MALE SEX HORMONES:  BY DR.UMA KADAM   M.B.B.S. MD ASSOCIATE PROFESSOR PHARMACOLOGY SKNMC DR.UMA K.
Male sex hormones <ul><li>Androgens </li></ul><ul><li>Synthesis& secretion </li></ul><ul><li>Regulation </li></ul><ul><li>...
Androgens: <ul><li>Includes testosterone, DHT & androstenedione </li></ul><ul><li>Testosterone serves as a prohormone for ...
DR.UMA K. Estriol  Estrone  Cholesterol Pregnenolone Progesterone 17- α - Hydroxy pregnenolone 17- Hydroxy progesterone De...
DR.UMA K. (DHT)
DR.UMA K. Testes Leydig Cells Sertoli Cells Negative  feedback Estradiol  Inhibin  Negative  feedback FSH Negative  feedba...
<ul><li>LH: Promotes testosterone synthesis </li></ul><ul><li>FSH: Promotes spermatogenesis (in concert </li></ul><ul><li>...
DR.UMA K.
Mechanism of action of steroid hormones <ul><li>Hormone enters cell by diffusion across plasma membrane </li></ul><ul><li>...
DR.UMA K. MECHANISM OF ACTION: T DHT DHT- R T- R R R T- R Nucleus 90% 10% 5-  -reductase Cytoplasm
DR.UMA K. <ul><li>Change in transcriptional activity: </li></ul><ul><li>Testosterone, like the other steroid hormones, act...
Actions of Testosterone & DHT  : <ul><li>Pharmacologic Effects: </li></ul><ul><li>Large doses of testosterone suppress gon...
Pharmacokinetics: <ul><li>Absorption:  undergoes high first pass metabolism. Therefore i.m. injections or synthetic prepar...
DR.UMA K. Testosterone Preparations Dose Testosterone aqueous suspension 50-100mg / 2 weeks <ul><li>Testosterone esters: <...
Clinical uses of testosterone: <ul><li>Testicular failure: Primary & Secondary </li></ul><ul><li>Wasting syndromes - HIV, ...
DR.UMA K. Adverse effects of testosterone: <ul><li>Virilization (female), Acne </li></ul><ul><li>Feminizing side effects (...
Anabolic steroids….. DR.UMA K.
DR.UMA K. Anabolic Steroids Drug Anabolic  Androgenic ratio Preparation & Dose Methandienone 3:1 5 – 15 mg/day, p.o.  Nand...
Uses of anabolic steroids <ul><ul><li>Osteoporosis </li></ul></ul><ul><ul><li>Catabolic states </li></ul></ul><ul><ul><li>...
Anti-androgens DR.UMA K. <ul><li>Receptor antagonists: flutamide, bicalutamide </li></ul><ul><li>GnRH analog: </li></ul><u...
Danazol DR.UMA K. <ul><li>FSH & LH release in both sexes </li></ul><ul><li>Binding of steroids to receptors </li></ul><ul>...
DR.UMA K. Cyproterone acetate: <ul><li>Block androgen receptors; therefore blocks the effects of androgens </li></ul><ul><...
Flutamide: <ul><li>Non-steroidal anti-inflammatory </li></ul><ul><li>Antagonize androgens:  </li></ul><ul><ul><li>Accessor...
DR.UMA K. Finasteride <ul><li>Orally active </li></ul><ul><li>DHT levels </li></ul><ul><li>Benign prostatic  </li></ul><ul...
SILDENAFIL…… DR.UMA K.
DR.UMA K. Parasympathetic Sympathetic Acetylcholine Noradrenaline Hypothalamus ANS Muscarinic Receptors vasoconstriction P...
DR.UMA K. Penile Erection Vasodilatation Muscarinic Receptors    Ca  ++ ↑  NO GTP cGMP cAMP ATP ↑  VP AC GC 5’ GMP PDE V ...
Sildenafil: <ul><li>Inhibits PDE5 in the corpus cavernosa of the penis </li></ul><ul><li>50mg, p.o. 1 h before sexual acti...
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Testosterone & Antitestoterones(7)

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Testosterone & Antitestoterones(7)

  1. 1. MALE SEX HORMONES: BY DR.UMA KADAM M.B.B.S. MD ASSOCIATE PROFESSOR PHARMACOLOGY SKNMC DR.UMA K.
  2. 2. Male sex hormones <ul><li>Androgens </li></ul><ul><li>Synthesis& secretion </li></ul><ul><li>Regulation </li></ul><ul><li>Mechanism of action </li></ul><ul><li>Pharmacological actions </li></ul><ul><li>Pharmacokinetics </li></ul><ul><li>Preparations </li></ul><ul><li>Therapeutic uses </li></ul><ul><li>Adverse effects </li></ul><ul><li>Anabolic steroids </li></ul><ul><li>Differ from androgens? </li></ul><ul><li>Preparations </li></ul><ul><li>Therapeutic uses </li></ul><ul><li>Adverse effects </li></ul><ul><li>Anti-androgens </li></ul><ul><li>Danazole </li></ul><ul><li>Cyproterone acetate </li></ul><ul><li>Flutamide </li></ul><ul><li>Finasteride </li></ul><ul><li>Sildenafil </li></ul>DR.UMA K.
  3. 3. Androgens: <ul><li>Includes testosterone, DHT & androstenedione </li></ul><ul><li>Testosterone serves as a prohormone for </li></ul><ul><ul><li>Dihydrotestosterone (DHT) </li></ul></ul><ul><ul><li>Estradiol </li></ul></ul>DR.UMA K.
  4. 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. 5. DR.UMA K. (DHT)
  6. 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. 7. <ul><li>LH: Promotes testosterone synthesis </li></ul><ul><li>FSH: Promotes spermatogenesis (in concert </li></ul><ul><li>with testosterone) </li></ul><ul><li>Testosterone secretion is pulsatile i.e. </li></ul><ul><li>Highest- 8 am </li></ul><ul><li>Lowest- 8 pm </li></ul><ul><li>Decreases with age </li></ul>Regulation of secretion: DR.UMA K.
  8. 8. DR.UMA K.
  9. 9. Mechanism of action of steroid hormones <ul><li>Hormone enters cell by diffusion across plasma membrane </li></ul><ul><li>binds to specific cytoplasmic receptor </li></ul><ul><li>translocation to nucleus </li></ul><ul><li>alteration in gene transcription </li></ul><ul><li>alteration in level of </li></ul><ul><li>active mediator of effect </li></ul>DR.UMA K.
  10. 10. DR.UMA K. MECHANISM OF ACTION: T DHT DHT- R T- R R R T- R Nucleus 90% 10% 5-  -reductase Cytoplasm
  11. 11. DR.UMA K. <ul><li>Change in transcriptional activity: </li></ul><ul><li>Testosterone, like the other steroid hormones, acts intracellularly in target cells. </li></ul><ul><li>Androgen-receptor complex acts at level of transcription. In skin, prostate, epididymis and seminal vesicles, dihydrotestosterone is the dominant androgen. </li></ul><ul><li>Testosterone binds to the androgen receptor in cytoplasm of cells Binding causes a change in conformation and localization in the nucleus </li></ul><ul><li>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) </li></ul><ul><li>Mutations in the gene for the receptor can cause resistance to testosterone </li></ul>
  12. 12. Actions of Testosterone & DHT : <ul><li>Pharmacologic Effects: </li></ul><ul><li>Large doses of testosterone suppress gonadotropic secretion in adult males </li></ul><ul><li>Androgens produce changes similar to male puberty in females </li></ul><ul><li>Natural androgens stimulate erythrocyte production </li></ul><ul><li>Androgens increase protein synthesis/decrease protein breakdown (anabolic effects). Effects last 1-2 months. </li></ul><ul><li>Anabolic effects are due to increase in nitrogen balance and retention of phosphate, sulfur, K+, NA+, Cl-, and water. </li></ul>DR.UMA K. <ul><ul><li>Physiological effects: </li></ul></ul><ul><ul><li>Growth of genitals in a boy </li></ul></ul><ul><ul><li>Production of sperm </li></ul></ul><ul><ul><li>Growth of facial, pubic & auxiliary hairs </li></ul></ul><ul><ul><li>Muscular development </li></ul></ul><ul><ul><li>Growth of larynx & voice deepens </li></ul></ul><ul><ul><li>Inhibition of bone growth </li></ul></ul><ul><ul><li>Thickening of skin, loss of S.C. Fat </li></ul></ul><ul><ul><li>Behavioral changes in men </li></ul></ul><ul><ul><li>Nitrogen retaining effect </li></ul></ul><ul><ul><li>Erythropoietin secretion increased </li></ul></ul><ul><ul><li>Increased LDL & decreased HDL </li></ul></ul>
  13. 13. Pharmacokinetics: <ul><li>Absorption: undergoes high first pass metabolism. Therefore i.m. injections or synthetic preparations are used. </li></ul><ul><li>Transport: highly protein bound </li></ul><ul><li>(98%, SHBG ,albumin) </li></ul><ul><li>Metabolism: </li></ul><ul><ul><li>By liver enzymes : androsterone & etiocholanolone </li></ul></ul><ul><ul><li>Excretion by urine after conjugation </li></ul></ul><ul><ul><li>Small quantity of oestrogen also produced from testosterone </li></ul></ul>DR.UMA K.
  14. 14. DR.UMA K. Testosterone Preparations Dose Testosterone aqueous suspension 50-100mg / 2 weeks <ul><li>Testosterone esters: </li></ul><ul><li>Testo. propionate </li></ul><ul><li>Testo. phenylpropionate </li></ul><ul><li>Testo. cypionate </li></ul><ul><li>Testo. enanthioate </li></ul>25-50 mg / 3 times a week 40-60mg / 1 or 2 week 100 – 200mg / 2 weeks 250 mg / 2 weeks <ul><li>Orally active preparations: </li></ul><ul><li>Methyl testosterone tab. </li></ul><ul><li>Fluoxymesterone </li></ul><ul><li>Mesterolone </li></ul>Transdermal patches 2 patches /day (back, abdomen, thigh) Implants wall of abdomen/thigh
  15. 15. Clinical uses of testosterone: <ul><li>Testicular failure: Primary & Secondary </li></ul><ul><li>Wasting syndromes - HIV, cancer, acute necrotizing fasciitis </li></ul><ul><li>Chronic illness, Burns </li></ul><ul><li>Osteoporosis & decreased muscle strength </li></ul><ul><li>Long term corticosteroid therapy </li></ul><ul><li>Pituitary dwarfism </li></ul><ul><li>Carcinoma of breast </li></ul><ul><li>Hereditary angioneurotic oedema </li></ul><ul><li>Anaemia (refractory) </li></ul><ul><li>Menopausal syndrome </li></ul><ul><li>Aging (andropause (“male menopause” or PADAM- P artial </li></ul><ul><li>A ndrogen D eficiency in the A ging Male; frailty syndrome-easy tiring, </li></ul><ul><li>decrease of libido, mood disturbance, accelerated osteoporosis, </li></ul><ul><li>decreased muscle strength, and high susceptibility to disease. </li></ul>DR.UMA K.
  16. 16. DR.UMA K. Adverse effects of testosterone: <ul><li>Virilization (female), Acne </li></ul><ul><li>Feminizing side effects (male) </li></ul><ul><li>Precocious puberty & stunted growth </li></ul><ul><li>Cholestatic jaundice </li></ul><ul><li>Enlargement of prostate </li></ul><ul><li>Atherosclerosis </li></ul><ul><li>Hepatic carcinoma </li></ul><ul><li>Oedema </li></ul><ul><li>Decreased spermatogenesis </li></ul><ul><li>Gynecomastia (male breasts) </li></ul><ul><li>Testicular atrophy </li></ul>
  17. 17. Anabolic steroids….. DR.UMA K.
  18. 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. 19. Uses of anabolic steroids <ul><ul><li>Osteoporosis </li></ul></ul><ul><ul><li>Catabolic states </li></ul></ul><ul><ul><li>Short stature </li></ul></ul><ul><ul><li>Anaemia (refractory) </li></ul></ul><ul><ul><li>Athletic performance </li></ul></ul>DR.UMA K.
  20. 20. Anti-androgens DR.UMA K. <ul><li>Receptor antagonists: flutamide, bicalutamide </li></ul><ul><li>GnRH analog: </li></ul><ul><li>Agonists: Leuprolide (also Goserelin, nafarelin) </li></ul><ul><li>Antagonist: Abarelix (extended release) </li></ul><ul><li>5  -reductase inhibitor: Finasteride </li></ul><ul><li>Progestin analog: Cyproterone acetate </li></ul><ul><li>Others: Danazol </li></ul>
  21. 21. Danazol DR.UMA K. <ul><li>FSH & LH release in both sexes </li></ul><ul><li>Binding of steroids to receptors </li></ul><ul><li>Enzymes needed for steroid synthesis </li></ul><ul><li>Weak androgenic, anabolic, progestational & glucocorticoid </li></ul><ul><li>action </li></ul><ul><li>Uses: </li></ul><ul><li>Endometriosis </li></ul><ul><li>Menorrhagia </li></ul><ul><li>Fibrocystic breast disease </li></ul><ul><li>Hereditary angioneurotic oedema </li></ul><ul><li>Gynecomastia </li></ul><ul><li>Infertility </li></ul>Side effects: Dose related Amenorrhea (High doses) Androgenic side effects
  22. 22. DR.UMA K. Cyproterone acetate: <ul><li>Block androgen receptors; therefore blocks the effects of androgens </li></ul><ul><li>secretion of gonadotropins </li></ul><ul><li>Uses: </li></ul><ul><li>Reduce sex drive </li></ul><ul><li>Acne </li></ul><ul><li>Male pattern of baldness </li></ul><ul><li>Hirsutism </li></ul><ul><li>Ca. of prostate </li></ul><ul><li>Virilizing syndrome </li></ul><ul><li>Precocious puberty </li></ul><ul><li>Inappropriate behavior </li></ul>
  23. 23. Flutamide: <ul><li>Non-steroidal anti-inflammatory </li></ul><ul><li>Antagonize androgens: </li></ul><ul><ul><li>Accessory sex organs </li></ul></ul><ul><ul><li>Pituitary </li></ul></ul><ul><li>Uses: </li></ul><ul><li>Cancer of prostate along with GnRH agonist </li></ul><ul><li>Female hirusitism </li></ul><ul><li>Dose: 250 mg tds. </li></ul>DR.UMA K.
  24. 24. DR.UMA K. Finasteride <ul><li>Orally active </li></ul><ul><li>DHT levels </li></ul><ul><li>Benign prostatic </li></ul><ul><li>hyperplasia </li></ul><ul><li>Dose: 5mg/day </li></ul>5  reductase inhibitors Side effects: Loss of libido & impotence in 5 % pts . Also used for prevention of hair loss <ul><ul><li>Prostate volume </li></ul></ul><ul><ul><li>Symptom score </li></ul></ul><ul><ul><li>Peak urine flow rate </li></ul></ul><ul><ul><li>DHT level in prostate </li></ul></ul>
  25. 25. SILDENAFIL…… DR.UMA K.
  26. 26. DR.UMA K. Parasympathetic Sympathetic Acetylcholine Noradrenaline Hypothalamus ANS Muscarinic Receptors vasoconstriction Penile flaccidity Penile erection
  27. 27. DR.UMA K. Penile Erection Vasodilatation Muscarinic Receptors  Ca ++ ↑ NO GTP cGMP cAMP ATP ↑ VP AC GC 5’ GMP PDE V SILDENAFIL
  28. 28. Sildenafil: <ul><li>Inhibits PDE5 in the corpus cavernosa of the penis </li></ul><ul><li>50mg, p.o. 1 h before sexual activity </li></ul><ul><li>Potentiate nitrate’s hypotension activity </li></ul><ul><li>Ketoconazole & erythromycin increases its level </li></ul><ul><li>Renal & hepatic disease increases its level </li></ul><ul><li>Side effects: </li></ul><ul><li>headache, flushing, dyspepsia, myalgia </li></ul>DR.UMA K.

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