3. Polycystic Ovarian Syndrome

Polycystic Ovarian Syndrome

This PatientPlus article is written for healthcare professionals so the language may be more technical than the condition leaflets. You may find the abbreviations list helpful.

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]

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  • 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.

Useful clinical signs include:
  • The presence of hirsutism, (often on the upper lip, chin, around the nipples and in a line beneath the umbilicus)
  • Male-pattern balding, alopecia
  • Deep voice
  • Increased muscle mass
  • Clitoromegaly
  • Obesity is present in around 50% of women with the condition.
  • Acanthosis nigricans may be present and is thought to be a manifestation of insulin resistance.[4]
  • 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 eg 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 .
Two of the three following criteria are diagnostic of the condition:[6]
  • Polycystic ovaries (either 12 or more peripheral follicles or increased ovarian volume (greater than 10 cm3)
  • Oligo- or anovulation
  • Clinical and/or biochemical signs of hyperandrogenism

NB: A raised luteinising hormone/follicle-stimulating hormone ratio is no longer a diagnostic criteria for PCOS because of the inconsistency.[7]

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 has been shown to significantly reduce body weight and hyperandrogenism in women with PCOS.[18]
  • 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.[19] However it is associated with around an 11% risk of multiple pregnancy, so the ovarian response should be carefully monitored with ultrasound.[20]
  • 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.[21]
  • The combined contraceptive pill:
    This will control bleeding (eg 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.[22] 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 acne[23]
  • 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.[24]

  • There is an increased risk of endometrial carcinoma in untreated cases.[25] 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.[26] There is some dispute over this.[27][28]
  • 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.[29]
  • 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.[30]
  • There is a higher risk of gestational diabetes in women with PCOS.[31] 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.
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Further reading & references

  1. Polycystic Ovary Syndrome, Online Mendelian Inheritance in Man (OMIM)
  2. Azziz R, Woods KS, Reyna R, et al; The prevalence and features of the polycystic ovary syndrome in an unselected population. J Clin Endocrinol Metab. 2004 Jun;89(6):2745-9.
  3. Homburg R; Polycystic ovary syndrome in adolescence. New insights in pathophysiology and treatment. Endocr Dev. 2005;8:137-49.
  4. Curran DR, Moore C, Huber T; Clinical inquiries. What is the best approach to the evaluation of hirsutism? J Fam Pract. 2005 May;54(5):465-7.
  5. Long-term consequences of polycystic ovary syndrome, Royal College of Obstetricians and Gynaecologists (2007)
  6. No authors listed; Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome. Fertil Steril. 2004 Jan;81(1):19-25.
  7. Cho LW, Jayagopal V, Kilpatrick ES, et al; The biological variation of C-reactive protein in polycystic ovarian syndrome. Clin Chem. 2005 Oct;51(10):1905-7.
  8. Balen AH, Rutherford AJ; Managing anovulatory infertility and polycystic ovary syndrome. BMJ. 2007 Sep 29;335(7621):663-6.
  9. Nestler JE, Jakubowicz DJ; Decreases in ovarian cytochrome P450c17 alpha activity and serum free testosterone after reduction of insulin secretion in polycystic ovary syndrome. N Engl J Med. 1996 Aug 29;335(9):617-23.
  10. Moghetti P, Tosi F, Tosti A, et al; Comparison of spironolactone, flutamide, and finasteride efficacy in the treatment of hirsutism: a randomized, double blind, placebo-controlled trial. J Clin Endocrinol Metab. 2000 Jan;85(1):89-94.
  11. Lord JM, Flight IH, Norman RJ; Metformin in polycystic ovary syndrome: systematic review and meta-analysis. BMJ. 2003 Oct 25;327(7421):951-3.
  12. Yilmaz M, Biri A, Karakoc A, et al; The effects of rosiglitazone and metformin on insulin resistance and serum androgen levels in obese and lean patients with polycystic ovary syndrome. J Endocrinol Invest. 2005 Dec;28(11):1003-8.
  13. Sattar N, Hopkinson ZE, Greer IA; Insulin-sensitising agents in polycystic-ovary syndrome. Lancet. 1998 Jan 31;351(9099):305-7.
  14. Moghetti P, Castello R, Negri C, et al; Metformin effects on clinical features, endocrine and metabolic profiles, and insulin sensitivity in polycystic ovary syndrome: a randomized, double-blind, placebo-controlled 6-month trial, followed by open, long-term clinical evaluation. J Clin Endocrinol Metab. 2000 Jan;85(1):139-46.
  15. Morin-Papunen LC, Koivunen RM, Ruokonen A, et al; Metformin therapy improves the menstrual pattern with minimal endocrine and metabolic effects in women with polycystic ovary syndrome. Fertil Steril. 1998 Apr;69(4):691-6.
  16. Maciel GA, Soares Junior JM, Alves da Motta EL, et al; Nonobese women with polycystic ovary syndrome respond better than obese women to treatment with metformin. Fertil Steril. 2004 Feb;81(2):355-60.
  17. Rowan JA; A trial in progress: gestational diabetes. Treatment with metformin compared with insulin (the Metformin in Gestational Diabetes - MiG - trial). Diabetes Care. 2007 Jul;30 Suppl 2:S214-9.
  18. 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.
  19. Beck JI, Boothroyd C, Proctor M, et al; Oral anti-oestrogens and medical adjuncts for subfertility associated with anovulation. Cochrane Database Syst Rev. 2005 Jan 25;(1):CD002249.
  20. Kousta E, White DM, Franks S. Modern use of clomiphene citrate in induction of ovulation. Hum Reprod Update 1997;3:359-65.
  21. Shapiro J, Lui H; Treatments for unwanted facial hair. Skin Therapy Lett. 2005 Dec-2006 Jan;10(10):1-4.
  22. Guillebaud J. Contraception, your questions answered. 3ed (1999) p137 Churchill Livingstone ISBN 0-4430-6153-X
  23. Costello MF, Shrestha B, Eden J, et al; Metformin versus oral contraceptive pill in polycystic ovary syndrome: a Cochrane review. Hum Reprod. 2007 May;22(5):1200-9. Epub 2007 Jan 29.
  24. Gjonnaess H; Late endocrine effects of ovarian electrocautery in women with polycystic ovary syndrome. Fertil Steril. 1998 Apr;69(4):697-701.
  25. Jafari K, Javaheri G, Ruiz G; Endometrial adenocarcinoma and the Stein-Leventhal syndrome. Obstet Gynecol. 1978 Jan;51(1):97-100.
  26. Wild RA; Long-term health consequences of PCOS. Hum Reprod Update. 2002 May-Jun;8(3):231-41.
  27. Bickerton AS, Clark N, Meeking D, et al; Cardiovascular risk in women with polycystic ovarian syndrome (PCOS). J Clin Pathol. 2005 Feb;58(2):151-4.
  28. Brinkworth GD, Noakes M, Moran LJ, et al; Flow-mediated dilatation in overweight and obese women with polycystic ovary syndrome. BJOG. 2006 Nov;113(11):1308-14.
  29. Ehrmann DA, Barnes RB, Rosenfield RL, et al; Prevalence of impaired glucose tolerance and diabetes in women with polycystic ovary syndrome. Diabetes Care. 1999 Jan;22(1):141-6.
  30. Fogel RB, Malhotra A, Pillar G, et al; Increased prevalence of obstructive sleep apnea syndrome in obese women with polycystic ovary syndrome. J Clin Endocrinol Metab. 2001 Mar;86(3):1175-80.
  31. Radon PA, McMahon MJ, Meyer WR; Impaired glucose tolerance in pregnant women with polycystic ovary syndrome. Obstet Gynecol. 1999 Aug;94(2):194-7.
Original Author: Dr Hayley Willacy Current Version:
Last Checked: 22/06/2011 Document ID: 2628  Version: 23 © EMIS

Disclaimer: This article is for information only and should not be used for the diagnosis or treatment of medical conditions. EMIS has used all reasonable care in compiling the information but make no warranty as to its accuracy. Consult a doctor or other health care professional for diagnosis and treatment of medical conditions. For details see our conditions.