1. Hyperandrogenism Beata Banaszewska Department of Infertility and Reproductive Endocrinology

2. Androgens are C-19 steroids produced in:  Ovary  Adrenal gland Androgens are metabolised in:  Skin  Adipose tissue  Liver  Placenta

3. The production rate of testosterone in the normal female is 0.2 to 0.3 mg/day Normal total testosterone concentration in serum is below 0.8ng/ml

4. Testosteron is transported: Normal women Hirsute women 80% SHBG 79% SHBG 19% Albumin 1% Free 2% Free

5. The main androgens  Dehydroepiandrosterone (DHEA)-a weak carbon-5 androgen secreted principally by the andrenal gland  Androstendione (A) - a weak carbon-4 androgen secreted in equal amounts by the adrenal glands and ovaries  Testosterone (T)- a potent carbon-4 androgen secreted by the adrenal glands and ovaries and produced in adipose tissue from the conversion of androstendione  Dihydrotestosterone (DHT)-even more potent than testosterone.The conversion from testosterone is the result of action of 5  reductase

6. Origin of circulating androgens Testosterone Androstendione DHA DHAS 25% 99%90%50% 10% OVARY ADRENAL CORTEX

7. Causes of hyperandrogenism:  PCOS75%  Idiopatic hirsutism15%  Adrenal hyperplasia3%  Cushing’s disease1%  Hyperprolactinemia1%  Tumor of the ovary1%  Tumor of the adrenal0,1%  After medications1%

8. Hyperandrogenism- clinical symptoms:  Irregularity of menstrual cycle  Hirsutism  Acne  Clitorimegaly  Alopecia  Deepending of the voice  The changes in the body shapes  Increased muscular mass  Infertility

9. Hirsutism  It is cutaneus manifestation of hyperandrogenism  Women have male-pattern hair growth  In areas : –upper lip –chin –sideburn area –upper neck –chest –upper arm –lower abdomen –intergluteal region –perineum –thigh Hirsutism rating scale by Ferriman Gallwey >8 points - hirsutism

10. Polycystic ovary syndrome (PCOS)  5-10% of women in reproductive age  Hyperandrogenism  Amenorrhoea  Anovulation  Infertility  Obesity

11. The clinical consequences of chronic anovulation in PCOS women  Infertility  Oligomenorrhea and amenorrhea  Hirsutism and acne  An increased risk of endometrial cancer  An increased risk of cardiovascular disease  An increased risk of diabetes mellitus in patients with hyperinsulinemia

12. Sign and symptoms of PCOS patients Observation Average incidence Infertility75% Hirsutism56% Amenorrhea47% Obesity33% Regular menses16% Virilisation17%

13. Endocrine abnormalities in PCOS  testosterone  or normal LH/FSH ratio  Normal Estrogens  SHBG  or normal Insulin  or normal Prolactin  or normal DHS

14. Characteristic of the polycystic ovary  The surface area is doubled  The number of growing and atretic follicles is doubled (Each ovary may contain 20-100 cystic follicles)  The thickness of the tunica is increased by 50%  There are 4 times more ovarian hilus cells nests

15. The Polycystic Ovary on ultrasound  The ovaries have pericentic cysts of 5 to 10 mm - usually at least 10 in one sonographic plane  Increased ovarian stroma  Only 75-80% wonem with the clinical diagnosis of PCOS had polycystic ovary  Prevalence of the polycystic ovaries in 16 to 23% of „normal” women  In 50% women with hyperprolactinemia  24% of women with hypothalamic amenorrhoea  100% of women with CAH

16. Constitutional hirsutism  Women with greater activity of 5  reductasein in the skin  Normal ovulation  Regular menstrual cycle  Normal hormone concentrations

17. Polycystic ovary syndrome (PCOS) -patogenesis  Insulin resistance: -postreceptor defect in tyrosine kinase activity, dysfunction of GLUT-4 -defect of insulin receptor -anti-receptor antibodies  Compensatory hyperinsulinemia  Decrease in SHBG and IGFBP-1 production  Excessive androgen production

18.   Insulina Types of insulin resistance Type B Type A Type C Autoantibodies to insulin receptors Genetic defect of insulin receptor (Kahn syndrome) Defect of tyrozine kinase tyrozine kinase

19. Wchich comes first, the hyperinsulinemia or the hyperandrogenism ? There are 6 reasons that hyperinsulinemia causes hyperandrogenism  The administration of insulin to women with PCOS increases circulating androgen levels  The administration of glucose to women with PCOS increases the circulating levels of both insulin and androgen  Weight loss decreases the levels of both insulin and andrgens  In vitro, insulin stimulates thecal cell androgren productions  The experimental reduction of insulin levels in PCOS women reduces androgen levels  After normalisation of androgen with GnRH agonist treatment, the hyperinsulin response toglucose tolerance testing remains abnormal in obese women with polycystic ovaries

20. IGFBP-1 IGF1 Hyperinsulinemia Ovarian stymulation Hyperandrogenizm Insulin resistance Genetic defects of insulin receptor Autoantibodies to insulin receptor Ovarian insulin receptors LH/FSH Ovarian IGF-I receptors PCOS Hyperthecosis SHBG Free Testosterone Defects of tyrosine kinase

21. cholesterol Pregnenolone Progesterone 17  hydroksyprogesterone Androstenedione Testosterone THECA CELL GnRH pulse frenuency LH/FSH ratio LH receptor   Insulin IGF receptor 17  hydroksylase 17  -lyase 17  -reductase Steps involving P450c17 

22. Ovarian defect in the pathogenesis of PCOS  Dysregulation of cytochrome P450c17  that results in : –increased activity of 17  hydroksylase –disordered 17,20-lyase activity –excessive ovarian androgen production  There is hypothesis that hyperinsulinemia stimalates ovarian cytochrome P450c17   Defect in 3  -hydroksysteroid dehydrogenase or aromatase activity

23. Two Clinical categories of Functional Ovarian Hyperandrogenism Hyperandrogenism Hyperandrogenism with insulin resistance without insulin resistance Testosterone Elevated Elevated Fasting insulin Elevated Normal or minimally elevated LH Minimally elevated Markedly elevated LH response Normal Exaggerated to GnRH DHAS Low-normal Normal or elevated Ovarian pathology Stromal hyperthecosis Polycystic ovaries

24. Differentation of hyperandrogenism Diagnosis Menstrual Total DHAS LH 17OHProg Sourse of Pattern Testoste- Androgens rone PCOS Irregular Elevated Elevated Elevated Normal OVARY Hyper- Amenorrhea Elevated Normal Normal Normal OVARY thecosis often>1.5 ng/ml Idiopatic Regular Normal Normal Normal Normal SKIN hirsutism Adrenal Irregular Elevated Often Usually Elevated ADRENAL hyperpla- Normal Normal >4ng/ml sia at 8pm in follicular phase

25. Congenital adrenal hyperplasia (CAH) Enzyme deficiency:  21 hydroksylase deficiency (85% of cases of CAH) -without sait wasting – cortisol – 17OHprog, DHAS – 17-KS, prednantiol, pregnandiol  21 hydroksylase deficiency -with sait wasting  11-hydroksylase deficiency Late onset adrenal hyperplasia sometimes occurs in women in reproductive age.

26. Differentation of ovarian and adrenal hyperandrgenism  DHAS  17-OH Progesterone  17-KS  Test with dexamethasone

27. Treatment of infertile PCOS women  Induction of ovulation –Clomiphene citrate –gonadotropins  Treatment of hyperinsulinemia –weight loss –metformin, troglitasone  Surgical treatment –ovarian wedge resection by laparotomy –ovarian wedge resection by laparoscopy –ovarian cauterisation by laparoscopy

28. OGTT in PCOS Chang et al 1983, JCEM, 57:356

29. Hyperinsulinemia treatment  Metformin  Troglitasone  Weight loss

30. Metformin  Biguanide used in NIDDM  Inhibits hepatic glucose production  Suppresses intestinal glucose absorption  Increases insulin sensitivity in peripheral tissues  Regulates lipid metabolism

31. Metformin in PCOS therapy  Improvement in insulin sensitivity, hyperinsulinemia and androgen levels Velazquez et al. 1994, Metabolism, 43, 647-54;Velazquez et al. 1997, Metabolism, 46, 454-7; Nestler et Jakubowicz, N Engl J Med., 335, 617-23  Significant decrease in BMI and WHR Velazquez et al. 1994, Metabolism, 43, 647-54  Improvement of menstrual regularity Morin-Papunen et al..1998, Fertil Steril, 69, 691-6, Velazquez et al. 1997, Obstet Gynecol, 90, 392-9  No beneficial effects in some studies Acbay et al,1996 Fertil Steril, 65, 949-9; Ehrmann et al., 1997, JCMB, 82, 524-30  No data on effects on clinical parameters : hirsutism and acne

32. Effect of metformin therapy on insulin * statistically different, p<0,001 0 5 10 15 20 25 30 35 Insulin(  U/ml)  Insulin before treatment Insulin after treatment * mean +/_ SEM

33. 0 0,2 0,4 0,6 0,8 1 1,2 1,4 Testosterone (ng/mL) Testosterone before treatment Testosterone after treatment * Effect of metformin therapy on testosterone * statistically different, p<0,001 mean +/_ SEM

34. * statistically different, p<0,05 Effect of metformin therapy on SHBG 0 10 20 30 40 50 60 SHBG (nmol/L) SHBG before treatment SHBG after treatment * mean +/_ SEM

35. Effect of metformin therapy on FTI * statistically different, p<0.001 mean +/_ SEM 0 5 10 15 20 25 FTI FTI before treatment FTI after treatment *

36. Effect of metformin therapy on LH, FSH and LH/FSH ratio 0 5 10 15 LH (mIU/mL) 0 5 10 15 FSH (mIU/mL) 0 5 10 15 LH/FSH Before treatment After treatment LH FSH LH/FSH mean +/_ SEM

37. Effect of metformin therapy on body mass index * statistically different, p<0.005 mean +/_ SEM 0 10 20 30 40 BMI (kg/m2) BMI before treatment BMI after treatment *

38. 0 20 40 60 80 Lenght of menstrual cycle (days) Lenght of cycle before treatment Lenght of cycle after treatment Effect of metformin therapy on lenght of menstrual cycle mean +/_ SEM * statistically different, p<0,001 *

39. Effect of metformin therapy on WHR * statistically different, p<0.001 mean +/_ SEM 0 0,2 0,4 0,6 0,8 1 1,2 WHR WHR before treatment WHR after treatment *

40. Troglitasone  Mechanism of action is not completely anderstood  Enhance insulin action without insulin secetion  It is a selective ligand for peroxisome proliferation-activated receptor in adipose tissue  hepatotoxity ?

41. Results of clomiphene therapy in PCOS patients Ovulation 80% Pregnancy rate 75% Pregnancies/ovulatory cycle 25-35% Multiple pregnancies 8% Abortion rate 30-40%

42. Results of gonadotropin therapy in PCOS women Ovulation 90% Pregnancy rate 70% Pregnancies/ovulatory cycle 25-30% Multiple pregnancies 10% Abortion rate 25-30%

43. Women with PCOS have a higher incidence of ovarian hyperstimulation syndrome after ovulation stymulation

44. Treatment of hirsutism  Cyproterone acetate (It bloks androgen action by competitive binding to androgen receptor) 50-100mg/day on days 5-14 of the cycle nad ethinyl estradiol 30-35ug/day on cycle days 5-25 or combination of CPA (2mg/day) and EE (35ug/day) on cycle days 5-25  Spironolactone (aldosteron antagonist) 50-200mg/day between days 4 and 22 of cycle ; 50-75mg/day-mild to moderate hirsutism; 100-200mg/day severe hirsutism  Flutamide (used in prostate cancer,It inhibits the binding of 5  -DHT to androgen receptor ; 250mg twice a day - it was used continuosly  Cimetidine (Imidazole is an antagonist of H2 receptor) 300mg four to five times daily for3-12 months

45. Androgen-producing ovarian neoplasm  Sertoli-Leydig cell tumors (Androblastoma, Arrhenoblastoma)  Hilus cell tumors  Lipoid cell tumor  Granulosa-theca cell tumors on ocassion  Gynandoblastoma in wchich both granulosa and leydig cell elements coexist <1% of all ovarian tumors

46. Androblastoma  Sertoli-Leydig cell tumors  The ovarian neoplasms secrete testosterone  Less than 0.4%  The tumors occur in women between the ages of 20 and 40  The most often unilateral  Rapid onset of hirsutism and virilisation  Surgical treatment

47. Gynandroblastoma  Tumors have both granulosa cells and androblastoma components  Masculinisation  Estrogen production produce endometrial hyperplasia and irregular uterine bleeding  Surgical treatment

48. Iatrogenic androgen levels  Danazol It is administered in endometriosis Spome women develop hirsutism, acne and deepening of the voice  Oral contraceptives Progestins compartment Ralely women develop acne and even hirsutism

49. Hyperandrogenism and menopause  The high circulating LH levels activates ovarian stroma and hilus cells steroidogenesis  The menopausal ovary is a major source of testosterone, secretes moderate amounts of androstendione  The pattern of androgen secretion is changed: Before menopause After menopause A>>T T>A

50. Increased risk of diabetes mellitus in PCOS women PCOS Age 40-49 lat 50-61 lat WHR 0.81 +/- 0.06 0.84+/- 0.09 Diabetes (%) 11.1 20.0 Controls Age 40-49 lat 50-61 lat WHR 0.78 +/- 0.06 0.79+/- 0.09 Diabetes (%) 3.5 1.3 Dahlgren, Acta Obstet Gynecol Scand,1992,71,599

51. Abnormalities in lipid profile in PCOS women  Increased total cholesterol  Increased triglycerides  Increased LDL  Deacrised HDL Talbott et al.,1998,J Clin Epidemiol,51,41 Conway et al.,1992,Clin Endocrinol,37,119 von Eckardstein,1996,Gynecol Endocrinol,10,311

52. Abnormalities in lipid profile in PCOS women Abnormal lipids pattern is independent of body weight Wild et al.,1992, Am J Obstet Gynecol,166,1191 Graf et al., 1990, Clin Endocrinol,33.119

53. Insulin resistance and Hyperinsulinemia Advers lipid profile Glucose intolerance NIDDM Cardiovascular disease PAI-1 Obesity