Male sex hormones include testosterone and dihydrotestosterone. Testosterone is produced in the testes and regulates the development of male sexual characteristics. It acts through binding to androgen receptors and altering gene expression. Common therapeutic uses of testosterone and related compounds include treating testicular failure, muscle wasting, osteoporosis, and symptoms of aging in men. Side effects can include virilization, acne, and risks to the prostate.

1. MALE SEX HORMONES: BY DR.UMA KADAM M.B.B.S. MD ASSOCIATE PROFESSOR PHARMACOLOGY SKNMC DR.UMA K.

2. Male sex hormones Androgens Synthesis& secretion Regulation Mechanism of action Pharmacological actions Pharmacokinetics Preparations Therapeutic uses Adverse effects Anabolic steroids Differ from androgens? Preparations Therapeutic uses Adverse effects Anti-androgens Danazole Cyproterone acetate Flutamide Finasteride Sildenafil DR.UMA K.

3. Androgens: Includes testosterone, DHT & androstenedione Testosterone serves as a prohormone for Dihydrotestosterone (DHT) Estradiol DR.UMA K.

4. DR.UMA K. Estriol Estrone Cholesterol Pregnenolone Progesterone 17- α - Hydroxy pregnenolone 17- Hydroxy progesterone Dehydro-epi androsterone Andro-stenedione TESTOSTERONE ESTRADIOL Aromatase Aromatase Corticosteroids Corticosteroids DHT 5  -reductase

5. DR.UMA K. (DHT)

6. DR.UMA K. Testes Leydig Cells Sertoli Cells Negative feedback Estradiol Inhibin Negative feedback FSH Negative feedback Testosterone LH LH & FSH HYPOTHALAMUS ENDOCRINE FACTORS Pituitary GnRH Regulation of secretion

7. LH: Promotes testosterone synthesis FSH: Promotes spermatogenesis (in concert with testosterone) Testosterone secretion is pulsatile i.e. Highest- 8 am Lowest- 8 pm Decreases with age Regulation of secretion: DR.UMA K.

8. DR.UMA K.

9. Mechanism of action of steroid hormones Hormone enters cell by diffusion across plasma membrane binds to specific cytoplasmic receptor translocation to nucleus alteration in gene transcription alteration in level of active mediator of effect DR.UMA K.

10. DR.UMA K. MECHANISM OF ACTION: T DHT DHT- R T- R R R T- R Nucleus 90% 10% 5-  -reductase Cytoplasm

11. DR.UMA K. Change in transcriptional activity: Testosterone, like the other steroid hormones, acts intracellularly in target cells. Androgen-receptor complex acts at level of transcription. In skin, prostate, epididymis and seminal vesicles, dihydrotestosterone is the dominant androgen. Testosterone binds to the androgen receptor in cytoplasm of cells Binding causes a change in conformation and localization in the nucleus Receptor is a transcription factor that binds to the regulatory region of genes having an androgen response element (ARE) e.g. Prostate specific antigen (PSA) Mutations in the gene for the receptor can cause resistance to testosterone

12. Actions of Testosterone & DHT : Pharmacologic Effects: Large doses of testosterone suppress gonadotropic secretion in adult males Androgens produce changes similar to male puberty in females Natural androgens stimulate erythrocyte production Androgens increase protein synthesis/decrease protein breakdown (anabolic effects). Effects last 1-2 months. Anabolic effects are due to increase in nitrogen balance and retention of phosphate, sulfur, K+, NA+, Cl-, and water. DR.UMA K. Physiological effects: Growth of genitals in a boy Production of sperm Growth of facial, pubic & auxiliary hairs Muscular development Growth of larynx & voice deepens Inhibition of bone growth Thickening of skin, loss of S.C. Fat Behavioral changes in men Nitrogen retaining effect Erythropoietin secretion increased Increased LDL & decreased HDL

13. Pharmacokinetics: Absorption: undergoes high first pass metabolism. Therefore i.m. injections or synthetic preparations are used. Transport: highly protein bound (98%, SHBG ,albumin) Metabolism: By liver enzymes : androsterone & etiocholanolone Excretion by urine after conjugation Small quantity of oestrogen also produced from testosterone DR.UMA K.

14. DR.UMA K. Testosterone Preparations Dose Testosterone aqueous suspension 50-100mg / 2 weeks Testosterone esters: Testo. propionate Testo. phenylpropionate Testo. cypionate Testo. enanthioate 25-50 mg / 3 times a week 40-60mg / 1 or 2 week 100 – 200mg / 2 weeks 250 mg / 2 weeks Orally active preparations: Methyl testosterone tab. Fluoxymesterone Mesterolone Transdermal patches 2 patches /day (back, abdomen, thigh) Implants wall of abdomen/thigh

15. Clinical uses of testosterone: Testicular failure: Primary & Secondary Wasting syndromes - HIV, cancer, acute necrotizing fasciitis Chronic illness, Burns Osteoporosis & decreased muscle strength Long term corticosteroid therapy Pituitary dwarfism Carcinoma of breast Hereditary angioneurotic oedema Anaemia (refractory) Menopausal syndrome Aging (andropause (“male menopause” or PADAM- P artial A ndrogen D eficiency in the A ging Male; frailty syndrome-easy tiring, decrease of libido, mood disturbance, accelerated osteoporosis, decreased muscle strength, and high susceptibility to disease. DR.UMA K.

16. DR.UMA K. Adverse effects of testosterone: Virilization (female), Acne Feminizing side effects (male) Precocious puberty & stunted growth Cholestatic jaundice Enlargement of prostate Atherosclerosis Hepatic carcinoma Oedema Decreased spermatogenesis Gynecomastia (male breasts) Testicular atrophy

17. Anabolic steroids….. DR.UMA K.

18. DR.UMA K. Anabolic Steroids Drug Anabolic Androgenic ratio Preparation & Dose Methandienone 3:1 5 – 15 mg/day, p.o. Nandrolone phenylpropionate 3:1 10 – 50 mg/wk, i.m. Nandrolone decanoate 3:1 25 – 50 mg/3 wk, i.m. Stanozolol 3:1 2 - 6 mg/day, p.o. Ethyloestrenol 3:1 8 - 16 mg/day, p.o. Oxandrolone 3:1 5 – 10 mg/day, p.o. Fluoxymesterone 3:1 5 – 10 mg/day, p.o.

19. Uses of anabolic steroids Osteoporosis Catabolic states Short stature Anaemia (refractory) Athletic performance DR.UMA K.

20. Anti-androgens DR.UMA K. Receptor antagonists: flutamide, bicalutamide GnRH analog: Agonists: Leuprolide (also Goserelin, nafarelin) Antagonist: Abarelix (extended release) 5  -reductase inhibitor: Finasteride Progestin analog: Cyproterone acetate Others: Danazol

21. Danazol DR.UMA K. FSH & LH release in both sexes Binding of steroids to receptors Enzymes needed for steroid synthesis Weak androgenic, anabolic, progestational & glucocorticoid action Uses: Endometriosis Menorrhagia Fibrocystic breast disease Hereditary angioneurotic oedema Gynecomastia Infertility Side effects: Dose related Amenorrhea (High doses) Androgenic side effects

22. DR.UMA K. Cyproterone acetate: Block androgen receptors; therefore blocks the effects of androgens secretion of gonadotropins Uses: Reduce sex drive Acne Male pattern of baldness Hirsutism Ca. of prostate Virilizing syndrome Precocious puberty Inappropriate behavior

23. Flutamide: Non-steroidal anti-inflammatory Antagonize androgens: Accessory sex organs Pituitary Uses: Cancer of prostate along with GnRH agonist Female hirusitism Dose: 250 mg tds. DR.UMA K.

24. DR.UMA K. Finasteride Orally active DHT levels Benign prostatic hyperplasia Dose: 5mg/day 5  reductase inhibitors Side effects: Loss of libido & impotence in 5 % pts . Also used for prevention of hair loss Prostate volume Symptom score Peak urine flow rate DHT level in prostate

25. SILDENAFIL…… DR.UMA K.

26. DR.UMA K. Parasympathetic Sympathetic Acetylcholine Noradrenaline Hypothalamus ANS Muscarinic Receptors vasoconstriction Penile flaccidity Penile erection

27. DR.UMA K. Penile Erection Vasodilatation Muscarinic Receptors  Ca ++ ↑ NO GTP cGMP cAMP ATP ↑ VP AC GC 5’ GMP PDE V SILDENAFIL

28. Sildenafil: Inhibits PDE5 in the corpus cavernosa of the penis 50mg, p.o. 1 h before sexual activity Potentiate nitrate’s hypotension activity Ketoconazole & erythromycin increases its level Renal & hepatic disease increases its level Side effects: headache, flushing, dyspepsia, myalgia DR.UMA K.