Professional Reference articles are written by UK doctors and are based on research evidence, UK and European Guidelines. They are designed for health professionals to use, so you may find the language more technical than the condition leaflets.
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.
Polycystic ovaries on ultrasound are very common and can be seen in up to 33% of women of reproductive age.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 age.
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 patient often presents in the peripubertal period through to her mid-20s.
- Oligomenorrhoea (defined as <9 periods per year).
- Infertility or subfertility.
- Obesity or difficulty losing weight.
- Psychological symptoms - mood swings, depression, anxiety, poor self-esteem.
- Sleep apnoea.
- 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.
- 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).
Two of the three following criteria are diagnostic of the condition, assuming other causes have been excluded (Rotterdam criteria):
- 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.
- Thyroid disorder (particularly hypothyroidism).
- Cushing's syndrome.
- 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.
- 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.
- Sex hormone-binding globulin. 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 sex hormone-binding globulin 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 PCOS.
- Fasting lipid levels should be checked.
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. They 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. 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 ranges.It has been shown to improve ovulation, pregnancy rates and outcomes.
It makes sense that a low GI diet would be most beneficial in women with PCOS and there is some evidence for this.[8, 9] Hypertension should be treated but there is no use for routine use of statins in women with PCOS, other than normal guidelines for use.[6, 10]
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 pill (COCP). 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.
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
- Co-cyprindrol: is licensed for treating hirsutism and acne, although not specifically in PCOS. It is also used to induce regular endometrial bleeds and thereby reduce the risk of endometrial carcinoma.
- COCP: 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 it to be less effective than the COCP for menstrual irregularity, hirsutism and acne, and 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 benefits.[11, 12] Metformin should not be initiated in primary care other than for diabetes; women considering metformin should be referred to secondary care.
- Eflornithine: may be used for hirsutism, as can cosmetic treatments (electrolysis, laser, waxing, bleaching). There is some limited evidence that eflornithine improves the appearance of facial hair in the short term; however, prescribing may depend on local policy.
- Orlistat: can help with weight loss in obese women with PCOS and may improve insulin sensitivity.[14, 15]
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 two.A Cochrane review in 2012, however, found no benefit in live birth rates from the use of metformin or other insulin-sensitising drugs, although it did improve numbers of pregnancies.
- 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 treatment.
- 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.
- Laparoscopic ovarian drilling or gonadotrophins: are second-line treatments for those who are resistant to clomifene.
- 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 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 diabetes.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 disease.
- 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 double.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.
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Further reading & references
- Moran LJ, Hutchison SK, Norman RJ, et al; Lifestyle changes in women with polycystic ovary syndrome. Cochrane Database Syst Rev. 2011 Jul 6 (7):CD007506. doi: 10.1002/14651858.CD007506.pub3.
- Polycystic ovary syndrome; NICE CKS. February 2013 (UK access only)
- Roos N, Kieler H, Sahlin L, et al; Risk of adverse pregnancy outcomes in women with polycystic ovary syndrome: population based cohort study. BMJ. 2011 Oct 13 343:d6309. doi: 10.1136/bmj.d6309.
- Fauser BC, Diedrich K, Bouchard P, et al; Contemporary genetic technologies and female reproduction. Hum Reprod Update. 2011 Nov-Dec 17(6):829-47. doi: 10.1093/humupd/dmr033. Epub 2011 Sep 6.
- Zhao H, Lv Y, Li L, et al; Genetic Studies on Polycystic Ovary Syndrome. Best Pract Res Clin Obstet Gynaecol. 2016 May 19. pii: S1521-6934(16)30024-4. doi: 10.1016/j.bpobgyn.2016.04.002.
- Teede H, Deeks A, Moran L; Polycystic ovary syndrome: a complex condition with psychological, reproductive and metabolic manifestations that impacts on health across the lifespan. BMC Med. 2010 Jun 30 8:41. doi: 10.1186/1741-7015-8-41.
- Long-term Consequences of Polycystic Ovary Syndrome; Royal College of Obstetricians and Gynaecologists (November 2014)
- Fertility - Assessment and treatment for people with fertility problems; NICE Guidance (February 2013, updated Aug 2016)
- Marsh KA, Steinbeck KS, Atkinson FS, et al; Effect of a low glycemic index compared with a conventional healthy diet on polycystic ovary syndrome. Am J Clin Nutr. 2010 Jul 92(1):83-92. doi: 10.3945/ajcn.2010.29261. Epub 2010 May 19.
- Mehrabani HH, Salehpour S, Amiri Z, et al; Beneficial effects of a high-protein, low-glycemic-load hypocaloric diet in overweight and obese women with polycystic ovary syndrome: a randomized controlled intervention study. J Am Coll Nutr. 2012 Apr 31(2):117-25.
- Raval AD, Hunter T, Stuckey B, et al; Statins for women with polycystic ovary syndrome not actively trying to conceive. Cochrane Database Syst Rev. 2011 Oct 5 (10):CD008565. doi: 10.1002/14651858.CD008565.pub2.
- Costello M, Shrestha B, Eden J, et al; Insulin-sensitising drugs versus the combined oral contraceptive pill for hirsutism, acne and risk of diabetes, cardiovascular disease, and endometrial cancer in polycystic ovary syndrome. Cochrane Database Syst Rev. 2007 Jan 24 (1):CD005552.
- Polycystic ovary syndrome: metformin in women not planning pregnancy; NICE Evidence Summary, February 2013
- Hirsutism; NICE CKS, December 2014 (UK access only)
- Jayagopal V, Kilpatrick ES, Holding S, et al; Orlistat is as beneficial as metformin in the treatment of polycystic ovarian syndrome. J Clin Endocrinol Metab. 2005 Feb 90(2):729-33. Epub 2004 Nov 9.
- Ghandi S, Aflatoonian A, Tabibnejad N, et al; The effects of metformin or orlistat on obese women with polycystic ovary syndrome: a prospective randomized open-label study. J Assist Reprod Genet. 2011 Jul 28(7):591-6. doi: 10.1007/s10815-011-9564-2. Epub 2011 Apr 12.
- Tang T, Lord JM, Norman RJ, et al; Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo amenorrhoea and subfertility. Cochrane Database Syst Rev. 2012 May 16 5:CD003053. doi: 10.1002/14651858.CD003053.pub5.
- Balen AH, Rutherford AJ; Managing anovulatory infertility and polycystic ovary syndrome. BMJ. 2007 Sep 29 335(7621):663-6.
- Dokras A; Cardiovascular disease risk factors in polycystic ovary syndrome. Semin Reprod Med. 2008 Jan 26(1):39-44. doi: 10.1055/s-2007-992923.
- Sprung VS, Atkinson G, Cuthbertson DJ, et al; Endothelial function measured using flow-mediated dilation in polycystic ovary syndrome: a meta-analysis of the observational studies. Clin Endocrinol (Oxf). 2013 Mar 78(3):438-46. doi: 10.1111/j.1365-2265.2012.04490.x.
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