Polycystic ovary syndrome

Synonym: Stein-Leventhal syndrome

Originally described by Doctors Stein and Leventhal in 1935, the cause of this common, poorly understood syndrome is uncertain. It encompasses a syndrome of polycystic ovaries, in association with systemic symptoms causing reproductive, metabolic and psychological disturbances. These most commonly present with infertility, amenorrhoea, acne or hirsutism.

Epidemiology

Polycystic ovaries on ultrasound are very common and can be seen in up to 33% of women of reproductive age¹. However, the majority of women with polycystic ovaries do not have features of polycystic ovary syndrome (PCOS) and do not require intervention. Prevalence figures vary depending on diagnostic criteria used, but PCOS is thought to affect 5-15% of women of reproductive age².

Pathophysiology¹

The cause remains unclear but is likely to be multifactorial. The essential changes are:

• Excess androgens produced by the theca cells of the ovaries (due either to hyperinsulinaemia or increased luteinising hormone (LH) levels).

• Insulin resistance, ie loss of sensitivity to insulin, resulting in hyperinsulinaemia in many women with PCOS. Weight gain further increases insulin resistance. Effects of this increase in insulin are:

  • Increased androgen production through more than one mechanism

  • Reduced production of sex hormone-binding globulin (SHBG) in the liver. Free testosterone may subsequently be raised as testosterone is bound to SHBG, even if total testosterone is normal.

• Raised LH levels due to increased production from the anterior pituitary (in around 40% of women with PCOS).

• Raised oestrogen levels in some women, which may lead to a hyperplastic endometrium.

The underlying endocrine disturbance can exist in the absence of polycystic ovaries; affected women may have classical clinical features, yet biochemically normal androgen levels.

The condition appears to have a genetic link in some cases, as there is familial clustering; however, the gene involved and mode of inheritance have not yet been identified³⁴.

Presentation

The patient often presents in the peripubertal period through to her mid-20s.

Symptoms

These include:

• Oligomenorrhoea (defined as <9 periods per year).

• Infertility or subfertility.

• Acne.

• Hirsutism.

• Alopecia.

• Obesity or difficulty losing weight.

• Psychological symptoms - mood swings, depression, anxiety, poor self-esteem⁵.

• Sleep apnoea.

Clinical signs

These include:

• The presence of hirsutism, (often on the upper lip, chin, around the nipples and in a line beneath the umbilicus). This occurs in 60% of women with PCOS⁵.

• Male-pattern balding, alopecia.

• Obesity - this is common (usually central distribution).

• Acanthosis nigricans - may be present and is thought to be a sign of insulin resistance.

• Occasionally, clitoromegaly, increased muscle mass, deep voice (more usually, these are signs of more severe hyperandrogenism syndromes).

Diagnostic criteria⁶

• Polycystic ovaries (either 12 or more peripheral follicles or increased ovarian volume (greater than 10 cm³).

• Oligo-ovulation or anovulation.

• Clinical and/or biochemical signs of hyperandrogenism.

Differential diagnosis¹

• Thyroid disorder (particularly hypothyroidism).

• Hyperprolactinaemia.

• Cushing's syndrome.

• Acromegaly.

• Side-effects of medication (medication causing hirsutism, weight gain or oligomenorrhoea as side-effects, for example).

• Late-onset congenital adrenal hyperplasia (CAH).

• Androgen-secreting ovarian or adrenal tumours.

• Ovarian hyperthecosis.

If there are signs of virilisation, rapidly progressing hirsutism or high total testosterone level then suspect one of the latter three. 17-hydroxyprogesterone, measured in the follicular phase, will be raised in CAH. Consider checking levels even where testosterone is not significantly raised in those with higher risk, such as Ashkenazi Jews or people with a family history of CAH.

Investigations¹

• Total testosterone: normal to slightly raised in PCOS.

• Free testosterone levels may be raised but if total testosterone is >5 nmol/L, exclude androgen-secreting tumours and CAH.

• SHBG: normal or low in PCOS. This can also be used to calculate the free androgen index (= 100 times the total testosterone value divided by the SHBG value). Free androgen index is usually normal or elevated in PCOS and can be used as an alternative to measuring free testosterone if this is not locally available.

• LH may be elevated, with the LH:follicle-stimulating hormone (FSH) ratio increased (>2), with FSH normal; however, this is not part of the diagnostic criteria and may be normal. (Remember the oral contraceptive pill affects levels.) This also helps to exclude premature ovarian insufficiency (LH and FSH both raised) and hypogonadotropic hypogonadism (LH and FSH reduced).

• Ultrasound scan demonstrates characteristic ovaries (the average volume is three times that of normal ovaries); however, the syndrome can exist without the presence of polycystic ovaries. In adolescence a scan should be interpreted with caution as follicle counts are higher.

• Other blood tests, where indicated from the clinical picture, to exclude other potential causes - eg, TFT (thyroid dysfunction), 17-hydroxyprogesterone levels (CAH), prolactin (hyperprolactinaemia), DHEA-S and free androgen index (androgen-secreting tumours), and 24-hour urinary cortisol (Cushing's syndrome).

• Fasting glucose and oral glucose tolerance tests are useful in assessing insulin resistance/diabetes. Women who are overweight or have other risk factors for diabetes should have an oral glucose tolerance test on diagnosis of PCOS⁶.

• Assess cardiovascular risk, including lipid levels.

Management

See also the separate articles on Acne, Hirsutism, Obesity, Alopecia, and Infertility.

General points⁶

Women diagnosed with PCOS should be informed of the possible long-term risks to health that are associated with their condition.

Associations with obesity, dyslipidaemia and insulin resistance are likely to result in increased cardiovascular risk. Women should be offered screening for impaired glucose tolerance and diabetes, and screening for other cardiovascular risk factors. See also the separate Prevention of Cardiovascular Disease and Prevention of Diabetes articles.

Women should also be asked about symptoms of sleep apnoea and informed this is also a risk.

Women diagnosed with PCOS should be advised on weight control and exercise:

• Lifestyle intervention may improve the free androgen index (FAI), weight and BMI in women with PCOS⁷.

• Weight loss has been shown to improve fertility, psychological symptoms and metabolic features (insulin resistance and cardiovascular risks), even when BMI remains in the high ranges⁵.

• Weight loss has also been shown to improve ovulation, pregnancy rates and outcomes⁸.

It makes sense that a low-GI diet would be most beneficial in women with PCOS and there is some evidence for this⁹¹⁰. Hypertension should be treated but there is no use for routine use of statins in women with PCOS, other than normal guidelines for use⁶¹¹.

Oligomenorrhoea or amenorrhoea may predispose women to endometrial hyperplasia and cancer. Treatment which leads to a withdrawal bleed every three or four months should be recommended with cyclical progestogen or the combined oral contraceptive (COC) pill. Alternatively the intrauterine system (IUS) may be used to prevent hyperplasia. Ultrasound of the endometrium should be done if withdrawal bleeds do not occur, and endometrial biopsy if the endometrial thickness is greater than 7-10 mm.

Pharmacological treatment

There is no treatment which reverses the hormonal disturbances of PCOS and treats all clinical features, so medical management is targeted at individual symptoms and only in association with lifestyle changes.

For women not planning pregnancy

• COC pill: is also used to control menstrual irregularity. If risk factors deem women ineligible, progestogens may be used to induce bleeds to protect the endometrium (eg, medroxyprogesterone 10 mg daily for 7-10 days every three months). Alternatively the IUS may be used as endometrial protection.

• Metformin:

  • Has been increasingly used off-licence for PCOS; however, a Cochrane review showed uncertainty regarding the relative benefits and adverse effects of metformin compared with the COC pill¹².

  • The National Institute for Health and Care Excellence (NICE) Evidence Summary suggests its side-effects and cost outweigh its benefits and any, as yet unproven, long-term health benefits¹³.

  • Metformin should not be initiated in primary care other than for diabetes; women considering metformin should be referred to secondary care¹.

• Orlistat: can help with weight loss in overweight/obese women with PCOS and may improve testosterone and insulin sensitivity with similar efficacy to metformin¹⁴.

For women wishing to conceive and presenting with infertility
2013 NICE guidelines advise (after weight loss where indicated and a full fertility work-up) women should be treated with clomifene, metformin or a combination of the two⁸.

A Cochrane review found a benefit in live birth rates from the use of metformin but the evidence quality was low. An improvement in clinical pregnancy and ovulation suggested that clomiphene citrate is preferable to metformin for ovulation induction in obese women with PCOS¹⁵.

• Clomifene: induces ovulation and has been proven to improve pregnancy rates. It should not be used for more than six months and, as it is associated with an 11% risk of multiple pregnancy, women should have ultrasound monitoring during treatment⁸.

• Metformin: may be used instead of or together with clomifene to improve pregnancy rates, according to 2013 NICE guidelines. Women should be warned of the side-effects. NB: metformin is not recommended in pregnancy.

• Laparoscopic ovarian drilling or gonadotrophins: are second-line treatments for those who are resistant to clomifene.

Complications⁶

• Infertility. PCOS is the cause of infertility in 75% of women who are infertile due to anovulation¹.

• Oligomenorrhoea or amenorrhoea are known to predispose to endometrial hyperplasia and endometrial cancer in untreated cases. 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, as they have increased cardiovascular risk factors such as obesity, hyperandrogenism, and hyperinsulinaemia, and a higher prevalence of risk factors such as hyperlipidaemia, hypertension, the metabolic syndrome and diabetes¹⁶. There have not yet been studies which confirm the greater cardiovascular morbidity or mortality. However, there is some evidence of compromise of endothelial function in women with PCOS, which is an early marker of cardiovascular disease¹⁷.

• Women presenting with PCOS, particularly if they are obese (BMI 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 screening. The risk of diabetes is increased to some degree in women with PCOS even if they are not overweight. Screening should be with a glucose tolerance test, as HbA1c has not yet been defined in this situation.

• 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. They should be offered investigation and treatment when necessary.

Complications in pregnancy
There is a higher risk of gestational diabetes in women with PCOS, which may be more than double². Women who have been diagnosed as having PCOS before pregnancy (such as those requiring ovulation induction for conception) should be screened for gestational diabetes at 24-28 weeks of gestation (by oral glucose tolerance test, with referral to a specialist obstetric diabetic service if abnormalities are detected. Women with PCOS also have higher risks of preterm birth and pre-eclampsia.