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PCOS is extremely common, estimated to occur in 3%-7% of women of reproductive age.^1,2 Because of the heterogeneous nature of the disorder, there is no universal consensus on the diagnostic criteria for PCOS. However, the classic features of the syndrome are well established and include chronic anovulation and hyperandrogenism (with or without skin manifestations). In most women, characteristic polycystic ovaries will be observed on ultrasonography. The criterion of enlarged ovaries, with 8-10 peripherally oriented cystic structures in a single sonographic plane,³ is best detected with the use of a vaginal probe. While many affected women are of normal body weight, obesity is common, as is the tendency to gain weight easily. However, there is less agreement about the diagnosis of PCOS in women who are ovulatory, and the relevance of isolated ultrasonographic findings in asymptomatic women is uncertain.

The high prevalence of PCOS and its potential for causing significant morbidity⁴ has prompted investigators to call this syndrome a disorder for the "generalist".² Heightened awareness and early diagnosis provide the opportunity to intervene and thus prevent certain sequelae of the disorder. The Figure provides a crude depiction of the risks associated with PCOS from the time of early diagnosis (by 20 years of age) throughout life. Reproductive concerns, which begin in the second to third decade, relate to infertility because of anovulation and increased pregnancy wastage, as well as the risks of endometrial disease (hyperplasia and cancer) and probably also ovarian cancer. Dysfunctional uterine bleeding and skin manifestations of androgen excess (acne, hirsutism) are also causes for concern. Among the many diseases associated with PCOS and shown in the Figure, breast cancer, although it has been suggested,⁵ has not been included because there are no supporting data.

Metabolic risks, particularly in obese women, increase by the time women reach their mid-30s. Diabetes has been found to occur in 7.5% of women with PCOS in this age group, and impaired glucose tolerance in 31%.⁶ Cardiovascular risks include dyslipidaemia, hypertension, atherosclerosis, and an increased risk of myocardial infarction,⁴ although mortality per se may not be increased, except in women with diabetes.⁷ Cardiovascular risks have been most closely linked to abnormalities of insulin action.

Insulin resistance has been found to occur in most women with PCOS and is more severe in obese women and in those with greater menstrual irregularity.¹ The insulin resistance in PCOS may also be associated with -cell dysfunction, as occurs in type 2 diabetes.⁸ Insulin resistance in PCOS, although often subtle, has been found consistently and has been implicated as the proximate instigating factor leading to the complications of the syndrome (from endometrial disease to dyslipidaemia, hypertension and atherosclerotic cardiovascular disease).

It is generally thought that if insulin status can be normalised many of the clinical manifestations of the disorder, as well as the associated risks, may be eliminated. Certainly, the characteristic symptoms of PCOS in one young woman with an insulinoma were seen to dissipate when the tumour was removed.⁹ Reductions in insulin resistance have been shown to normalise hormonal abnormalities (luteinising hormone, androgens) and restore normal menstrual function as well as ovulation in some women with PCOS.

In this issue of the Journal, Norman and colleagues review data on the use of metformin in PCOS.¹⁰ This article, on behalf of the Endocrine Society of Australia, the Australian Diabetes Society and the Australasian Paediatric Endocrine Group, is timely in bringing attention to the metabolic aspects of this very common disorder. The authors stress the importance of screening all patients for diabetes, as well as taking note of additional cardiovascular risk factors. In general, as suggested by the authors, lifestyle modifications should be the cornerstone of any therapy for PCOS.¹¹

The review by Norman et al is comprehensive, but there are even more data emerging in the literature. Metformin is generally well tolerated, apart from the gastrointestinal disturbance, which precludes its use in some women. Consistent with the view of Norman et al, metformin is considered to be most appropriate as a short-term measure to improve ovulatory function (with or without ovulation-inducing agents) in women seeking fertility. It has been suggested that metformin may also help in reducing the high pregnancy wastage which is characteristic of PCOS.¹² However, there is less consensus about its long-term use. While metformin is increasingly being used as an adjunct for weight loss¹³ and to prevent the development of diabetes in high-risk individuals, there are no data at present to support this preventive strategy. There is also uncertainty about how best to monitor patients who are taking metformin. Norman et al have suggested measuring "clinically useful endpoints".¹⁰ While this is a logical approach, it is not known which measurements, if any, correlate with the benefits of metformin treatment. Moreover, it is difficult to assess insulin resistance in PCOS with simple, non-invasive outpatient tests.

Unlike the thiazolidinediones, metformin is not a true insulin-sensitising agent. However, metformin has been reported to give similar results in terms of ovulatory function to those with the thiazolidinedione troglitazone. This product has been withdrawn from the US market because of hepatic toxicity. Other thiazolidinediones (rosiglitazone and pioglitazone) may be useful but do not facilitate weight loss. A more natural product, D-chiro-inositol, which works as a second messenger for insulin, is well tolerated and offers promise as a new medication for potential long-term use.¹⁴

As noted above, there are hyperandrogenic women with polycystic ovaries who have normal menstrual cycles. These women may also be considered to have PCOS, although there is no clear consensus on this issue. In general, such women have less severe insulin resistance, and may be at reduced risk of developing the morbid sequelae of PCOS, although there are no definitive data on this. There is currently a dilemma about characterising completely asymptomatic women who have polycystic ovarian morphology only. This ovarian finding may occur in 16%-20% of the normal population. Recent data suggest that some women exhibit subtle abnormalities (such as low high-density cholesterol levels and mild insulin resistance),¹⁵ suggesting that, while the risk is probably low, this phenotype may also require close monitoring over time.

Although the cause of PCOS remains elusive, it can no longer be denied that it is a metabolic syndrome with associated morbidities which are reproductive, metabolic and cardiovascular in nature. Early diagnosis and monitoring throughout life is imperative. While low-dose oral contraceptives have a beneficial role earlier in life and can prevent excess risk of ovarian and endometrial cancer, screening for diabetes, dyslipidemia and cardiovascular disease assumes importance by the fourth decade. Diet and exercise are of paramount importance life-long, and medications to correct insulin abnormalities are considered important adjuncts which may prove to be a mainstay of management.

Rogerio A Lobo
Chairman
Department of Obstetrics and Gynecology
Columbia University College of Physicians and Surgeons and
New York Presbyterian Hospital, New York, NY, USA

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13. Pasquali R, Gambineri A, Biscotti D, et al. Effect of long-term treatment with metformin added to hypocaloric diet on body composition, fat distribution, and androgen and insulin levels in abdominally obese women with and without the polycystic ovary syndrome. J Clin Endocrinol Metab 2000; 85: 2767-2774.
14. Nestler JE, Jakubowicz DJ, Reamer P, et al. Ovulatory and metabolic effects of D-chiro-inositol in the polycystic ovary syndrome. N Engl J Med 1999; 340: 1314-1320.
15. Chang PL, Lindheim SR, Lowre C, et al. Normal ovulatory women with polycystic ovaries have hyperandrogenic pituitary-ovarian responses to gonadotropin-releasing hormone-agonist testing. J Clin Endocrinol Metab 2000; 85: 995-1000.

©MJA 2001
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