Polycystic ovary syndrome

Synonym: Stein-Leventhal syndrome

Overview

What is polycystic ovary syndrome?

Originally described by Doctors Stein and Leventhal in 1935, it encompasses a metabolic syndrome with polycystic ovaries alongside systemic symptoms, including infertility, amenorrhoea, insulin resistance, acne and hirsutism.

Polycystic ovaries are not diagnostic of PCOS. Polycystic ovaries are a common stand-alone finding and polycystic ovary syndrome can occur without the typical findings of polycystic ovaries on a scan.

Polycystic ovaries on ultrasound are very common and can be seen in up to 21% of randomly-selected women of reproductive age.²The women with polycystic ovaries on scan were more likely to have irregular periods and raised testosterone but were otherwise indistinguishable from women without polycystic ovaries in terms of their BMI, fertility status, parity, LH and SHBG.

Prevalence figures for polycystic ovary syndrome vary depending on diagnostic criteria used, but it is thought to affect 4-21% of women of reproductive age.³⁴It has been found to be slightly more prevalent in women of Black or Middle-Eastern ethnicities compared with white or Chinese women.⁴The global incidence appears to be increasing.⁴

There is likely to be a genetic component to PCOS though no genes have yet been identified. It is likely that various factors affect the development of PCOS, including diet and lifestyle choices, obesity, environmental pollutants and gut dysbiosis. Smoking is well known to increase the risks of developing polycystic ovary syndrome. Exposure to air pollutants, smoke from coal and wood, and bisphenol A (a chemical found in plastics) has been found to increase the risks of developing PCOS. There is also an association with increased rates of polycystic ovary syndrome in women who had prepubertal obesity, those with congenital virilizing disorders, those with above-average or low birth weight for gestational age, those with premature adrenarche, and the use of valproic acid as an antiepileptic drug. ⁵

Polycystic ovary syndrome is a metabolic condition of hyperandrogenism rather than a primary gynaecological one. The essential changes are:

• Excess androgen synthesis by the ovaries and the adrenal glands, leading to the abnormal development of ovarian follicles and a dysregulation of the neuroendocrine system which then causes an imbalance in the hypothalamic–pituitary–ovarian (HPO) axis leading to an excess of gonadotropin.

• Insulin resistance, ie loss of sensitivity to insulin, resulting in hyperinsulinaemia. This also occurs as a result of the HPO axis imbalance. Insulin mimics the action of LH and thus raises GnRH. Sex hormone binding globulin (SHBG), a key circulatory protein that regulates testosterone levels, is decreased by insulin which leads to higher levels of free androgens.

תסמינים במבוגרים

כוללים:

• Evidence of hyperandrogenism: acne, female pattern hair loss (thinning on the crown), hirsutism.

• Amenorrhoea or oligomenorrhoea (defined as <8 periods per year or a cycle of longer than 90 days).

• Infertility or subfertility.

Symptoms in adolescents

כוללים:

• Severe acne and hirsutism.

• Irregular periods, a year after menarche:

  • A full year's history of periods occurring at less than 21 day intervals or greater than 45 day intervals.

  • 3 years' history of periods occurring at greater than 35 day intervals or fewer than 8 periods in a year.

  • One cycle of longer than 90 days at least 1 year post-menarche.

  • Primary amenorrhoea aged 15 years.

Remember: infrequent and irregular periods are normal in the first year after menarche.

Clinical signs

כוללים:

• 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 PCOS.

• Female-pattern hair loss, alopecia.

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

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

• Thyroid disorder (particularly היפותירואידיזם).

• 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.

• Simple obesity which can itself cause hyperandrogenism but does not normally affect menses.

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 people with a family history of CAH. 1% of the general population and 30% of hirsute women have late-onset CAH.

• Total testosterone: normal to slightly raised in PCOS.

• SHBG: normal or low in PCOS.

• Free androgen index (FAI) (= 100 times the total testosterone value divided by the SHBG value). Free androgen index is usually normal or elevated in PCOS (normal is <5).

• 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 reduces levels so must be stopped at least 6 weeks before a blood test for hormone levels.) This also helps to exclude premature ovarian insufficiency (LH and FSH both raised) and hypogonadotropic hypogonadism (LH and FSH reduced).

• 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/סוכרת. .

• Assess cardiovascular risk, including lipid levels.

• 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. Adolescents should not be scanned for PCO until 8 years post-menarche.

Diagnosis in adults

Diagnosis in adults requires 2 of the following 3:

• Infrequent or absent periods (fewer than 8 in a year or a cycle of over 90 days).

• Clinical and/or biochemical signs of hyperandrogenism.

• Polycystic ovaries on ultrasound scan.

Diagnosis in adolescents

Diagnosis in adolescents requires both of the following:

• Clinical and/or biochemical signs of hyperandrogenism.

• Irregular periods as defined in the symptoms section.

Do not scan adolescents for PCO in the first 8 years after menarche. Polycystic ovaries are very common in teenage girls.⁶

See also the separate articles on Acne, Hirsutism, השמנת יתר, Alopecia, and אי פוריות.

General points

Women diagnosed with PCOS should be informed of the possible long-term risks to health that are associated with their condition, particularly סוכרת סוג 2 ו cardiovascular disease.

Women should be offered screening for non-diabetic hyperglycaemia and diabetes, and screening for other cardiovascular risk factors. See also the separate Prevention of cardiovascular disease ו Prevention of diabetes articles.

Women should also be asked about symptoms of sleep apnoea and informed this is also a risk. Adolescents should be asked about any depression, anxiety or eating disorders.

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 PCOS.⁹

• Weight loss has also been shown to improve ovulation, pregnancy rates and outcomes.¹⁰

• A low-GI diet has been shown to improve clinical and biochemical features of PCOS.¹¹

• Hypertension should be treated but there is no use for routine use of statins in women with PCOS, other than normal guidelines for use - evidence in this area is of low quality.¹²

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, in association with lifestyle changes.

Treatments of adults¹

• Women who are trying to conceive should be referred earlier than normal. There is no need to wait for 12 months (or 6 months if over the age of 35).

• For women who are not planning a pregnancy and who have no contra-indications, the combined oral contraceptive pill should be offered. This can reduce some of the androgenic symptoms of PCOS.

• Acne should be treated as normal.

• There are limited options for hirsutism. The COCP may help. Topical eflornithine is licensed for facial hirsutism but its use is often limited to secondary care initiation.¹³

• If the woman has not had a bleed for 3 months or longer at initial presentation, a withdrawal bleed should be induced with medroxyprogesterone and then an ultrasound scan performed. Referral should be made if the endometrium thickness exceeds 10mm.

• If she is having fewer than 4 periods a year, the following treatments can be used to reduce the risks of endometrial hyperplasia and associated risks of endometrial carcinoma:

  • Cyclical progestogens, for example medroxyprogesterone 10mg a day for 14 days every 3 months

  • Low dose COCP.

  • Levonorgestrel intrauterine device (LNG-IUD).

• If women refuse any hormonal treatment and are not having 3-monthly bleeds then the guidelines suggest seeking specialist advice. However this advice is to offer ultrasound scans of the endometrium at least annually, and endometrial biopsy is indicated if the endometrial thickness is raised.

• Metformin is off-license for PCOS but may be of benefit in those of higher risk - women whose BMI is greater than 25, or those who are of Black, Asian, Hispanic, Native Australian ethnicities. The main risks are gastrointestinal side effects and reduced B12 levels. It can be used in conjunction with the COCP. There is no evidence of harm or benefit in pregnancy; studies suggest that there may be a great risk of obesity in the exposed child.

• Orlistat and GLP-1s could be considered to help with weight reduction in PCOS (though GLP1s are not available on the NHS for this indication).

Treatment of adolescents¹⁶

• Consider the COCP to manage the irregular periods and the clinical signs of hyperandrogenism.

• The guidelines do not advise that endometrial hyperplasia needs actively preventing under the age of 18 so irregular periods do not need management other than for symptomatic relief.

• Specialist advice should be sought before starting metformin in adolescents.

For adolescents who are high risk for developing polycystic ovary syndrome but who do not meet the diagnostic criteria, consider the COCP for management of troublesome symptoms and re-assess at 8 years post-menarche (stopping the COCP 3 months before re-assessing).

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

• Oligomenorrhoea or amenorrhoea are known to predispose to endometrial hyperplasia ו endometrial cancer in untreated cases.

• Women with PCOS 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 diabetes.

• 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 ⁵

Women with PCOS have an increased risk of miscarriage, gestational diabetes, hypertension and pre-eclampsia, low birth weight, premature delivery and needing a Caesarean section.