Polycystic Ovarian Syndrome

Synonym: Stein-Leventhal Syndrome

The cause of this common, poorly-understood syndrome is uncertain. Initially classed as a primary ovarian dysfunction, it is now thought to reflect a more systemic disturbance in the metabolism of sex hormones. It causes menstrual dysfunction and signs of androgen excess.

Approximately 20% of asymptomatic women who have ultrasound are found to have polycystic ovaries - but without the clinical features of the syndrome (irregular or absent menses and signs of excess androgen); intervention is rarely required.
European estimates of prevalence are between 2-20%.¹
Most clinical data suggests a prevalence of 6–7% of the UK population.²

• Current theories indicate that above normal anterior-pituitary LH secretion leads to over stimulation of the ovarian theca cells, causing excessive androgen production (predominantly testosterone and androstenedione).
• Low FSH levels mean that ovarian granulosa cells fail to adequately convert these androgens into oestrogens, leading to ovulatory impairment and the development of unruptured cysts.
• Associated hyperinsulinaemia causes dyslipidaemia and increased plasminogen activation, thought to increase the risk of intravascular thrombosis.

This condition is often familial, but no culprit genes have been identified.³

The condition is heterogeneous; sufferers may have classical clinical features but biochemically normal androgen levels. Insulin resistance and hyperinsulinaemia are often present. Physiological hormonal cycling is disrupted and the ovaries become enlarged by multiple follicles which have failed to rupture. The theca stroma cells surrounding the arrested follicles are markedly hyperplastic. However, the underlying endocrine disturbance can exist in the absence of polycystic ovaries.

The patient often presents in the peripubertal period through to her mid 20's.
She may be obese, virilised, with acne, hirsutism and irregular or absent menses.
Oligomenorrhoea, the commonest form of ovulatory disturbance, is defined as <9 periods per year. Infertility or sub fertility are common presenting complaints.

• Drug-induced hyperandrogenism
• Androgen-secreting ovarian or adrenal tumours
• Ovarian hyperthecosis (signs of virilism and biochemical androgen excess much more prominent in the latter two)
• Late-onset congenital adrenal hyperplasia (very rare)

• This may show LH elevated, LH:FSH ratio increased, with FSH normal.
• Exclude other potential causes e.g. thyroid dysfunction, congenital adrenal hyperplasia (check basal serum 17-hydroxyprogesterone levels and seek expert advice), hyperprolactinaemia, androgen-secreting tumours and Cushing's syndrome.⁵
• Testosterone levels may be elevated and oestriol reduced (less consistently). NB: Very high androgen levels are more indicative of an androgen-secreting tumour.
• Laparoscopy or ultrasound show characteristic ovaries (average volume is three times that of normal ovaries), but the syndrome can exist without the presence of polycystic ovaries.
• Fasting glucose and oral glucose tolerance test are useful in assessing insulin resistance/diabetes.
• Fasting lipid levels should be checked.
• If late-onset congenital adrenal hyperplasia is suspected then it is worth checking .

General points

Women diagnosed with PCOS should be informed of the possible long-term risks to health that are associated with their condition. They should be advised regarding weight control and exercise - helps regulate periods, reduce hirsutism and reduce insulin levels, but is often demoralisingly difficult.⁸

Pharmacological treatment

• Metformin and glitazones:
  • Although there is a body of evidence demonstrating the safety of these drugs, there is no evidence for a long-term benefit for use of metformin in women with PCOS who are not diabetic.^9,10
  • There is evidence that metformin may modestly reduce androgen levels by around 11% in women with PCOS compared with placebo and modest reductions in body weight have been reported by some.⁵
  • Both metformin and the glitazones are unlicensed for use in PCOS in the UK and patients should be counselled before initiating therapy:
    • This may be useful to moderate insulin resistance and reduce menstrual and ovarian dysfunction in the short-term.^11,12
    • Ovulatory function may be restored with metformin so contraceptive advice may be needed.^13,14
    • This can lead to more regular cycles, but not necessarily to reduced hirsutism or weight.¹⁵ Normal weight range women respond better to treatment than obese women.¹⁶
    • Usual starting dose 500 mg twice daily. Renal and hepatic function should be checked before starting metformin.
  NB: The RCOG DO NOT recommend its use in pregnancy at present until further randomised prospective study results are available to provide adequate evidence of safety and efficacy of its use. The MiG trial is key in assessing the potential role of metformin treatment during pregnancy.¹⁷ Recruitment finished in October 2006 and outcomes will give detailed information about effects of treatment on the fetus and the mother.
• Orlistat and sibutramine have been shown to significantly reduce body weight and hyperandrogenism in women with PCOS.^18,19 However, the use of sibutramine is not recommended in patients with systolic hypertension.
• Clomiphene:
  This is the first-line agent for anovulatory polycystic ovary syndrome.⁸ A recent meta-analysis confirmed that it increased pregnancy rates compared with placebo as first line therapy.²⁰ However it is associated with around an 11% risk of multiple pregnancy, so the ovarian response should be carefully monitored with ultrasound.²¹
• Hirsutism:
  Patients may be treated cosmetically, or with an anti-androgen eg cyproterone 2 mg/day, as in Dianette® (avoid pregnancy) or spironolactone. Weight loss helps reduce the signs of hyperandrogenism. Eflornithine is a new topical treatment for hirsutism and appears to be effective.²²
• The combined contraceptive pill:
  This will control bleeding (e.g. 20-35μg oestrogen with desogestrel or gestodene) and will increase SHBG to mop up androgens and prevent endometrial over stimulation. Caution with the COC if BMI >30, and oestrogens should be avoided if BMI >39.²³ A recent Cochrane review to compare the use of insulin
  sensitising drugs versus combined oral contraceptive pills concluded that the limited data available demonstrated no evidence of difference in effect between metformin and the pill on hirsutism and acne²⁴
• Progestogens:
  These may be used alone to control irregular, or induce cyclical bleeding with absent menstruation (reducing the risk of endometrial carcinoma).

Surgical treatment

Anovulation associated with PCOS has long been known to be amenable to surgical treatment. A recent long-term cohort study up to 20 years after laparoscopic ovarian electrocautery has shown persistence of ovulation and normalisation of serum androgens and SHBG in over 60% of subjects, particularly if they have a normal BMI.²⁵

• There is an increased risk of endometrial carcinoma in untreated cases.²⁶ It is good practice to recommend treatment with progestogens to induce a withdrawal bleed at least every 3–4 months.
• It has been suggested that women with PCOS may have a higher cardiovascular risk than weight-matched controls with normal ovarian function. They have increased cardiovascular risk factors such as obesity, hyperandrogenism, hyperlipidaemia and hyperinsulinaemia.²⁷ There is some dispute over this.^28,29
• Women presenting with PCOS, particularly if they are obese (body mass index greater than 30), have a strong family history of type 2 diabetes or are over the age of 40 years, are at increased risk of type 2 diabetes and should be offered a glucose tolerance test.³⁰
• Women diagnosed with PCOS (or their partners) should be asked about snoring and daytime fatigue/somnolence and informed of the possible risk of sleep apnoea, and offered investigation and treatment when necessary.³¹
• There is a higher risk of gestational diabetes in women with PCOS.³² Women who have been diagnosed as having PCOS before pregnancy (such as those requiring ovulation induction for conception) should be screened for gestational diabetes before 20 weeks of gestation, with referral to a specialist obstetric diabetic service if abnormalities are detected.
• There does not appear to be an association with breast or ovarian cancer and no additional surveillance is required.