eMJA: Kidson, Polycystic ovary syndrome: a new direction in treatment

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Polycystic ovary syndrome: a new direction in treatment

Warren Kidson

MJA 1998; 169: 537-540

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Abstract - Introduction - Insulin resistance in the polycystic ovary syndrome - Polycystic ovaries and the "metabolic syndrome" - Diabetes therapies in the polycystic ovary syndrome - Managing polycystic ovary syndrome - Conclusion - References - Authors' details
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Abstract

Polycystic ovary syndrome is a diagnosis made in 5%-10% of women between late adolescence and the menopause. Patients may present with oligomenorrhoea or amenorrhoea, anovulation or infertility, hirsutism or acne.

Women with the syndrome have at least seven times the risk of myocardial infarction and ischaemic heart disease of other women, and by the age of 40 years up to 40% will have type 2 diabetes or impaired glucose tolerance.

Polycystic ovary syndrome is associated with insulin resistance, with consequent hyperinsulinaemia and (frequently) hyperlipidaemia and obesity.

Recent research has shown that the application of diabetes management techniques aimed at reducing insulin resistance and hyperinsulinaemia (such as weight reduction and the administration of oral hypoglycaemic agents) can not only reverse testosterone and luteinising hormone abnormalities and infertility, but can also improve glucose, insulin and lipid profiles.

The management of polycystic ovary syndrome should now include patient education and attention to diabetes and cardiovascular risk factors such as hyperlipidaemia, obesity, physical exercise, glucose intolerance, hypertension and cigarette smoking.

Introduction

The finding of polycystic ovaries on ultrasound is not an unusual one, occurring in 21% of premenopausal women in population surveys.¹ Polycystic ovaries are due to incomplete follicular development or to failure of ovulation, and are therefore often seen in women with bulimia, recovery from anorexia nervosa, conditions of increased adrenal androgen production and hyperprolactinaemia.² In early to mid adolescence, the ultrasound finding of polycystic ovaries is common and not regarded as abnormal, presumably because of the high prevalence of non-ovulatory cycles at this age.

Polycystic ovary syndrome, which affects 5% to 10% of premenopausal women,^3,4 is one of the most common endocrinopathies of women. It consists of at least two of the following features: polycystic ovaries, hyperandrogenism and anovulation (see Box 1).

The classic therapy for symptoms of hyperandrogenism (such as hirsutism and acne) was to suppress ovarian testosterone production with an oral oestrogen/progestogen contraceptive, often with the addition of the antiandrogenic progestogen cyproterone acetate. Infertility and anovulation are usually treated with clomiphene citrate, gonadotropins or laparoscopically applied physical therapies to the ovaries, such as laser or diathermy.^12-14 Open wedge resection of ovaries is rarely used because of the risk of obstructive infertility from adhesions.

Insulin resistance in the polycystic ovary syndrome

In a study of women with polycystic ovary syndrome performed 18 years ago, most were found to be hyperinsulinaemic and to have a glucose metabolism that was resistant to the stimulatory effects of insulin.¹⁵

The insulin resistance in type 2 diabetes and polycystic ovary syndrome occurs mainly in muscles,¹⁶ but also in the liver in obese women with polycystic ovary syndrome.¹¹ Insulin resistance is aggravated by physical inactivity, upper abdominal obesity, hyperandrogenism, pregnancy, the ageing process and by medications such as thiazide diuretics, corticosteroids and certain hormonal steroid preparations. Insulin resistance in polycystic ovary syndrome is not due primarily to obesity (as lean women with polycystic ovary syndrome are insulin resistant) or to hyperandrogenism¹⁷ (as androgen blockade reduces insulin resistance by only 10%-15%).¹⁸

Insulin resistance leads to hyperinsulinaemia as pancreatic insulin secretion rises to maintain normoglycaemia. Hyperinsulinaemia can then stimulate lipid storage, altered lipoprotein and cholesterol metabolism and (possibly) altered steroid hormone metabolism. Hyperinsulinaemia increases ovarian androgen production¹⁹ by stimulating an ovarian enzyme complex cytochrome P450c17, either directly and/or by stimulating pituitary luteinising hormone secretion.

Box 2

The accurate measurement of insulin resistance is an expensive, labour-intensive research technique. The easiest, but least sensitive, measure of insulin resistance is fasting serum insulin, with values between 10 and 14 mU/L (72-100 pmol/L) indicating mild insulin resistance and values above 14 mU/L indicating moderate or severe insulin resistance. As fasting serum insulin values lie in the least sensitive range of the immunoassay curve, fasting serum insulin is more accurate if a mean of three specimens taken over 10 minutes is used. The insulin assay should have no cross-reactivity with proinsulin.

Insulin resistance can also be assessed by the serum insulin response to an oral glucose load during an oral glucose tolerance test, peak serum insulin levels above 100 mU/L (718 pmol/L) being highly suggestive of insulin resistance. As most women with polycystic ovary syndrome should have a glucose tolerance test, serum insulin can be measured on three fasting specimens, as well as at one and two hours, so that both parameters of insulin resistance can be assessed.

Various measures of insulin resistance in polycystic ovary syndrome have recently been studied, and the ratio of fasting insulin (mU/L) to fasting glucose (mmol/L) has been found to be a simple and accurate indicator of insulin resistance (sensitivity 95%, specificity 84%, positive predictive value 87% and negative predictive value 94%) at values above 4mU/mmol.²⁰

Polycystic ovaries and the "metabolic syndrome"

Over the past decade, studies have shown that women with polycystic ovary syndrome have a high prevalence of hyperlipidaemia,^5-7 hypertension,⁸ and progression to type 2 diabetes mellitus,¹¹ similar to the features of the so-called "metabolic syndrome" or "syndrome X".

Of greatest concern is an estimate that the relative risk of myocardial infarction in women with polycystic ovary syndrome is 7.4 times that of other women.⁹ An ovarian ultrasound study found that 46% of women undergoing coronary angiography for ischaemic heart disease before the age of 60 years had polycystic ovaries and that the degree of coronary narrowing was greater than in the remaining 54%.¹⁰ Assuming a prevalence rate of polycystic ovary syndrome of 10%, I calculate the relative risk of premature ischaemic heart disease in polycystic ovary syndrome in this study was 7.7.

Diabetes therapies in the polycystic ovary syndrome

The growing body of evidence linking polycystic ovary syndrome to an inherited resistance to insulin action, aggravated by lifestyle problems such as obesity, poor diet and physical inactivity (such as happens with type 2 diabetes mellitus), has led to trials of diabetic therapies in patients with the polycystic ovary syndrome. Many studies, not all referenced in this article, have demonstrated that the lifestyle measures of diet and weight reduction can not only lower insulin levels and reduce hyperlipidaemia, but can lower androgen and luteinising hormone levels, restore regular menstruation and ovulation and hence improve fertility.^21-23 Regular physical exercise is often recommended,²⁴ but has been poorly studied and documented, despite its apparent efficacy.

Four trials (two controlled and two uncontrolled) of metformin, a diabetes medication that reduces insulin resistance, have demonstrated a fall in serum androgens, luteinising hormone and weight and an improvement in fertility and fibrinolysis in both obese and lean women with polycystic ovary syndrome.^19,25-27 Two studies have shown no improvement with metformin.^28,29 The women in the first of these two studies were Turkish, which may have influenced the result as it is known that many intracellular enzyme defects can lead to insulin resistance and that the nature of insulin resistance can vary between racial groups. In the second negative study, the diet of the subjects was modified to prevent weight loss during metformin therapy.

A recent controlled trial was performed in the United States, Venezuela and Italy in which obese women with polycystic ovary syndrome were given either metformin or placebo.³⁰ Women in both groups who had not ovulated by Day 35 were given clomiphene as additional medication. By Day 35, 34% of women taking metformin had ovulated, compared with only 4% of the placebo-treated women (P < 0.001). Within 18 days after the addition of clomiphene, 90% of the remaining women taking metformin ovulated, compared with 8% of the placebo-treated women (P < 0.001). In summary, within 53 days only 7% of women treated with metformin or metformin plus clomiphene had not ovulated, compared with 88% of women treated with clomiphene alone.

Troglitazone, another diabetes medication, has been demonstrated to improve insulin sensitivity and to lower serum insulin, androgen and luteinising hormone levels without causing weight loss in two studies.^31,32

A recent Lancet editorial on the use of insulin-sensitising agents in polycystic ovary syndrome concluded that "confirmation of the beneficial effects of metformin on hormonal and metabolic variables in women with polycystic ovary syndrome will have implications not only for the treatment of the common gynaecological presenting features, but also for the burden of vascular disease in women".³³

Managing polycystic ovary syndrome

Glucose tolerance testing and lipid measurements

Most women with polycystic ovary syndrome should have an oral glucose tolerance test at diagnosis and at five-yearly intervals thereafter, and measurement of fasting lipids at diagnosis and at two- to three-yearly intervals. The exception would be a woman aged less than 20 who is not overweight and who does not have a family history of diabetes mellitus, gestational diabetes or large birth weight.

A considerable number will be found to have impaired glucose tolerance or mild type 2 diabetes. The measurement of serum insulin in the fasting state and at one and two hours will detect most insulin-resistant women.

The parents of the woman with polycystic ovary syndrome should also have glucose tolerance tests. Her siblings' glucose tolerance should be assessed if a parent is shown to be diabetic.

Lifestyle changes

Obesity should be treated with a structured diet and exercise program,³⁴ with appropriate dietary modification for the woman with hyperlipidaemia. Simply telling a patient to "lose weight" or "eat less" is unlikely to result in a significant reduction in weight, judging from experience in the management of type 2 diabetes. Consultation with dietitians working in type 2 diabetes or commercial weight reduction programs may be useful in refractory obesity.

Hyperlipidaemia persisting after dietary modification and weight reduction may require drug therapy.

Cigarette smoking should be vigorously discouraged in all women with polycystic ovary syndrome as it will exacerbate the increased risk of atherosclerosis. Cigarette smoking has recently been shown to aggravate insulin resistance in type 2 diabetes mellitus.³⁵

Attempts to reduce weight, increase exercise and stop smoking will fail if the woman with polycystic ovary syndrome is not educated about the long term adverse health implications of this condition. Too often these women are told only about the cosmetic nuisances of hirsutism or acne.

Oral contraceptives

Oral contraceptives reduce acne and hirsutism by inhibiting ovarian steroid production, including androgens, and by suppressing pituitary follicle stimulating hormone and luteinising hormone secretion. The effect is dependent on the oestrogen dose in the contraceptive.

Oral contraceptives are also used to effect secretory change in the endometrium and reduce the suggested, but unproven, increased risk of endometrial carcinoma in polycystic ovary syndrome.^36,37 Any therapy that results in regular ovulation, however, should reduce the risks of endometrial carcinoma.

A recent uncontrolled study of 16 non-diabetic hyperandrogenic women treated with a combined oral contraceptive containing 150 µg of desogestrel and 30 µg of ethinyloestradiol demonstrated a significant deterioration in glucose tolerance over six months, with two women developing frank diabetes.³⁸ This raises doubts about the short and long term safety of ovarian suppression in polycystic ovary syndrome with oral contraceptives. The effects of individual oral contraceptives on glucose tolerance will now need to be studied specifically in polycystic ovary syndrome before their use can be advocated.

The use of a "triphasic" combined oral contraceptive should be avoided as the early cycle ethinyloestradiol dose is often too low to inhibit dominant follicle selection and hence follicular development,³⁹ theoretically having the potential to increase, rather than reduce, the number of ovarian cysts.

Androgen-blocking drugs

Spironolactone and cyproterone acetate preparations are generally equally effective in the treatment of hirsutism and acne, with occasional patient differences in response.

Spironolactone generally does not cause weight gain and slightly reduces insulin resistance,¹⁸ but can cause polymenorrhoea (which may respond to a reduction in dose from 100 mg daily to 50 mg). Serum potassium levels and renal function should be checked. Non-steroidal anti-inflammatory drugs can potentiate the effects of spironolactone on renal potassium retention. Ovulation is commonly restored by spironolactone therapy, an event which may or may not be desired by the patient.

Cyproterone acetate not infrequently causes depression and, at a dose of 100 mg, weight gain,⁴⁰ the latter aggravating insulin resistance. Cyproterone preparations are relatively expensive.

Insulin-sensitising drugs

Metformin is now being suggested as initial therapy for women with polycystic ovary syndrome whose condition does not respond to lifestyle measures, ahead of traditional hormonally active agents, for amelioration of hirsutism and for the restoration of regular menses and ovulation.^41,42 The drug should be withdrawn after conception. My limited experience with metformin suggests that it is at least as effective as spironolactone or cyproterone in the treatment of hirsutism and acne.

Further studies will undoubtedly define the indications for insulin-sensitising medications in polycystic ovary syndrome, but they are already indicated for women with established diabetes and may be useful for women with refractory obesity or hyperlipidaemia.

Infertility

Infertility in polycystic ovary syndrome is usually treated successfully by improving diet and exercise, weight reduction and spironolactone therapy. If these measures are not successful, conception can usually be achieved by one or more of clomiphene citrate, gonadotropins, gonadotropin-releasing hormone analogues, laparoscopically applied therapies to the ovaries and assisted reproductive techniques. Metformin therapy increases spontaneous ovulation and dramatically enhances the ovulatory response to clomiphene²⁹ and will hopefully reduce the need for more expensive forms of ovulation induction.

Pregnancy in polycystic ovary syndrome

Women with polycystic ovary syndrome have recently been shown to have an increased prevalence of gestational diabetes or impaired glucose tolerance during pregnancy^43,44 and should therefore have a glucose tolerance test early in pregnancy and again at 26 to 28 weeks.

Conclusion

Much epidemiological and basic endocrine research is yet required to answer questions about the proportion of women with type 2 diabetes who have had polycystic ovary syndrome and the role of other hormones such as androstenedione, dihydroepiandrosterone sulfate, oestrone, insulin-like growth factor and opioid receptors.

However, we now have sufficient scientific information to recommend randomised controlled trials of new therapies that should not only make treatment of immediate problems more effective, but which should also reduce the long term prevalence of ischaemic heart disease and diabetes, with all of its attendant complications. Never before have we been able to identify such a large group of women at risk of diabetes and vascular disease at such an early age, when preventive measures are most effective.

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(Received 27 Jan, accepted 21 Jul, 1998)

Author's details

Sydney, NSW.
Warren Kidson, MB BS, FRACP, Visiting Endocrinologist, Prince of Wales Hospital Randwick and Visiting Physician, Royal Hospital for Women, Paddington, NSW.

Reprints: Dr Warren Kidson, 24 Blenheim Street, Randwick, NSW 2031.
E-mail: wkidsonATmedeserv.com.au

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