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Hyperandrogenism Beata Banaszewska

Hyperandrogenism Beata Banaszewska. Department of Infertility and Reproductive Endocrinology. Androgens are C-19 steroids produced in:. Ovary Adrenal gland. Androgens are metabolised in:. Skin Adipose tissue Liver Placenta.

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Hyperandrogenism Beata Banaszewska

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

  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 a-reductase

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

  7. Causes of hyperandrogenism: • PCOS 75% • Idiopatic hirsutism 15% • Adrenal hyperplasia 3% • Cushing’s disease 1% • Hyperprolactinemia 1% • Tumor of the ovary 1% • Tumor of the adrenal 0,1% • After medications 1%

  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 Infertility 75% Hirsutism 56% Amenorrhea 47% Obesity 33% Regular menses 16% Virilisation 17%

  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 a-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. Types of insulin resistance Type B Type A Insulina Autoantibodies to insulin receptors Genetic defect of insulin receptor (Kahn syndrome) a a Type C b b tyrozine kinase Defect of 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. Defects of tyrosine kinase Autoantibodies to insulin receptor Genetic defects of insulin receptor Insulin resistance Hyperinsulinemia Ovarian insulin receptors Ovarian IGF-I receptors IGFBP-1 SHBG LH/FSH IGF1 Free Testosterone Ovarian stymulation Hyperthecosis PCOS Hyperandrogenizm

  21. GnRH pulse frenuency LH/FSH ratio THECA CELL LH receptor cholesterol Pregnenolone Progesterone 17a hydroksyprogesterone Androstenedione Testosterone 17a-hydroksylase Steps involving P450c17a 17, 20 -lyase b 17b-reductase a Insulin IGF receptor

  22. Ovarian defect in the pathogenesis of PCOS • Dysregulation of cytochrome P450c17a that results in : • increased activity of 17a-hydroksylase • disordered 17,20-lyase activity • excessive ovarian androgen production • There is hypothesis that hyperinsulinemia stimalates ovarian cytochrome P450c17a • Defect in 3b-hydroksysteroid dehydrogenase or aromatase activity

  23. 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 hyperthecosisPolycystic ovaries Two Clinical categories of Functional Ovarian Hyperandrogenism

  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 35 Insulin before treatment Insulin after treatment 30 25 * 20 Insulin(mU/ml) 15 10 5 mean +/_ SEM 0 * statistically different, p<0,001

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

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

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

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

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

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

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

  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 5a-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

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