term risk.1 Body mass index and blood pressure should be assessed at each visit, regardless of age, and a lipid panel and assessment of glycemic status should be performed at the initial diagnosis. If normal, repeat testing every 1 to 3 years, depending on other CVD risk factors, is recommended. Lifestyle modification (preferably multicomponent including diet, exercise, and behavioral intervention) plays an important role in prevention of metabolic sequelae and is first-line treatment for PCOS. No specific diet has been shown to provide greater weight loss in PCOS, and general healthy eating principles should be followed across the life course, per general population recommendations. Metformin, an insulin-sensitizing drug, in addition to lifestyle interventions should be considered in women who are overweight or obese.1 There are no data on the use of hormone therapy, specifically in women with history of PCOS, and its effect on CVD risk.

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Women with PCOS have an increased risk of type 2 DM and other cardiometabolic risk factors during their early reproductive years, underscoring the need for regular risk assessment and management. Although there is a paucity of large prospective studies evaluating the continued CVD risk, especially related to CVD events after menopause, continued surveillance of midlife women previously diagnosed with PCOS, especially if one or more CVD risk factors are present, is recommended. Follow-up of well-defined PCOS cohorts for longer periods is essential to understanding the effect of the menopause transition on cardiometabolic risk in this population.

Financial disclosure/conflicts of interest: Dr. Alur-Gupta and Dr. Dokras each report no relevant financial relationships.

This Practice Pearl, developed by the authors, provides practical information on current controversial topics of clinical interest. It is not an official position of The North American Menopause Society (NAMS). Clinicians must always take into consideration the individual patient along with any new data published since the publication of this statement. The Practice Pearl series is coordinated by the NAMS Practice Pearl Task Force, edited by Dr. Andrew Kaunitz, and approved by the NAMS Board of Trustees.

Made possible by donations to the NAMS Education & Research Fund.

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© 2019 by The North American Menopause Society.