8.1.9 Polycystic ovary syndrome: metabolic aspects

Polycystic ovary syndrome (PCOS) is thought to be primarily a disorder that affects women during their reproductive years. The diagnostic criteria reflect ovarian dysfunction, i.e. hyperandrogenism, anovulation, and polycystic ovaries. However, women with PCOS appear to be uniquely insulin resistant, are frequently obese, and may be at risk for a variety of long-term health disorders including diabetes, cardiovascular disease, and cancers. Although the endocrine and reproductive features of the disorder improve with age, the associated metabolic abnormalities, particularly components of the metabolic syndrome, may actually worsen. This chapter will explore the pathophysiology of aberrant insulin action in women with PCOS, recognition of long-term risks, and preventive strategies.

Women with PCOS show multiple abnormalities in insulin action. Dynamic studies of insulin action have shown that women with PCOS, both lean and obese, are more insulin resistant than weight-matched control women (1). This is a defect primarily present in skeletal muscle with conflicting results in adipose tissue, and some have theorized there is selective tissue insulin sensitivity in women with PCOS, with the ovary thought to be sensitive to excess insulin functioning as a cogonadotropin to stimulate androgen biosynthesis. Early in the ontogeny of the syndrome, as in type 2 diabetes, decreased peripheral insulin sensitivity leads to increased pancreatic beta cell production of insulin that lowers glucose levels. Thus many women with PCOS have normal fasting glucose levels, but fasting and meal challenged hyperinsulinaemia (Fig. 8.1.9.1). However, this compensatory response by the pancreatic beta cell is often inadequate for the degree of peripheral insulin resistance and progressive, leading to postprandial and eventually fasting hyperglycaemia (2).

Hyperinsulinaemia and/or disordered insulin action may have an impact on the reproductive axis in multiple ways as suggested above by serving as a facilitator, in conjunction with disordered gonadotropin secretion, of both ovarian and adrenal hyperandrogenism. In vitro cultures of human PCOS thecal cells overproduce androgens in response to insulin (3). Treatment of women with PCOS with insulin sensitizers decreases both ovarian (e.g. testosterone) and adrenal (e.g. dehydroepiandrosterone sulphate DHEAS) androgens. Further evidence is provided by the inherited disorders of insulin resistance (i.e. leprechaunism, the Rabson–Mendenhall syndrome, lipodystrophies, etc.), which are characterized by both compensatory hyperinsulinaemia and hyperandrogenism in affected women (4).

Insulin excess also increases the peripheral availability of sex steroids through its suppressive effect on circulating sex hormone-binding globulin (SHBG) (5). Insulin may also act at the hypothalamus to stimulate gonadotropin production, although this has not been demonstrated well in humans. Androgens also induce insulin resistance, best illustrated by the example of female to male transsexuals who have increased insulin resistance after supplementation with androgens (6). However, the contribution of hyperandrogenism in PCOS where circulating androgen levels are well below the lower limits in males to insulin resistance is probably minimal.

Many gynaecological cancers have been reported to be more common in women with PCOS, including ovarian, breast, and endometrial carcinomas. The strongest case for an association can be made for endometrial cancer, as many risk factors for this cancer are present in PCOS, i.e. centripetal obesity, hypertension, chronic anovulation with unopposed oestrogen, and diabetes (7, 8), although the epidemiological evidence of an increased incidence with PCOS women per se is weak (9).

Women with PCOS have an increased risk for sleep apnoea and other sleep disorders, such as sleep disordered breathing with PCOS (10) (Fig. 8.1.9.2), although obesity contributes to risk. Increased risk for these disorders in PCOS has been associated with both hyperandrogenism and insulin resistance (10). Daytime sleepiness, poor sleep, or snoring should alert suspicion of a sleep disorder.

The prevalence of the disorder is debated among women with PCOS, but it is clearly elevated in patients with obesity. A recent multi-centre trial that screened over 1000 women with PCOS found that only a small fraction (5%) had elevated liver transaminases (11), comparable with that found in the U.S. population. Routine screening is probably unnecessary at this time.

The inherent insulin resistance present in many with PCOS, aggravated by the high prevalence of obesity in these individuals, places these women at increased risk for impaired glucose tolerance and type 2 DM. About 30–40% of obese reproductive-aged PCOS women have been found to have impaired glucose tolerance (IGT), and about 10% have frank type 2 DM based on a 2-hour glucose level > 200 mg/dl (12, 13). The conversion rate from normal glucose tolerance to glucose intolerance over time is low per year in the range of 3–5% (14).

There are a paucity of data showing increased or premature onset of CVD events, such as stroke or myocardial infarcation, although there is evidence of increased prevalence of CVD equivalents, such as coronary artery calcification (15). Women with PCOS tend to have multiple CVD risk factors (16) including dyslipidaemia, with lower high-density lipoprotein (HDL), and higher triglyceride and low-density lipoprotein (LDL) levels than age, sex, and weight-matched controls (17, 18) metabolic syndrome is common in women with PCOS affect a third or more (19). Centripetal obesity is the most common abnormality among women with PCOS and the metabolic syndrome (Fig. 8.1.9.3) (19). In postmenopausal women, a history of irregular menses and/or current hyperandrogenism has been associated with increased CV events (20, 21).

Evaluation should cover the multiple metabolic abnormalities present in women with PCOS (Box 8.1.9.1). A family history of diabetes and cardiovascular disease especially first-degree relatives with premature onset of cardiovascular disease is important. Additionally, PCOS clusters in families, and having sister or mother with PCOS, probably increases the risk of the disorder for other family members. Lifestyle factors, such as smoking, alcohol consumption, diet, and exercise, are particularly important in these women. An astonishingly high number of women with PCOS are either current (17%) or past smokers (22%) (11). The routine use of insulin levels in the diagnosis and management of women with PCOS is probably not indicated, as they are poor markers of insulin resistance and they have not been found to predict response to therapy.

The best long-term therapy for women with PCOS is a matter of debate, and often extrapolated from diabetes or cardiovascular prevention trials in similar populations, because such studies do not exist for women with PCOS.

The gold standard for improving insulin sensitivity in obese PCOS women should be weight loss, diet modification, and exercise. Hypocaloric diets result in appropriate weight loss in women with PCOS (arguing against any special defect in losing weight). There is no particular dietary composition that benefits weight loss, or reproductive or metabolic changes in women with PCOS (22) or in the general population (23). There have been, unfortunately, few studies on the effect of exercise alone on PCOS (24). It is reasonable to assume that exercise would have the same beneficial in type 2 DM on glycaemic parameters, though it must be tailored to the degree of obesity, and the patient’s baseline fitness. Significant weight loss without concomitant caloric reduction is unlikely.

Bariatric surgery is increasingly used in morbidly obese patients as a first line obesity therapy. The current National Institute of Health recommendations are to utilize bariaric surgery in patients with a BMI greater than 40 or with a BMI greater than 35, and serious medical co-morbidities (25). Women with PCOS appear to experience a dramatic improvement in symptoms after surgery, implying this may be in some subjects a “cure” for the syndrome (26), but to date there have been no adequate trials to assess the risk/benefit ratio.

Metformin is useful in the long-term maintenance of PCOS. Metformin does lower serum androgens, and improves ovulatory frequency (27). The Diabetes Prevention Program demonstrated that metformin can prevent the development of diabetes in high-risk populations by roughly a third (28). Metformin is frequently used in PCOS because of its favourable safety profile and the familiarity caregivers have with the medication. However, there are no long-term studies of metformin in women with PCOS to show diabetes prevention or endometrial protection. Among women with PCOS who use metformin, glucose tolerance improves or stays steady over time (29).

Metformin also may be associated with weight loss in women with PCOS (30). Metformin is often used in conjunction with lifestyle therapy to treat PCOS. Recent studies suggest that there is limited benefit to the addition of metformin above lifestyle therapy alone (31, 32). Metformin carries a small risk of lactic acidosis, most commonly among women with poorly-controlled diabetes and impaired renal function. Gastrointestinal symptoms (diarrhoea, nausea, abdominal bloating, flatulence, and anorexia) are the most common adverse reactions, and may be ameliorated by starting at a small dose and gradually increasing the dose or by using a sustained-release pill. Long term metformin use has recently been linked to Vitamin B12 deficiency through maladsorption.

Improving insulin sensitivity with these drugs is associated with a decrease in circulating androgen levels, improved ovulation rate, and improved glucose tolerance (33). However, the concern about hepatotoxicity, cardiovascular risk, weight gain, and the pregnancy effects have limited the use of these drugs in PCOS. One of the thiazolidinediones, troglitazone, was removed from the market due to hepatotoxicity, and there has been increasing scrutiny of rosiglitazone because of increased cardiovascular events.

Oral contraceptives have been the mainstay of long-term management of PCOS among gynaecologists, though there are few well designed trials specifically in PCOS. Oral contraceptives offer benefit through suppression of the ovary and by increasing SHBG levels. The “best” oral contraceptives for women with PCOS is unknown. Oral contraceptives also are associated with a significant reduction in risk for endometrial cancer with a reduction of risk by 56% after four years of use and 67% after eight years in users compared to non-users (34), as well as a significant decrease in ovarian cancer (Fig. 8.1.9.4) (35).

Individual oral contraceptives may have different doses and drug combinations and, thus, have varying risk/benefit ratios. Because women with PCOS may have multiple risk factors for adverse effects and serious adverse events on oral contraceptives, they must be screened carefully for risk factors for these events (Box 8.1.9.2). There is no evidence to suggest that women with PCOS experience more cardiovascular events than the general population when they use oral contraceptives, or that oral contraceptives increase diabetes risk. There are often adverse effects on insulin sensitivity that may be dose and drug dependent (36). Oral contraceptives may also be associated with a significant elevation in circulating triglycerides, as well as in HDL levels, although these do not appear to progress over time (37). A low dose oral contraceptive pill is therefore recommended. There is a theoretical benefit to treating hyperandrogenism with extended cycle formulations, as these are less likely to result in rebound ovarian function and likely to lead to more consistently suppressed ovarian steroid levels (38). However, there have been few studies to uphold this in practice.

Both depot and intermittent oral medroxyprogesterone acetate have been shown to suppress pituitary gonadotropins and circulating androgens in women with PCOS (39) and are thought to reduce the risk of bleeding disorders and uterine pathology, such as endometrial hyperplasia and cancer. Progestin-only oral contraceptives are an alternative for endometrial protection, but they are associated with a high incidence of breakthrough bleeding.

Ovarian drilling is primarily used for fertility, and does not appear to improve metabolic abnormalities in women with PCOS (40). Ovarian drilling may also be used to restore menstrual cyclicity in women not seeking pregnancy and there is evidence in some series of long-term improvement in menses as a result of surgery. In patients with intractable uterine bleeding who have completed their child-bearing, consideration may be given to either an endometrial ablation or more definitive surgical therapy, such as hysterectomy. The long-term risk of endometrial cancer developing in isolated pockets of endometrium after ablation remains a theoretical concern without clear data.

Women with PCOS tend to be insulin resistant, obese, and at risk for diabetes, and an adverse cardiovascular risk profile. Treatment tends to be symptom-based, with focused treatments for infertility, obesity, hirsutism, etc. Few therapies address all signs and symptoms of the syndrome. It is hoped that a deeper understanding of the genetics and pathophysiology of the syndrome will lead to more specific therapies.