1. Hyperandrogenism in the adolescent girl Dr. Mona Shroff, M.D. Diploma in Obs. & Gynaec Ultrasound EMOC Clinical Trainer (JHPIEGO)

2. Mild symptoms of hyperandrogenism are common in adolescents Hirsutism – 6% Acne – 36-98% in western countries 1. Hashemipour M. et al. Horm Res. 2004;62(6):278-82. Epub 2004 Oct 29. 2. J.J. Chan and J.B. Rohr. Australas J Dermatol 41 (2000) (Suppl), pp. S69– S72 3. Freyre EA et al. J Adolesc Health. 1998 Jun;22(6):480-4.

3. .... In some girls These features persist and even make worse.. Additionally :: These HA symptoms may be associated with irregular menstrual cycles. Three years post menarche 20 -40% cycles are irregular (Physiological HA of Puberty). Hashemipour M. et al. Horm Res. 2004;62(6):278-82. Epub 2004 Oct 29. Widholm & Kantero.. Act Obstet Gynecol Scand;1971:14:1-36

4. Subjects with persistent symptoms of hyperandrogenism Most frequently associated with PCOS But another etiologies must be ruled out. Clinicians main aim should be to Establish an early PCOS diagnosis. Rule out Adrenal/Ovarian Tumor & NCAH

5. This presentaton includes Aetiology of HA Approach to an adolescent with HA - Important clinical features to look for -the optimum necessary Ix -Evidence based best possible Rx protocol Case studies

6. Adult v/s Adolescent HA FOH or Organic cause??? USG not reliable-ovaries may be N. Premature adrenarche –strong predictor. Long term Rx-choose drugs with min. lipid & metabolic S/E. Lifestyle changes – biggest impact- Prevention of PCOD !!! J Pediatr Endocrinol Metab. 2000;13 Suppl 5:1285-9

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

9. Abnormalities Associated with Androgen Excess Acne Hirsutism Alopecia Android obesity Menstrual dysfunction Infertility Cardiovascular disease Dyslipidemia Glucose intolerance/insulin resistance/T2NIDDM Hypertension Signs of Virilization Acne Hirsutism Clitoromegaly Deepening of voice Increased libido Increased muscle mass (primarily shoulder girdle) Infrequent or absent menses Loss of breast tissue or normal female body contour Malodorous perspiration Temporal hair recession and balding

10. Diagnosis of HA in Female Adolescents 1. Clinical assessment 2. Laboratory screening 3. Further investigations

11. 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

12. 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

15. Age-related changes in the PCOS phenotype Reproductive abnormalities Clinical hyperandrogenism Metabolic abnormalities Adolescence Adult fertile ageMenopausePostmenopause

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

17. INITIAL LAB SCREENING Testosterone total – may be N in hirsute woman if T> 200 screen for tumor free – no clinical need to check if HA effect seen then free T must be raised

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

19. 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

20. 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

21. DHEAS ??? Moderate elevation common in anovulatory females > 700 micgm/dl – v.rare if T> 200 – screen for tumor must No further benefit by testing,not cost effective Gordon,Speroff 2002

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

23. 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

24. 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.

25. 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. –

26. 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 COCPs270-350 KetoconazoleG.I, Liver180-360

27. 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.

28. 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.

29. 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.

30. TUMOUR SURGICAL REMOVAL

31. 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

32. 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.

33. Case A 16 y/o female Menses q 3--4 months Mild facial acne FG Score of 5 (1 lip, 1 chin, 2 lower abd, 1 back) BMI 33.3 kg/m2 No galactorrhoea How would you evaluate this patient?

34. Lab results TSH, Prolactin, 17OH P : normal Total T : 70 ng/mL [<72 ng/mL] Fasting Insulin : 22 mIU/mL [<17 mIU/mL] Fasting Glucose 92 mg/dL How would you treat this patient?

35. Patient was treated with metformin (consider adding COCs) After 3 months: Spontaneous resumption of monthly menses Hirsutism and acne improved

36. Case B 16 y/o Hispanic 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 How would you evaluate this patient?

37. 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?

38. ACTH Stimulation Test Baseline 17 OH P 2..5 ng/dL 60 min 17 OH P 18 ng/dL How would you treat this patient?

39. 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

40. THANK YOU