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Editorial |
British Heart Foundation Glasgow Cardiovascular Research Centre (N.S.), University of Glasgow, Glasgow G12 8TA, Scotland, United Kingdom; and Reproductive and Maternal Medicine (S.M.N.); University of Glasgow, Glasgow G31 2ER, Scotland, United Kingdom
Address all correspondence and requests for reprints to: Naveed Sattar, Professor of Metabolic Medicine, British Heart Foundation, Glasgow Cardiovascular Research Center, University of Glasgow, Glasgow G12 8TA, Scotland, United Kingdom. E-mail: nsattar{at}clinmed.gla.ac.uk.
The potential long-term metabolic and vascular consequences of polycystic ovarian syndrome (PCOS), the commonest reproductive endocrine disorder of women, continue to attract considerable interest. There have been numerous reports of perturbances in a range of potential vascular risk parameters in this condition. It is now well appreciated that women with PCOS as a group appear more insulin resistant for a given body mass index (BMI) and, linked to this, are at increased risk of glucose intolerance. They also display slightly raised triglyceride and lower high-density lipoprotein-cholesterol levels compared with women without PCOS and, in concert with this dyslipidemic pattern, exhibit a greater preponderance of smaller denser low-density lipoprotein particles (1). Modest elevations in inflammatory parameters such as C-reactive protein (CRP) (2, 3), indicating subclinical inflammation and independent of degree of obesity, have also been noted in PCOS. Additionally, affected women exhibit endothelial dysfunction in both micro- and macrovasculature (4), perturbation of fibrinolytic pathways (5), and subclinical atherosclerosis (6). Thus, the general thrust of evidence favors an enhanced vascular risk in women with PCOS.
In this issue of JCEM, Heutling et al. (7) report yet another perturbance in a novel vascular risk parameter in women with PCOS. These investigators measured circulating asymmetric dimethylarginine (ADMA) levels in 83 women with PCOS, comparing results with data from 39 controls without PCOS. ADMA is a potent endogenous inhibitor of endothelial nitric oxide synthase, and accordingly, higher ADMA levels correlate to lower NO formation and endothelial dysfunction. The authors show that ADMA levels are not only significantly higher in women with PCOS but that they also correlate to BMI and fasting insulin in affected women. Moreover, in the subgroup of women treated with metformin, ADMA levels decreased significantly independent of a reduction in BMI, with a concurrent improvement in carotid intima-media thickness (IMT). These latter results, although of interest, should be examined with caution because the number of women receiving metformin was small (n = 21), and duration of treatment was short. Moreover, there was no placebo arm, and the IMT findings have not been replicated in non-obese PCOS (8) and may be solely attributable to weight loss (9).
Consequently, although of potential great interest, there is a need to put both the current study and many previous similar studies relating PCOS and cardiovascular risk factors into a clinical context. With respect to the current report, although ADMA has been linked independently to risk for incident vascular events, the prospective data are limited to a few relatively small studies (most having <150 incident vascular events), and thus confidence intervals have been large. Moreover, the majority of such studies have been conducted in individuals with existing vascular disease (10, 11). In one of the largest studies in terms of number of events (n = 182), patients in the top quarter of ADMA levels at baseline had an adjusted hazard ratio of 1.70 [95% confidence intervals (CI), 1.02–2.88] for incident major cardiovascular events (10). This hazard ratio, achieved with incomplete consideration of all established coronary heart disease (CHD) risk factors with no adjustment for high-density lipoprotein-cholesterol, is in fact relatively modest and suggests ADMA levels may not necessarily enhance CHD risk prediction beyond established risk factors. On the basis of predictive studies employing receiver operating characteristics analyses or equivalent, many other novel risk factors also fail to significantly enhance risk prediction (12). Indeed, even the value of CRP for risk factor stratification is now increasingly questioned (13).
Nevertheless, if we accept that many risk factors are perturbed in women with PCOS, and that vascular risk is elevated, to what extent does this translate into more frequent or earlier events, thereby providing a rationale if any for screening? The definitive answer is unfortunately lacking because there have been no adequately powered prospective epidemiological studies with the requisite baseline phenotyping. However, analysis of the contribution from the relative components of the diagnosis of PCOS is helpful in this respect. In a long-term follow-up study of 786 women diagnosed with PCOS, primarily based on ovarian wedge resection histopathology, there was no significant increased risk of death from cardiovascular-related causes after an average follow-up of 30 yr (14). Although this finding was confirmed in a subsequent study of a subgroup of 319 women with better defined PCOS (15), an excess of nonfatal cerebrovascular events (PCOS, 13 of 319; controls, 10 of 1060) despite adjustment for BMI was evident (odds ratio 3.4, 95% CI 1.2–9.6). Similarly, with respect to hyperandrogenism per se, the association with cardiovascular disease in women is weak. Perhaps the best indication of CHD risk in PCOS comes from a study by Solomon and colleagues (16). In a prospective cohort of 82,439 female nurses, they linked history on prior menstrual regularity (at ages 20–35 yr) in 1982 to subsequent CHD endpoints over 14 yr of follow-up. There were 1417 incident cases of CHD. Compared with women reporting a history of very regular menstrual cycles, women reporting usually irregular or very irregular cycles had an increased risk for nonfatal or fatal CHD [age-adjusted relative risks 1.25 (95% CI 1.07–1.47) and 1.67 (95% CI 1.35–2.06), respectively]. Importantly, the increased risk for CHD associated with very irregular cycle group remained significant (relative risk 1.53, 95% CI 1.24–1.90) after adjustment for BMI and several potential confounders inclusive of age, smoking, parity, and menopausal status. Although chronic anovulation and cycle irregularity can be heterogeneous in origin, approximately 80–90% of women with very irregular cycles are likely to have PCOS. Accounting for this, the data suggest that PCOS is associated with approximately a 50% increased risk for CHD compared with age- and BMI-matched women without PCOS. However, the absolute risk for vascular events in the majority of women with PCOS will remain extremely low due to both young age and female gender. This point cannot be overemphasized because absolute rather than relative risks must influence clinical decision making.
Given this low incidence of events and relative mild excursions of risk factors, it could easily be argued that widespread risk factor screening for CHD risk in women with PCOS is not warranted. Although we appreciate that clinicians may feel that prior knowledge of cardiovascular risk factors may be a strong motivational factor for patients and facilitate maintenance of lifestyle modification, there is limited evidence for this, both in terms of practicality and cost-effectiveness. Consequently, formal CHD risk screening using conventional methods, e.g. Framingham risk score, should be restricted to women with significant other risk factors such as those with early-onset diabetes, or a strong family history of premature vascular disease.
A similar argument pertains to screening for diabetes in women with PCOS, although the evidence for a link is stronger. Again, the Nurses’ Health Study II provides the best data with 507 events of type 2 diabetes in a cohort of 101,073 women, with women with very irregular cycles having a relative risk of 2.08 (95% CI 1.62–2.66), adjusting for BMI at age 18 yr and several other potential confounding variables (17). Therefore, although this relative risk is modestly increased, the absolute risk is again on the whole low. Targeting screening with a formal oral glucose tolerance test of women with PCOS who are potentially at greatest risk, namely the obese, those with a family history of diabetes or who have raised fasting glucose (perhaps >5.5 mmol/liter) may again be the most cost-effective strategy. Indeed, the vast majority of women with PCOS studied by different groups who had impaired glucose tolerance or frank diabetes had BMI greater than 30 kg/m2, and frank diabetes by oral glucose tolerance test was rare if fasting glucose was less than 5.5 mmol/liter in the series reported by Legro and colleagues (18). Although we appreciate that insulin resistance is widely prevalent in PCOS, whether there is merit in identifying solely impaired glucose tolerance is debatable, because surely all overweight women with PCOS should be given similar lifestyle advice, and although metformin has been shown to reduce the risk of diabetes in those with impaired glucose tolerance (19), it is not currently licensed for this indication. Clearly, the best methods of screening for diabetes and whether metformin can facilitate risk reduction in women with PCOS requires further study.
Finally, what are we to make of the reduction in ADMA with metformin, albeit from an uncontrolled trial? Of course, metformin therapy has been widely explored in women with PCOS for a number of indications, often related to fertility, and has been widely used. It should be noted, however, that two recent prospective randomized trials and metaanalysis have concluded that metformin achieves little or no benefit in fertility treatments for PCOS (20, 21). Correspondingly, short-term use of metformin in PCOS may decline, and protracted use of the drug is not recommended by any authoritative organization. But in reality, because metformin is relatively cheap and safe, many women with PCOS are probably receiving protracted treatment, despite ill-defined metabolic and vascular benefits in this group. Metformin is of course a first-line treatment for individuals with type 2 diabetes on the basis of results from the UK Prospective Diabetes Study (22); metformin was the only treatment to significantly lower myocardial infarction risk and did so apparently independently of glycemic effects (22). Outside of diabetes, there is no endpoint trial data or indeed robust long-term surrogate atherosclerosis progression studies with metformin in nondiabetic subjects. Although benefits of metformin on a range of risk factors such as ADMA or CRP, or indeed on directly assessed endothelial function, are of interest, these studies merely function as pilot data stimulating the need for more formal randomized placebo-controlled trials to test for vascular protection. In the short term, such trials could use the Food and Drug Administration-acceptable surrogate for atherosclerosis: progression of ultrasound-determined common carotid artery IMT. These trials should also, if possible, include a third lifestyle arm and incorporate quality of life questionnaires and weight measurements as outcomes as well as include safety and economic evaluations. Of course, such work would require multicenter trials, but these have been shown to be possible in this group of patients. In the absence of large, adequately powered placebo-controlled trials, it is difficult to see how we can provide useful answers about the longer-term benefits (or otherwise) of metformin in women with PCOS.
Footnotes
Abbreviations: ADMA, Asymmetric dimethylarginine; BMI, body mass index; CHD, coronary heart disease; CI, confidence interval; CRP, C-reactive protein; PCOS, polycystic ovarian syndrome.
Received November 8, 2007.
Accepted November 9, 2007.
References
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