Uncertainty Remains in Women with PCOS Regarding the Increased Incidence of Cardiovascular Disease Later in Life, Despite the Indisputable Presence of Multiple Cardiovascular Risk Factors at a Young Age

It is increasingly recognized that crucial gender differences exist in heart disease, with men being at higher cardiovascular (CV) risk, especially at a young age. It is generally accepted that women often suffer most from the burden of CV disease after menopause (1), which has been attributed to a safer hormonal environment before menopause. However, as elegantly suggested recently, in women the CV risk increases exponentially with age with no specific increase after natural menopause (2). This further emphasizes the need for the early recognition of risk factors and for developing secondary prevention strategies in women. It has recently become apparent that multiple disease conditions in obstetrics and gynecology [such as pregnancy-induced hypertension (PIH), polycystic ovary syndrome (PCOS), but also hypothalamic amenorrhea, primary ovarian insufficiency, and early menopause] are associated with increased CV risk. Moreover, increased CV disease has been convincingly demonstrated for both PIH and primary ovarian insufficiency (3, 4). Much controversy remains regarding the many clinical issues associated with the enigmatic PCOS. Ongoing debate as to whether hyperandrogenemia should remain the hallmark for diagnosis has rendered the 2003 Rotterdam consensus criteria for PCOS diagnosis one of the most frequently cited papers in the (short) history of clinical reproductive medicine (5). Until recently, interest has focused mainly on infertility treatment of anovulatory PCOS (6). In more recent years, however, overall attention has shifted toward the more frequent occurrence of pregnancy complications in PCOS, such as gestational diabetes and PIH (7). Moreover, a wealth of literature—mostly published in this journal—has established the presence of metabolic abnormalities in the daughters of women with PCOS (8–10), with increasing claims for the need to treat such adolescent girls with multiple drugs such as flutamide, metformin, and pioglitazone (11). The diagnosis of the notoriously heterogeneous PCOS is based on three features, i.e. menstrual cycle abnormalities, polycystic ovaries, and hyperandrogenemia. In addition, many of these women are obese and present with impaired glucose tolerance (even in lean PCOS). Numerous studies have now established beyond any doubt that women with PCOS exhibit multiple CV risk factors such as impaired glucose tolerance, type 2 diabetes and the metabolic syndrome (12), dyslipidemia (13), and other CV risk markers such as C-reactive protein, homocysteine, TNF-α, and many others (14). Relatively few and small sample size studies have suggested subclinical arterial disease in women with PCOS, such as abnormal carotid intima media thickness or coronary artery calcification (15). The metabolic syndrome is associated with a 2-fold increase in CV disease and a 1.5-fold higher all-cause mortality, as demonstrated by a recent systematic review involving 87 studies and a total of almost 1 million patients (16). Based on the above-mentioned observations, firm position statements have been generated by the Androgen Excess Society—again published in JCEM—recommending that every woman with PCOS should undergo a 2-h glucose tolerance test and “should be rescreened at least once every 2 yr” (17). A subsequent paper by the same society recommends the assessment of CV risk and prevention of CV disease in women with PCOS by lifestyle management and “adding insulin-sensitizing and other drugs if dyslipidemia or other risk factors persist” (18). In contrast, others conclude that data suggesting increased CV disease in PCOS are weak and question whether screening and risk reduction are feasible (19). It seems reasonable to assume that lifelong metabolic dysfunction—often observed in women with PCOS—will predispose for CV disease with aging. So far, limited studies aimed to investigate the true occurrence of CV disease and/or death in women with PCOS. A first long-term follow-up of 33 women with PCOS aged 40 to 59 yr (originally diagnosed by ovarian morphology some 25 to 35 yr earlier), performed by Dahlgren et al. (20), suggested a 7-fold increased risk for myocardial infarction based on the observed frequent occurrence of hypertension and diabetes. Indeed, a recent systematic review and meta-analysis examining five controlled observational studies (two prospective and three retrospective) addressing the risk of CV disease and stroke in PCOS found an increased relative risk of 2 (21). However, a further follow-up of the same cohort of Swedish women with PCOS, now between 61 and 79 yr of age [and 21 yr after the initial follow-up study from 1987 (20)] published in the current issue of the JCEM (22) suggests no increased myocardial infarction, stroke, or mortality despite the higher prevalence of hypertension and dyslipidemia. These are convincing data, despite the fact that the limited number of subjects involved does not allow us to detect subtle differences in CV events. Establishing a relationship between abnormal biochemical markers at a young age and CV disease decades later is not an easy task. PCOS diagnosis and screening usually occur in women between 20 and 30 yr of age, and true CV events rarely occur before age 50. In addition, assessing PCOS later in life is a challenge, and the PCOS phenotype after menopause remains uncertain. Hence, most published studies are retrospective, with the usual uncertainties around initial diagnosis, the long duration of follow-up and loss to follow-up, small sample size, characteristics of the control group, and accuracy of events diagnosed at later ages. The obvious approach to improve future female CV health is to identify women at risk at a relatively young age and design multidisciplinary strategies for CV disease prevention. It so happens—as mentioned earlier—that obstetricians and gynecologists see various patient categories that may be at risk for developing CV disease later in life. Various societies (including The Endocrine Society and the European Society of Endocrinology) are currently developing guidelines for screening and follow-up of such women at risk. In this context, the continued inconclusive evidence for increased CV morbidity and mortality in PCOS generates a true dilemma. Why expose young women to costly and complex screening and medication regimens for many years—as proposed by some—if their true disease risk remains enigmatic, and how can the efficacy of such approaches ever be evaluated? The ongoing controversy around the increased occurrence of CV events in PCOS despite the presence of many risk factors at a young age also raises more general fundamental questions concerning female CV health and disease. Could it be that the added CV risk associated with metabolic dysfunction in PCOS is counterbalanced by additional protective factors? And if so, which are those factors? Possible candidates would be: hyperandrogenemia, absence of cyclic endogenous estrogen and/or progesterone rises, or delayed natural menopause. We need to understand a lot more in relation to CV risk and disease in women diagnosed with PCOS before widespread CV follow-up and CV disease prevention programs (especially involving multiple medication regimens such as antiobesity drugs, insulin sensitizers, statins, or glucagon-like peptide agonists) can be recommended. Practice guidelines should be evidence-based. Of course, in Western societies, more focus on exercise and diet is always good, especially in obese young women, regardless of being diagnosed with PCOS or not. Cardiovascular polycystic ovary syndrome pregnancy-induced hypertension. Disclosure Summary: The authors have nothing to declare.