1. Androgens & Antiandrogens Munir Gharaibeh, MD, PhD, MHPE Faculty of Medicine The Jordan University April 2014

2. Androgens The testes have two major functions: 1. Spermatogenesis occurring within the seminiferous tubules 2. Production of androgenic hormones

3. Androgens Naturally occurring androgenic hormones are: 1. Testosterone, the principal androgenic hormone, is mainly produced by the Leydig cells of testes. 2. Dehydroepiandrosterone (DHEA) is produced by adrenal cortex. 3. Androstenedione The testes also produce other hormones: Estradiol Inhibin( feedback inhibits FSH) Activin

4. Testosterone synthesis DE Deh DE Deh Cholesterol Pregnenolone Progesterone Hyd Hyd Testosterone Androstenedione Hydroxyprog. 5α-reductase 5α-reductase 5α-dihydrotestosterone 5α-dihydrotestosterone June 16 4 Munir Gharaibeh, MD, PhD, MHPE

5. GnRH GnRH - ↓ - ↓ LH; FSH LH; FSH - ↓ - ↓ Testosterone; spermatogenesis Testosterone; spermatogenesis June 16 5 Munir Gharaibeh, MD, PhD, MHPE

6. Transport & MOA of androgens: 65% is bound to SHBG, 2% is free, rest bound to albumin. 65% is bound to SHBG, 2% is free, rest bound to albumin. 5α-reductase 5α-reductase Testosterone 5α-dihydrotestosterone (sex organs) Testosterone 5α-dihydrotestosterone (sex organs) (skeletal muscles) (skeletal muscles) cytosloic; nuclear receptors increase transcription of a specific protein androgen effects cytosloic; nuclear receptors increase transcription of a specific protein androgen effects DHT is 10 times more potent than testosterone and mediates the effects of testosterone on skin and sexual apparatus (prostate; DHT is 10 times more potent than testosterone and mediates the effects of testosterone on skin and sexual apparatus (prostate; seminal vesicle, epididymis…) June 16 6 Munir Gharaibeh, MD, PhD, MHPE

7. Pharmacological effects - Virilizing=musculinizing effect 1° & 2° sexual characteristics 1° & 2° sexual characteristics - Spermatogenesis - Erythropoiesis - Anabolic or growth promoting effect (bone; skeletal muscles) June 16 7 Munir Gharaibeh, MD, PhD, MHPE

8. Clinical Uses - Testosterone deficiency Hypogonadism; impotence; ↓ libido; aging; infertility. Hypogonadism; impotence; ↓ libido; aging; infertility. - Anemia; leukemia; lymphoma - Endometriosis (Danazol is particularly used) June 16 8 Munir Gharaibeh, MD, PhD, MHPE

9. Clinical Uses - Antiestrogenic effect: Breast cancer. Breast cancer. - Anabolic effect. Osteoporosis Osteoporosis Abused by athletes. Abused by athletes. June 16 9 Munir Gharaibeh, MD, PhD, MHPE

10. Testosterone preparations For androgen replacement: - Testosterone I.M; S.C - Testosterone propionate I.M, S.L - Testosterone cypionate I.M; depo I.M - Methyltestosterone O; S.L - Fluoxymestrone O For breast cancer: Testolactone (progesterone derivative and aromatase inhibitor) O June 16 10 Munir Gharaibeh, MD, PhD, MHPE

11. Testosterone preparations For anabolism (osteoporosis): For anabolism (osteoporosis): Androgen:anabolic ratio=1:2 or 1:3 ( Androgen:anabolic ratio=1:2 or 1:3 (promote + ve anabolism and muscular growth but little effect on sex) - Ethylestrenol O - Stanozolol O - Oxandrolone O - Nandrolone decanoate I.M - - Methandienone O June 16 11 Munir Gharaibeh, MD, PhD, MHPE

12. Side Effects of Testosterone - Virilization (musculinization) Hirsutism; acne; menstrual disorders in ♀ ’s - Precocious puberty & hirsutism in children - Salt & water retention - Jaundice; gall bladder stones (methyltestosterone) - Enlargement of prostate - ? Liver cancer June 16 12 Munir Gharaibeh, MD, PhD, MHPE

13. Antiandrogens - Estrogens: Diethylstilbesterol; mestranol... - Progestins: Cyproterone acetate - GnRH superagonists (Leuprolide acetate); GnRH antagonists (Ganirelix) Flutamide; B Flutamide; Bicalutamide and Nilutamide - 5α- reductase inhibitors: Finasteride - Ketoconazole - Spironolactone - Gossypol June 16 13 Munir Gharaibeh, MD, PhD, MHPE

14. Gossypol Cottonseed derivative, China. Cottonseed derivative, China. Destroys elements of the seminifrous epithelium, but does not affect the endocrine function of the testes. Destroys elements of the seminifrous epithelium, but does not affect the endocrine function of the testes. Irreversible if continued more than 2 years. Irreversible if continued more than 2 years. Can cause hypokalemia and paralysis. Can cause hypokalemia and paralysis. Not used in western medicine. Not used in western medicine. June 16 14 Munir Gharaibeh, MD, PhD, MHPE

15. Clinical Uses of Antiandrogens - Ca prostate - Benign hyperplasia of the prostate (Finasteride) - Severe acne and hirsutism in ♀ ’s (Spironolactone; Cyproterone acetate) - Precocious puberty - ♂ antifertility agents ( ♂ contraceptive) (Gossypol) - ♂ baldness (Cyoctol - ♂ baldness (Cyoctol=topical antiandrogen; Finasteride) June 16 15 Munir Gharaibeh, MD, PhD, MHPE

16. Side Effects of Antiandrogens ↓ Libido Impotence ↓ Spermatogenesis ↓ Ejaculate June 16 16 Munir Gharaibeh, MD, PhD, MHPE