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EDITORIAL |
School of Medicine and Dentistry, University of Rochester, Rochester, New York 14642
Address all correspondence and requests for reprints to: David S. Guzick, Professor of Obstetrics and Gynecology, Dean, School of Medicine and Dentistry, University of Rochester, Rochester, New York 14642. E-mail: David_Guzick{at}URMC.Rochester.edu.
A perplexing conundrum has evolved in the literature regarding polycystic ovarian syndrome (PCOS): although several lines of investigation point to increased cardiovascular risk among women with PCOS, there are no convincing data showing that elevated risk translates into increased events. In this issue of JCEM, Shaw et al. (1) begin to resolve this conundrum, reporting that women with clinical features of PCOS have lower 5-yr cardiovascular event-free survival than women without clinical features of PCOS. Although the findings of Shaw et al. are not definitive because of methodological constraints, their report is important in providing the first suggestion that increased cardiovascular risk among women with PCOS indeed increases their risk of cardiovascular events.
Patients with PCOS typically have a long history of chronic anovulation in association with insulin resistance and androgen excess. Thus, they often present initially with complaints of irregular bleeding, infertility, acne, and hirsutism. Although it is important to recognize and address these immediate clinical problems, attention has also turned to the longer-term risks of diabetes (2) and cardiovascular disease (3). Across several geographic areas and ethnic groups, about 40% of women with PCOS have impaired glucose tolerance or overt type 2 diabetes (4). Moreover, women with PCOS show an adverse cardiovascular risk profile with respect to insulin resistance (5), central adiposity, dyslipidemia and hypertension (6), C-reactive protein (7), homocysteine (8), carotid intima-media thickness (9), coronary artery calcium and calcification (10, 11), endothelial function (12), and echocardiographic measures of heart disease (13). It is not surprising that women with PCOS fulfill the criteria for metabolic syndrome in 40% of cases (14).
If these markers of cardiovascular disease were at all predictive, one would expect that long-term follow-up of women with PCOS would demonstrate an increased likelihood of actual cardiovascular events. However, the evidence thus far is limited and inconsistent. In a Pittsburgh cohort of 126 Caucasian women with PCOS who were followed up for cardiovascular events for up to 12 yr, five women reported myocardial infarction, angina pectoris, and/or coronary bypass or angioplasty, whereas no events were observed among 142 control women who were similarly followed (15). Similarly, a 4-fold risk in cardiac events among women with PCOS was reported in a cohort from the Czech Republic (16). On the other hand, Pierpoint et al. (17) found no increase in the rate of deaths due to circulatory disease among a large sample of women with PCOS, relative to expected death rates based on age- and sex-specific rates of mortality in the United Kingdom. Interpretation of these data is constrained by the fact that PCOS cases were diagnosed mainly on the basis of hospital records related to wedge resection and by the absence of a matched control cohort. Wedge resection can correct the anovulation and metabolic changes that are seen in PCOS for long periods of time, and this method of case identification may under-ascertain PCOS cases as defined by clinical characteristics. Moreover, as Shaw et al. (1) point out, the United Kingdom results may in part reflect a lack of focus on women with more lengthy exposure to atherogenic risk factors.
There is a clear need for a prospective study of a large cohort of women with well-characterized PCOS who have not been surgically treated, along with an appropriate cohort of matched control women, with respect to the incidence of cardiovascular events over a prolonged follow-up period. The study by Shaw et al. (1) attempts to fill this void using a high-risk group of postmenopausal women who are undergoing angiographic evaluation for suspected ischemia as part of the Women’s Ischemia Syndrome Evaluation (WISE) study.
Among 855 WISE participants for whom data were complete, 390 were menopausal. Of these, 104 were found to have clinical features of PCOS as defined by a history of irregular menses during premenopausal years and evidence of biochemical hyperandrogenemia. Although the authors’ definition of PCOS is limited by the recall bias inherent in their measure of anovulation, and by the potential lack of correspondence between postmenopausal and premenopausal hyperandrogenemia, the identification of a subgroup of women with a PCOS-like profile provides a credible basis for estimates of cardiovascular event-free survival. Given this caveat regarding the definition of PCOS, the finding that high-risk women with clinical features of PCOS have more angiographic coronary artery disease and lower cardiovascular event-free survival is consistent with the hypothesis that the adverse profile of cardiovascular disease markers among women with PCOS translates into more cardiovascular events and shorter survival. Moreover, certain results are particularly noteworthy; for example, there appears to be an interaction between PCOS status and the inflammatory marker highly sensitive C-reactive protein (hs-CRP). Women with both PCOS and elevated hs-CRP were estimated to have a 12.2-fold higher risk of cardiovascular death (95% confidence interval = 4.3–35.0) than women without PCOS and with normal hs-CRP. As the authors point out, identification of postmenopausal women with clinical features of PCOS, especially high-risk women being evaluated for ischemia, may provide an opportunity for risk-factor intervention to prevent cardiovascular events.
In this context, the results of Shaw et al. (1) are important and should encourage longitudinal studies of well-characterized premenopausal PCOS cases and controls that can be followed into menopause. Such studies will address the hypothesis regarding elevated cardiovascular risk in PCOS more definitively and will generate estimates of the risk of cardiovascular events and mortality that can be more easily generalized to the overall population of women with PCOS. Recognition of PCOS as an independent risk factor for subsequent cardiovascular events would then justify earlier risk-factor intervention.
Footnotes
Abbreviations: hs-CRP, Highly sensitive C-reactive protein; PCOS, polycystic ovarian syndrome; WISE, Women’s Ischemia Syndrome Evaluation.
Received February 5, 2008.
Accepted February 8, 2008.
References
This article has been cited by other articles:
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  J. Hirshfeld-Cytron, R. B. Barnes, D. A. Ehrmann, A. Caruso, M. M. Mortensen, and R. L. Rosenfield Characterization of Functionally Typical and Atypical Types of Polycystic Ovary Syndrome J. Clin. Endocrinol. Metab., May 1, 2009; 94(5): 1587 - 1594. [Abstract] [Full Text] [PDF]
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 A. J. Cussons, G. F. Watts, V. Burke, J. E. Shaw, P. Z. Zimmet, and B. G.A. Stuckey Cardiometabolic risk in polycystic ovary syndrome: a comparison of different approaches to defining the metabolic syndrome Hum. Reprod., October 1, 2008; 23(10): 2352 - 2358. [Abstract] [Full Text] [PDF]
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