Polycystic ovary syndrome

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Polycystic ovary syndrome (PCOS, Stein-Leventhal syndrome, polycystic ovary disease PCOD) is a common disorder affecting up to 1 in 15 women. It is associated with susceptibility to metabolic syndrome and even if it has been recognised as a distinct condition since 1935[1] we still do not have a single agreed criteria for diagnosis[2].

Contents

Features

in patients who do not have:

Specifically obesity, insulin resistance or metabolic syndrome are secondary associations.

Feature PCOS on NIH criteria

(1990)[4]

PCOS on Rotterdam criteria

(2003)[5]

Rotterdam

Severe PCOS

Rotterdam

Hyperandrogenism & chronic anovulation

Rotterdam

Ovulatory PCOS

Rotterdam

Mild PCOS

Hyperadrogenism Clinical or biochemical evidence Present with one other androgens androgens androgens mildandrogens
Chronic anovulation Must be present Present with one other Irregular periods Irregular periods Normal periods Irregular periods
Polycystic ovaries Unnecessary Present with one other Present Normal Present Present
Insulin - - Normal
Risk - - ? ?
Prevalence in women 6.5-8% 9-12% ~6% ~1% ~2% ~2%

Aetiology

Its aetiology is poorly understood. Some blame the observed high testoserone, and less common raised prasterone sulfate (DHEAS). Others abnormal androgen signalling. There is abnormal gonadotrophin pulsatility with excessive LH and normal FSH so perhaps there is a defect in the hypothalamic-pituitary axis. The major genetic association is with the fibrillin 3 (FBN3) gene at 19p13.2 which is involved in growth factor regulation.

Diagnosis

If clinical presentation (as above) is consistent and no other clinical differential diagnosis proceed to[6]:

  • Vaginal U/S or U/S abdomen/pelvis if vaginal U/S inappropriate
  • Measure serum prolactin, TSH and early morning 17-hydroxyprogesterone to exclude other common endocrine conditions

Associations

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  • While the risk factors for cardiovascular disease are considerably increased in POCS, long term follow up suggests little cardiovascular risk increase so the jury is out !
  • Obstructive sleep apnoea must be considered in POCS, as rate so high and clinicians may not inquire for symptoms

If diagnosis confirmed proceed to investigations relevant to secondary associations:

  • Glucose &/or glucose tolerance test if evidence for possible metabolic syndrome or family history of diabetes mellitus
    • There is up to a 16% conversion to impaired glucose tolerance/annum[7] and up to 10% diabetes in early middle age[8]
  • Cholesterol/lipids
    • Although risk of hypercholesteraemia is increased by 3 times interestingly cardiovascular risk is not increased over normal women so treat on basis of usual cardiovascular risk for women[9]
  • Endometrial biopsy if risk assessment endometrial carcinoma justifies
    • Endometrial carcinoma association confined to premenopausal women with trend to cyclin D1-expressing endometrial tumours[10]
  • History to exclude obstructive sleep apnoea
    • There is a ten fold increase over weight matched controls[11][12] with evidence for gross underdiagnosis[13]
  • Monitor for hypertension and vascular disease
    • Although the associations are real they are not obviously associated with increased total cardiovascular risk[14].

Treatment

There is fair short term clinical evidence for a number of drug interventions tailored to an individual and their goals, particularly fertility. This does not guide the common necessity to give more than one drug when single drug therapy fails. However evidence for benefit for other long term outcomes such as reduction in cardiovascular risk (which may not be as relevant as some believed) is lacking.

  • Lifestyle
  • Cyproterone and oestrogen for hirsuitism[15] but there may be better alternatives now such as drospirenone containing OCPs[16]
  • Metformin has the advantage of fair tolerability[17] and the evidence base for other drugs directed at insulin resistance is much more limited.
    • Metformin treatment results in a better reduction in fasting insulin and lower triglyceride levels than the oral contraceptive[18]
  • Oral contraceptive (OCP)
    • Improves menstrual pattern and serum androgen levels compared with metformin[19]
    • Choice of oral contraceptive is important, since most progestins possess variable androgenic effects. Consider drospirenone containing pill[20][21].
  • Clomiphene which is superior to metformin in restoring fertility at the risk of multiple birth[22] so it is usually first choice in anovulatory PCOS with ultrasound monitoring as for gonadotrophins when treating infertility.

References

  1. Ehrmann DA. Polycystic ovary syndrome. The New England journal of medicine. 2005 Mar 24; 352(12):1223-36.(Link to article – subscription may be required.)
  2. Norman RJ, Dewailly D, Legro RS, Hickey TE. Polycystic ovary syndrome. Lancet. 2007 Aug 25; 370(9588):685-97.(Link to article – subscription may be required.)
  3. Visser JA, de Jong FH, Laven JS, Themmen AP. Anti-Müllerian hormone: a new marker for ovarian function. Reproduction (Cambridge, England). 2006 Jan; 131(1):1-9.(Link to article – subscription may be required.)
  4. Norman RJ, Dewailly D, Legro RS, Hickey TE. Polycystic ovary syndrome. Lancet. 2007 Aug 25; 370(9588):685-97.(Link to article – subscription may be required.)
  5. Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome (PCOS). Human reproduction (Oxford, England). 2004 Jan; 19(1):41-7.
  6. Ehrmann DA. Polycystic ovary syndrome. The New England journal of medicine. 2005 Mar 24; 352(12):1223-36.(Link to article – subscription may be required.)
  7. Legro RS, Gnatuk CL, Kunselman AR, Dunaif A. Changes in glucose tolerance over time in women with polycystic ovary syndrome: a controlled study. The Journal of clinical endocrinology and metabolism. 2005 Jun; 90(6):3236-42.(Link to article – subscription may be required.)
  8. Legro RS, Kunselman AR, Dodson WC, Dunaif A. Prevalence and predictors of risk for type 2 diabetes mellitus and impaired glucose tolerance in polycystic ovary syndrome: a prospective, controlled study in 254 affected women. The Journal of clinical endocrinology and metabolism. 1999 Jan; 84(1):165-9.
  9. Wild S, Pierpoint T, McKeigue P, Jacobs H. Cardiovascular disease in women with polycystic ovary syndrome at long-term follow-up: a retrospective cohort study. Clinical endocrinology. 2000 May; 52(5):595-600.
  10. Pillay OC, Te Fong LF, Crow JC, Benjamin E, Mould T, Atiomo W, Menon PA, Leonard AJ, Hardiman P. The association between polycystic ovaries and endometrial cancer. Human reproduction (Oxford, England). 2006 Apr; 21(4):924-9.(Link to article – subscription may be required.)
  11. Fogel RB, Malhotra A, Pillar G, Pittman SD, Dunaif A, White DP. Increased prevalence of obstructive sleep apnea syndrome in obese women with polycystic ovary syndrome. The Journal of clinical endocrinology and metabolism. 2001 Mar; 86(3):1175-80.
  12. Tasali E, Van Cauter E, Ehrmann DA. Relationships between sleep disordered breathing and glucose metabolism in polycystic ovary syndrome. The Journal of clinical endocrinology and metabolism. 2006 Jan; 91(1):36-42.(Link to article – subscription may be required.)
  13. Subramanian S, Desai A, Joshipura M, Surani S. Practice patterns of screening for sleep apnea in physicians treating PCOS patients. 2007 May 31.(Epub ahead of print) (Link to article – subscription may be required.)
  14. Legro RS. Polycystic ovary syndrome and cardiovascular disease: a premature association? Endocrine reviews. 2003 Jun; 24(3):302-12.
  15. Sahin Y, Dilber S, Keleştimur F. Comparison of Diane 35 and Diane 35 plus finasteride in the treatment of hirsutism. Fertility and sterility. 2001 Mar; 75(3):496-500.
  16. Batukan C, Muderris II, Ozcelik B, Ozturk A. Comparison of two oral contraceptives containing either drospirenone or cyproterone acetate in the treatment of hirsutism. Gynecological endocrinology : the official journal of the International Society of Gynecological Endocrinology. 2007 Jan; 23(1):38-44.
  17. Lord JM, Flight IH, Norman RJ. Insulin-sensitising drugs (metformin, troglitazone, rosiglitazone, pioglitazone, D-chiro-inositol) for polycystic ovary syndrome. Cochrane database of systematic reviews (Online). 2003; (3):CD003053.(Link to article – subscription may be required.)
  18. Costello M, Shrestha B, Eden J, Sjoblom P, Johnson N. 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 of systematic reviews (Online). 2007; (1):CD005552.(Epub) (Link to article – subscription may be required.)
  19. Costello M, Shrestha B, Eden J, Sjoblom P, Johnson N. 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 of systematic reviews (Online). 2007; (1):CD005552.(Epub) (Link to article – subscription may be required.)
  20. Pehlivanov B, Mitkov M. Efficacy of an oral contraceptive containing drospirenone in the treatment of women with polycystic ovary syndrome. The European journal of contraception & reproductive health care : the official journal of the European Society of Contraception. 2007 Mar; 12(1):30-5.(Link to article – subscription may be required.)
  21. De Leo V, Morgante G, Piomboni P, Musacchio MC, Petraglia F, Cianci A. Evaluation of effects of an oral contraceptive containing ethinylestradiol combined with drospirenone on adrenal steroidogenesis in hyperandrogenic women with polycystic ovary syndrome. Fertility and sterility. 2007 Jul; 88(1):113-7.(Link to article – subscription may be required.)
  22. Legro RS, Barnhart HX, Schlaff WD, Carr BR, Diamond MP, Carson SA, Steinkampf MP, Coutifaris C, McGovern PG, Cataldo NA, Gosman GG, Nestler JE, Giudice LC, Leppert PC, Myers ER. Clomiphene, metformin, or both for infertility in the polycystic ovary syndrome. The New England journal of medicine. 2007 Feb 8; 356(6):551-66.(Link to article – subscription may be required.)
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