1. HyperandrogenismHyperandrogenism Dr. Mona Shroff SOGOG CME 2007

2. Case A 14 y/o female (menarche 1 yr back) Menses q 3--4 months Mild facial acne FG Score of 5 (1 lip, 1 chin, 2 lower abd, 1 back) BMI 29 kg/m2 No galactorrhoea

3. What are the various causes of hyperandrogenism? In this adolescent girl what probable cause do you suspect?

4. Aetiology of hyperandrogenism FOH of puberty PCOS HAIR-AN syndrome Hyperprolactinemia Hypothyroidism NCAH TUMORS-Ovarian / Adrenal Cushings disease Drugs

5. What particular aspects of history & clinical features would you like to look for?

6. Clinical assessment History The following items are important:: Family History of HA/Obesity/temporal balding/infertility Hx of Precocious adrenarche More than 2 years of oligomenorrhea

7. Clinical assessment.. Physical examination Degree of hirsutism, acne Obesity,increased W/H ratio Acanthosis nigricans- r/o PCOS,HAIR-AN Rapidly growing hirsutism or Virilizing symptoms – r/o TUMOR Symptoms of hypercorticism –r/o CUSHING Galactorrhea – r/o HYPERPROLACTINEMIA

8. What is this C/F?

10. Would you like to investigate this patient at this juncture?

11. Would you like to start treatment at this time? In which particular patients would you evaluate & treat at an early age?

12. J Pediatr. 2004 Jan;144(1):23-9. Insulin sensitization early after menarche prevents progression from precocious pubarche to polycystic ovary syndrome in a high-risk group of formerly LBW girls.

13. LIFESTYLE MODIFICATIONS

14. Adult v/s Adolescent HA FOH or Organic cause??? USG not reliable-ovaries may be N. Premature adrenarche –strong predictor. Lifestyle changes – biggest impact-Prevention of PCOD !!! J Pediatr Endocrinol Metab. 2000;13 Suppl 5:1285- 9

15. Same patient comes to you after 2 yrs (age 16 yrs) - still having same clinical picture but worsened delayed periods mod. acne & hirsutism BMI 32

16. Would you like to evaluate this patient now? What initial screening investigations would you like to go for & why?

17. INITIAL LAB SCREENING TESTOSTERONE PROACTIN TSH Evaluation for HYPERINSULINEMIA 17 OH PROGESTERONE

18. INITIAL LAB SCREENING Testosterone total – may be N in hirsute woman if T> 200 screen for tumor free T?? Should we ask for? – no clinical need to check - if HA effect seen then free T must be raised - does not help in D/D or treatment

19. TSH - esp if alopecia PROLACTIN - DHEAS,free T (SHBG ) HYPERINSULINEMIA Fasting glucose : Insulin < 4.5 Fasting insulin > 20 2 hr GTT > 140

20. 17 OH P - for NCAH, follicular ph/morning -routine screen in HA indicated (esp if sev hirsutism at younger age,short stature) * <200 ng/dl : N * 200 – 800 : ACTH stimulation test * > 800 : diagnostic

21. Screen for Cushings if clinical suspicion late eve. plasma cortisol single dose overnight DST Imaging of adrenals & ovaries (USG/CT/MRI) * if rapid virilization * T > 200 micgm/ dl

22. Audience question Would you like to include S.DHEAS in her list of investigations? If YES - WHY? If NO – WHY NOT?

23. DHEAS ??? Moderate elevation common in anovulatory females > 700 micgm/dl – v.rare if T> 200 – screen for tumor must Mod. elevated DHEAS does not necessitate or prove the need & benefit of treatment with dexamethasone No further benefit by testing,not cost effective Gordon,Speroff 2002

24. Lab results of this patient TSH, Prolactin, 17OH P : normal Total T : 70 ng/mL [<72 ng/mL] Fasting Insulin : 22 mIU/mL [<20 mIU/mL] Fasting Glucose 92 mg/dL

25. What are the options available for treating HA?

26. COCPs ANTIANDROGENS SPIRONOLACTONE FUTAMIDE FINASTERIDE CYPROTERONE DEXAMETHASONE KETOCONAZOLE CIMETEDINE GnRH AGONISTS INSULIN SENSITIZERS MECHANICAL AGENTS(hirsutism) ANTIBIOTICS (acne)

27. Considering our diagnosis of PCOS in this girl what are your aims of treatment What treatment would you like to start in this patient? How long should you continue with this treatment?

28. Management of excess ovarian androgen production : Standard therapy is :combined E+P OCs It reduces ovarian androgen production It increases SHBG It induces competition at the cellular level for binding to the androgen receptor

29. METFORMIN In addition to the expected improvements in insulin sensitivity and glucose metabolism Ameliorates hyperandrogenism and menstrual irregularity. Reduces total cholesterol, LDL and triglycerides of PCOS adolescents while increasing HDL cholesterol. Decrease C-reactive protein and a normalization of the neutrophil/lymphocyte ratio, which are predictive of cardiovascular disease. Benefits both obese & non obese Hum Reprod. 2005 Sep;20(9):2457-62. Hum Reprod. 2002 Jul;17(7):1729- 37.

30. ANTIANDROGENS According to currenty available evidence no antiandrogen is superior to other in terms of clinical efficacy, so choice depends upon S/E & cost.Further studies needed. Chocrane reviews, Issue 1, 2006 Fertil Steril. 1999Mar;71(3):445-51. –

31. S/E & cost of antiandrogens drugS/ECost/mnth(Rs) spironolactoneMetrorrhagia,K G.I,drowsiness 120-480 Finasteridemild280-300 flutamideG.I, Liver750 Cyproterone acetate As with COCPs 270-350 KetoconazoleG.I, Liver180-360

32. Would you like to add a steroid (dexona) to your therapy in this patient?

33. AUDIENCE QUESTION WHICH PILL WOULD YOU CHOOSE FOR ADOLESCENT PCOS with HA & WHY? LNG containing (mala-D,ovral-L,Loette) DESOGESTREL containing (novelon,femilon) CYPROTERONE containing (Ginette,krimson35, diane35) DROSPIRINONE containing (yasmin)

34. COCs LNG vs Desogestrel vs CPA DSG & CPA pills comparable efficacy, better than LNG.(CPA slightly better for acne) DSG & CPA pills comparable side effects ( VENOUS THROMBOEMBOLISM & LIVER ) Acta Obstet Gynecol Scand Suppl. 1986;134:29-32. Int J Fertil Menopausal Stud. 1996 Jul-Aug;41(4):423-9. Fertil Steril. 2002 May;77(5):919-27. Eur J Contracept Reprod Health Care. 2001 Mar;6(1):46-53. J Obstet Gynaecol Can. 2003 Dec;25(12):1011-8. Pharmacoepidemiol Drug Saf. 2004 Jul;13(7):427-36. Pharmacoepidemiol Drug Saf. 2003 Oct-Nov;12(7):541-50.

35. Case B 16 y/o female Menses q 3-4 months Moderate facial acne FG Score of 5 (1 lip, 1 chin, 2 lower abd, 1 back) Tanner Stage breast 4, pubic hair 4 BMI 26..3 kg/m2 No galactorrhoea INITIAL SCREENING ??

36. Lab results TSH,, Prolactin normal 17OH P : 2.5 ng/mL [<2 ng/mL] Total T : 70 ng/mL [<72 ng/mL] Fasting Insulin 14 mIU/mL [<17 mIU/mL] Fasting Glucose 92 mg/dL What would you do next?

37. ACTH Stimulation Test Baseline 17 OH P 2..5 ng/dL 60 min 17 OH P 18 ng/dL What is your inference? How would you treat this patient?

38. Treat hyperandrogenism with dexamethasone or CPA or spironolactone or flutamide Treat irregular menses with combined oral contraceptive pills Treat infertility when patient desires pregnancy Consider adding dexamethasone to ovulation induction

39. NCAH J Clin Endocrinol Metab. 1990 Mar;70(3):642-6. Cyproterone acetate versus hydrocortisone treatment in late-onset adrenal hyperplasia. Peripheral antiandrogen therapy may be more appropriate in late-onset adrenal hyperplasia patients than conventional adrenal inhibition using cortisone therapy.

42. CONCLUSIONS HA is a common adolescent probem Our main aim is early PCOS diagnosis & ruling out tumor/NCAH. Watch for premature pubarche. Initial screen –T, TSH, Prolactin, fasting glucose:insulin, 17 OH P Imaging for tumor if T>200 or rapid virilisation

43. CONCLUSIONS (contd.) Lifestye modification & weight reduction plays a key role. Integrated approach – combination of drugs with best outcome & min. S/E. (COCs + IS +/- Antiandrogen). PCOS - Candidates for long term therapy.

44. THANK YOU