Managing PCOS in General Practice: Insights and Approaches

1. Managing PCOS in General Practice John Eden UNSW, RHW

2. Conflict of interest statement • In the last 10 years, I have been a paid scientific adviser for • Solvay Pharmaceuticals, Wyeth-Ayerst, Organon P/L, Novartis P/L, Novo-Nordisk, Arkopharma P/L, Roche Pharmaceuticals Lawley Pharmaceuticals, CSL, and AstraZenica P/L. • My research unit performs trials for the pharma, food & supplement industries

3. WHRIA and Country gynaecology services • What is WHRIA? • Clinical services • Information services (with UNSW). Example - PCOS awareness campaign. • Research (Barbara Gross Research Unit at RHW) • Country outreach clinics (with RDN) • Bourke, Moree • GPs – Other areas that need gynae services • Specialists who want to help • Contact me at info@WHRIA.com.au

4. Definition of hirsutism • Excessive terminal hair (black & coarse) that appears in a male pattern in women • Patient and doctor attitudes towards hirsutism can be quite different • Affects up to 15% of women • Obviously there are racial differences

5. Is Hirsutism hormonal? • Most hirsute women have PCO (90%, Adams, 1986) & the severity correlates some-what with serum androgens & 5a-reductase activity • Most women with acne have PCO (Bunker, 1989; severity poorly correlates with androgens) • PCO is found in 26% with amenorrhoea & 87% with oligomenorrhoea (Adams, 1986; severity correlates with serum androgens)

6. Differential Diagnosis • PCOS – the vast majority • Other medical causes • Cushing’s syndrome • Adrenal, ovarian tumours • Self-medication (testosterone, anabolic steroids) • Idiopathic

7. Polycystic ovaries A Morphologic diagnosis • ‘Presence of 12 or more follicles in each • ovary measuring 2-9mm in diameter &/or increased ovarian volume (>10ml)’ One in four women have PCO on scan

8. PCO syndrome definition Revised 2003 Rotterdam ESHRE/ASRM (2 out of 3) – • Irregular periods • Evidence of raised male hormone levels • PCO & exclusion of other causes

9. Genetic Intra-uterine Nutritional Hormonal Fat Insulin Skin sensitivity Disordered ovulation Hirsutism, acne

10. Probably all women with hirsutism should have some tests • LH, FSH, TSH, PRL, Total T, SHBG, DHEAS, 17OHP. • Fasting lipids, glucose. Maybe GTT (& insulins) • Scan – doesn’t add a lot • PCOS: Usually at least one of LH, T or SHBG is abnormal

11. Red Flags • Always repeat a grossly abnormal result • Congenital Adrenal Hyperplasia: markedly raised 17OHP (do Synacthen test) • Very high T (>6nmol/l) or DHEAS (twice the upper limit of normal): think tumour • Abnormal GTT • Raised triglycerides (may be a sign of severe IR)

12. Insulin Resistance IR occurs in 30-60% of women with PCOS (Dunaif, 1992) IR is a post-receptor phenomenon, multifactorial & is mostly sited in the fat, muscle & liver, but the ovaries remain spared. Raised serum insulin levels stimulate ovarian androgen production & decrease hepatic SHBG production. IR is associated with adverse CVS surrogates (raised lipids, especially triglycerides & hypertension) Insulin sensitizers (metformin, the glizones) improve the androgenic profile & may induce ovulation.

13. Management options for the hirsute woman

14. Hair removal • Waxes, creams • Shaving • Electrolysis • Laser

15. Insulin Resistance • Low GI diet • Exercise • Metformin • Other weight loss strategies • Weight loss drinks • Drugs • Weight loss surgery

16. Metformin • Safe when used to treat gestational diabetes (MiG trial, N= 751, N Engl J Med 2008; 358: 2003-15) • Not associated with increased fetal abnormalities when used in first trimester (meta-analysis, 172 treated, 235 controls, Fert Ster Vol. 86, No. 3, September 2006) • Helps restore the cycle, & lowers risk of diabetes but doesn’t help hirsutism much

17. Statins • Many women with PCOS have adverse CVS markers which can be reversed with a statin • Statins inhibit proliferation and steroidogenesis of ovarian theca–interstitial cells in culture • Pawelczyk recently presented data on 60 women with PCOS randomised to simvastatin 20mg or metformin 850mg bd or both (Society for Reproductive Endocrinology and Infertility meeting 2008)

18. Results • Note • These data are very preliminary • Statins have been linked to birth defects

19. Menstrual problems • delayed first period • infrequent periods • heavy bleeding • continual bleeding Contraception requirements

20. Tranexamic acid • Anti-fibrinolytic • Safe, sold over the counter in Europe. • Dosage: 1g 3-4 times a day, day 1-5 • Very effective for heavy periods – usually more than halves the flow. Superior to OCP. • Side effects: nausea with doses >6g/day

21. Contraceptive Pill • Takes months to help hirsutism. • Effective for heavy periods. Can skip periods. Contraceptive. Superior to metformin for skin problems • Side effects: watch triglycerides & BP (oestrogen) & weight gain with CPA. Might aggravate IR. ‘PMT’ with progestin.

22. Progestins • Cyclical vs continuous • Uses: to stop a heavy period. Every 2m to prevent uterine lining build up • Side effects: ‘PMT’ (1/8); some have an adverse effect on IR. Dydrogesterone has no measurable metabolic effect.

23. Spironolactone • Need at least 100mg for anti-androgen effect • Used for skin problems, but often shortens the cycle. • Takes months to work • Side effects: diuretic

24. Eflornithine Cream • Eflornithine is an irreversible inhibitor of ornithine decarboxylase which in turn slows hair growth. Works in 2/3 in 4-8 weeks • Use sparingly. Tube lasts 3-4 months • Side effects: ‘tingling’

25. Clinical Trials • Two double-blind, randomised, parallel, vehicle-controlled studies performed with 596 women diagnosed with UFH were carried out • Subjects were randomised to receive Eflornithine or vehicle cream, applied topically twice daily for 24 weeks • By 8-weeks the active treatment had significantly better results than placebo. Eflornithine helped around 2/3 women

26. Clinical Trials • Side effects reported occurred at similar frequencies in Eflornithine and control groups, with most being skin-related. Side effects are primarily mild and resolve without medical treatment or discontinuation. It can sometimes aggravate acne. • Eflornithine has not been associated with phototoxic or photosensitisation reactions • A trial combining Eflornthine with laser hair removal, showed the women on active treatment needed fewer laser treatments

27. Levonorgestrel-IUD • Mechanism of action: progestin containing IUD. Safe, cheap, lasts 5 years. Very effective for heavy periods. • Contraceptive, reversible. • Side effects: Might need a GA to get it in. • Spotting for up to 3m. Can fall out. Risk of PID is ½ normal because of progestin’s effect on cervical mucus. Very little systemic effect.

28. Take Home Messages • PCO is common (1 in 4) & women with PCO & >6 periods a year are normal. • PCOS = PCO and symptoms • Around ½ women with PCOS & irregular periods, have IR • Measure lipids & fasting glucose in everyone (even the young) • For women with PCOS think about doing a 75g GTT (insulin & glucose levels)

29. Take Home Messages • Dietary recommendations: low GI, low fat diet • OCP – may increase triglyceride levels, but OCP better than metformin for acne & hirsutism. • Anti-androgens & Eflornithine lotion for hirsutism or acne • Metformin may be useful to help IR, aids weight loss & may induce ovulation. Doesn’t help hirsutism much. • Consider weight loss surgery for severely obese patients

30. Take Home Messages • Tranexamic acid will control heavy periods if the uterus is normal. • The Levonorgestrel-IUD is an excellent option for many women with PCOS as it controls heavy periods & prevents uterine cancer; without metabolic effects. It is cheap, lasts 5 years and on removal, fertility returns immediately.

31. Cases

32. Ms TG, 14y young woman with irregular heavy periods with flooding. She has about 3-4 periods a year. Tests show she has PCOS, but no evidence of metabolic syndrome. She is anaemic with low iron studies. Ultrasound scan shows an 8cm normal uterus

33. Tranexamic acid Progestins OCP Metformin

34. A 25y woman having 1-2 periods per year. BP 150/90; BMI 32. General exam nad, except acanthosis both axillae. Cholesterol 6; TG 4.5 Fasting glucose 5.8 Fasting insulin 50u/l

35. Treat IR Tranexamic acid Cyclical dydrogesterone Levonorgestrel-IUD OCP

36. 28 year old with PCOS & heavy periods. She also has acne & excess hair. Normal BP and no evidence of metabolic syndrome

37. OCP (& spironolactone) Eflornithine cream Hair removal Levonorgestrel-IUD Tranexamic acid Progestins

38. 28 year old woman with 12m infertility. She has 6 periods a year. Tests confirm PCOS. BMI 31.

39. Check other fertility factors Weight loss Metformin or clomiphene Monitor ovulation when cycles regular (BBT charts, LH kits)

40. 58 year old post-menopausal woman with excess facial hair. Most is light, ‘peach-fuzz,’ and some dark course terminal hair. She is not on HRT. Serum androgens normal.

41. Eflornithine cream Hair removal Spironolactone