Polycystic ovary syndrome

Contributed by Professor Adam Balen, professor of reproductive medicine and surgery, Department of Reproductive Medicine, The General Infirmary, Leeds

Clinical features
Key features of polycystic ovary syndrome (PCOS) include menstrual cycle disturbance, hyperandrogenism and obesity. PCOS is the presence of  two out of three of: oligo- and/or anovulation; hyperandrogenism and polycystic ovaries, with the exclusion of other aetiologies.

The morphology of the polycystic ovary has been defined as an ovary with 12 or more follicles 2–9mm in diameter and/or increased ovarian volume (>10cm3).

Symptoms
There is considerable heterogeneity of symptoms. Polycystic ovaries can exist without clinical signs, which may become expressed over time.

Weight loss will ameliorate the endocrine and metabolic profile and symptomatology.

Normal ovarian function relies on the selection of a follicle, which responds to a signal such as FSH to grow, become ‘dominant’ and ovulate. This mechanism is disturbed in women with PCOS, resulting in multiple small cysts.

Elevated serum insulin is found to be more common in lean and obese women with PCOS than in weight-matched controls.

Hyperinsulinaemia appears to be key to the pathogenesis of the syndrome as insulin stimulates androgen secretion by the ovarian stroma and appears to affect the normal development of ovarian follicles.

The prevalence of diabetes in obese women with PCOS is at least 11 per cent, so a measurement of impaired glucose tolerance (IGT) is important and long-term screening advisable.

Insulin resistance
Obesity and PCOS have a synergistic effect on the degree and severity of insulin resistance and subsequent hyperinsulinaemia.

Insulin resistance correlates with inter-menstrual interval and with hyperandrogenaemia.

Exercise and weight loss will improve insulin sensitivity and the metabolic abnormalities associated with the syndrome.

Even partial weight loss improves the hormonal profile and reproductive outcome for all forms of fertility treatment. Since the association between insulin resistance and BMI is stronger in obese women with PCOS than in weight-matched controls, the benefits of weight loss should be even greater in these women than in women without PCOS. 

Diagnosis
Baseline investigations should include a measurement of FSH, LH testosterone, thyroid function, prolactin, glucose tolerance test if overweight, and lipid profile.

The endocrine profile should be measured on days one to three of a menstrual bleed or at random if the patient is oligo-/amenorrhoeic.

Women who are obese, and many slim women with PCOS, will have insulin resistance and elevated serum concentrations of insulin (usually <30mU/l fasting).

A 75g oral glucose tolerance test should be performed in women with PCOS and a BMI >30 kg/m2, with an assessment of fasting and two-hour glucose concentrations.

IGT is defined as normal fasting glucose but a two-hour value of >7.8 and <11.1mmol/l.

South Asian women should have an assessment of glucose tolerance if their BMI is greater than 25kg/m2 because of the greater risk of insulin resistance at a lower BMI than seen in the Caucasian population. 

Management
Management of PCOS should focus on the woman’s particular problems.

Obesity worsens symptomatology and the endocrine profile. Anti-obesity drugs may help. Orlistat and sibutramine have been shown to improve insulin resistance and orlistat has been shown to reduce testosterone.

Metformin can also improve insulin resistance. Combining metformin and an anti-obesity agent may be ideal.

A low-dose combined oral contraceptive Pill (COCP) will result in an artificial cycle and regular shedding of the endometrium. An alternative is a progestogen every one to three months to induce a withdrawal bleed.

In women with anovulatory cycles the action of oestradiol on the endometrium may cause episodes of irregular uterine bleeding and, in the long term, endometrial hyperplasia and even endometrial cancer.

Ultrasound assessment of endometrial thickness is important. If the endometrium is thicker than 15mm a withdrawal bleed should be induced and if does not shed endometrial sampling is required to exclude endometrial hyperplasia or malignancy.

Infertility
Ovulation can be induced with the anti-oestrogen clomifene citrate (50–100mg) on days two to six of a natural or artificially-induced bleed in over 80 per cent of women. Ultrasound monitoring is needed to minimise the risk of multiple pregnancy and to ensure that ovulation is taking place.

Patients resistant to anti-oestrogens can be treated with parenteral gonadotrophin therapy or ovarian diathermy. Women with PCOS are at increased risk of developing ovarian hyperstimulation syndrome with gonadotrophin therapy. Laparoscopic ovarian diathermy is free of the risks of multiple pregnancy and ovarian hyperstimulation.

Hirsutism
Hirsutism can be distressing and is characterised by terminal hair growth in a male pattern of distribution, including the chin, upper lip, chest, back, upper and lower abdomen, upper arm, thigh and buttocks.

As drug therapies may take nine months to improve hirsutism, physical treatments including electrolysis, waxing and bleaching may be helpful.

Eflornithine is a topical treatment that may be useful in those who wish to avoid hormonal treatments. The best pharmacological treatment is a combination of the synthetic progestogen cyproterone acetate with ethinyl oestradiol. The effect on acne and seborrhoea is usually evident within months. Cyproterone acetate can rarely cause liver damage so liver function should be checked regularly.

Spironolactone is a weak diuretic with anti-androgenic properties that may be used in women in whom the COCP is contraindicated. Drospirenone is a derivative of spironolactone contained in the COCP Yasmin, which also appears effective for women with PCOS.

Metformin
Metformin may have benefits for health by improving hyperandrogenism, fertility, insulin sensitivity and lipid profile.

Research is encouraging with respect to a direct effect on ovarian function and an improvement in insulin sensitivity. It does not appear to induce weight loss, although coincident weight loss will benefit. Metformin may also enhance the efficacy of clomifene citrate and gonadotrophin therapy. Predictive factors for response and the correct dose of metformin are still to be elucidated. 

Further information

  • National patient support network, Verity www.verity-pcos.org.uk
  • PCOS-UK www.pcos-uk.org.uk
  • Balen A H, Conway G, Homburg R, Legro R. Clinical management of polycystic ovary syndrome. Taylor & Francis: London & New York, 2005.

The spectrum of clinical manifestations of PCOs

Symptoms

  • Obesity.
  • Menstrual disturbance.
  • Infertility.
  • Hyperandrogenism.
  • Asymptomatic, with polycystic ovaries on ultrasound scan. 

Serum endocrinology

  • Increase in fasting insulin (not routinely measured; insulin resistance assessed by GTT).
  • Increase in androgens (testosterone and androstenedione).
  • Increase in luteinising hormone (LH), follicle-stimulating hormone (FSH).
  • Decrease in sex hormone binding globulin (SHBG), results in elevated ‘free androgen index’. 
  • Increase in oestradiol, oestrone.
  • Increase in prolactin.  

Possible late sequelae

  • Diabetes mellitus.
  • Dyslipidaemia.
  • Hypertension/cardiovascular disease.
  • Endometrial carcinoma – a pelvic ultrasound is therefore important not only to assess ovarian morphology but also endometrial thickness.

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