Polycystic Ovary Syndrome: Not Just a Fertility Problem

“…diet and lifestyle changes have been shown not only to reduce metabolic risk factors but also to improve rates of ovulation and fertility”

Polycystic ovary syndrome (PCOS) is the commonest endocrine disorder in women which typically presents itself during adolescence and is estimated to affect up to one in five of the female population of reproductive age [1]. As its name implies, ovarian dysfunction is a prominent feature of the syndrome. PCOS is the most prevalent cause of infertility due to infrequent or absent ovulation. Another important characteristic of PCOS is excessive secretion of ovarian androgens leading to distressing cutaneous symptoms of hirsutism, chronic acne and in some cases, alopecia. But PCOS is not just a disorder that affects ovarian function, it also has consequences for long-term health and it is the established (and potential) impact of these nonreproductive effects of PCOS on metabolic and cardiovascular health that has been the focus of a considerable interest and research in the recent years.

Clinical & biochemical features of PCOS

PCOS is a heterogeneous disorder of uncertain cause but both genetic and environmental factors have been implicated in its etiology [1]. There remains controversy about the diagnostic criteria. The most widely accepted definition of the syndrome is that produced by the 2003 Rotterdam International Consensus Meeting involving experts from the European Society for Reproduction & Embryology (ESHRE) and the American Society for Reproductive Medicine (ASRM). The ESHRE/ASRM ‘Rotterdam’ criteria [2] state that to make a diagnosis of PCOS a patient should have at least two of these three features: oligomenorrhea, clinical and/or biochemical evidence of androgen excess or polycystic ovaries on ultrasonography. These criteria reflect the broad spectrum of clinical presentation of PCOS which includes women who are hirsute but have regular, ovulatory menses and, conversely, those with oligo or amenorrhea who have neither hirsutism nor raised serum androgen levels. Overweight and obesity are common in women with PCOS but it is not clear that the prevalence of obesity is greater in women with PCOS than in the general population. It may simply be that, because obesity amplifies the clinical and biochemical abnormalities of the syndrome [3], women who have PCOS and are obese are more likely to present to an endocrine, gynecology or dermatology clinic than those who are lean.

The typical biochemical findings in women with PCOS are raised serum concentrations of testosterone and, less frequently, an elevated serum level of luteinizing hormone (LH) but with a normal level of follicle-stimulating hormone (FSH). Importantly, PCOS is also associated with metabolic dysfunction, central to which is insulin resistance, and this profile has implications for long-term health [4,5]. In other words, PCOS does not just have reproductive consequences but it is also a metabolic disorder and indeed because, in many cases, the consequences of metabolic dysfunction predominate, it has been proposed that a change in name for the syndrome is long overdue [6].

Fertility & infertility

Very irregular, infrequent or absent menses are common symptoms of PCOS and may cause problems (such as heavy and prolonged periods) even in those women who are not trying to conceive. Clearly, PCOS is the predominant cause of anovulatory infertility but the population of women seen in an infertility clinic may not reflect the impact of PCOS on fertility and fecundity in the general population. Studies of the North Finland Birth Cohort of 1966 (NFBC ‘66) have provided important insight into the effect of PCOS on both reproductive and metabolic health at a population level. This population, born in the north of Finland in 1966, includes an unselected series of over 4000 women, studied longitudinally from childhood until the age of 46 years [7]. Around 20% of women within NFBC ‘66 have symptoms of PCOS. Women with PCOS present more frequently to infertility clinics (as expected) and experience a longer delay to first pregnancy (reduced fecundibility) but have one child as often as those in the reference population [8]. Family size is slightly smaller in PCOS women compared with referents but the average number of children in women with PCOS still approaches two [7]. In other words, most women with PCOS can expect to have at least one, and often two or more children, even if some require medical intervention to stimulate ovulation.

“…no study to date has shown, convincingly, that there is a greater risk of cardiovascular events in women with polycystic ovary syndrome, even in obese subjects.”

For those women who do need to seek fertility treatment, most will respond to antiestrogens, usually clomiphene citrate. Clomiphene remains the treatment of first choice [9] but a recent large RCT of the aromatase inhibitor letrozole has yielded very promising results that suggest it may have some advantages (in terms of efficacy and fewer side effects) over clomiphene [10]. In women who do not conceive after clomiphene treatment, effective alternatives are low-dose FSH or laparoscopic ovarian diathermy [9]. For the best and safest outcomes, all fertility treatments, including clomiphene, should be undertaken in specialist clinics.

Metabolic & cardiovascular impact of PCOS

With the increasing prevalence of obesity in the population, there is increasing concern about the negative effects of PCOS on metabolic and cardiovascular health. It is of course well known that obesity alone increases the risk of diabetes and cardiovascular disease but being overweight and obesity have a more profound negative impact in women with PCOS (who are more likely to be insulin resistant) than in those without. Cross-sectional, clinic-based studies of women with PCOS suggest that 30–40% of young women with the disorder have impaired glucose tolerance (IGT) and a further 5–10% have frank Type 2 diabetes mellitus (T2DM). Epidemiological studies are likely to give a more accurate reflection of the risk of IGT and T2DM in women with PCOS and results suggest that there is up to a twofold increase in risk in lean women with PCOS but an alarming three- to fourfold increase in obese women with PCOS compared with the appropriate reference population [11,12]. Not surprisingly, the risk of gestational diabetes (GDM) is also increased. A recent prospective study of pregnancies in women with PCOS in The Netherlands reported a prevalence of GDM of 22% [13] against an expected background rate of less than 5% in the general population.

The effects of PCOS on cardiovascular health are less clear-cut. Biochemical risk factors for heart disease, including dyslipidemia and elevated concentrations of inflammatory markers [14] have been widely reported. In addition, other surrogate markers of cardiovascular dysfunction, such as impaired indices of endothelial function [15], are abnormal and point to increased risk of coronary heart disease and stroke. Even so, no study to date has shown, convincingly, that there is a greater risk of cardiovascular events in women with PCOS, even in obese subjects. This may simply reflect the fact that cardiovascular disease in young or middle-aged women is uncommon and that we lack longitudinal studies of women with PCOS into the postmenopausal years. It is also possible that there are, as yet unidentified, protective factors that compensate for the apparently adverse cardiovascular risk profile. Nevertheless, it seems wise to counsel strategies for intervention in women with PCOS and additional risk factors such as obesity and abnormal lipid profile (particularly lower than normal serum levels of HDL cholesterol).

It is helpful to consider which patients with PCOS are at increased risk of metabolic and cardiovascular disease. Among the varied phenotypes defined by the Rotterdam diagnostic criteria, it is those women with the ‘classic’ presentation of PCOS as defined by the experts' meeting at the NIH in 1990, in other words, those with both oligomenorrhea and hyperandrogenism, who are most at risk. Insulin resistance and other metabolic abnormalities appear to be fewer in those women with androgen excess and regular cycles or those with anovulation and normal androgens [16,17]. But it is important to bear in mind the clinical presentation may change within an individual. For example, weight gain in a woman with hyperandrogenism but regular menses may then lead to irregular periods and, at the same time, an increase in metabolic risk factors.

What then should be the optimum management of women with PCOS in terms of preventing or reducing the risk of T2DM and cardiovascular disease [18]? First, it is important to identify those who are most at risk, in other words, those with both menstrual disorders and hyperandrogenism (clinical and/or biochemical) who are overweight or obese. A positive family history of T2DM adds to the risk. Screening should include an oral glucose tolerance test because a fasting glucose measurement together with HBAlc is a poorer predictor of IGT or T2DM in women with PCOS than in the general population. There are no clear guidelines about how often an OGTT should be repeated but an annual assessment for those at highest risk of IGT (i.e., obese with a positive family history) seems sensible. For those at risk but without overt IGT or T2DM, diet and lifestyle changes have been shown not only to reduce metabolic risk factors but also to improve rates of ovulation and fertility. In women who already have IGT or T2DM, lifestyle changes may also be effective but there is an increased likelihood of the requirement for medication. Metformin has been used extensively in women with PCOS and often as a first-line treatment for symptoms of anovulation or androgen excess. But although metformin may have a minor benefit in improving menstrual regularity, it is neither an effective fertility drug nor a useful treatment for hirsutism. It is, however, of proven efficacy in reducing the rate of conversion from IGT to T2DM [19] and is therefore important in those women with PCOS and IGT who have not responded well to modulation of diet and lifestyle.

In summary, PCOS is very common endocrine disorder with a well-known impact on ovarian function but it is not just a reproductive disorder. Women with PCOS are at increased risk of diabetes and, potentially, heart disease and so it is important to recognize, as early as possible (and that may be in the teenage years), those who are particularly prone to problems with long-term health.