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Testosterone & Antitestoterones(7)
 

Testosterone & Antitestoterones(7)

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    Testosterone & Antitestoterones(7) Testosterone & Antitestoterones(7) Presentation Transcript

    • MALE SEX HORMONES: BY DR.UMA KADAM M.B.B.S. MD ASSOCIATE PROFESSOR PHARMACOLOGY SKNMC DR.UMA K.
    • 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.
    • Androgens:
      • Includes testosterone, DHT & androstenedione
      • Testosterone serves as a prohormone for
        • Dihydrotestosterone (DHT)
        • Estradiol
      DR.UMA K.
    • 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
    • DR.UMA K. (DHT)
    • 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
      • 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.
    • DR.UMA K.
    • 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.
    • 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.
      • 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
    • 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
    • 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.
    • 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
    • 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.
    • 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
    • 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. 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.
    • Uses of anabolic steroids
        • Osteoporosis
        • Catabolic states
        • Short stature
        • Anaemia (refractory)
        • Athletic performance
      DR.UMA K.
    • 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
    • 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
    • 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
    • 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.
    • 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
    • SILDENAFIL…… DR.UMA K.
    • DR.UMA K. Parasympathetic Sympathetic Acetylcholine Noradrenaline Hypothalamus ANS Muscarinic Receptors vasoconstriction Penile flaccidity Penile erection
    • DR.UMA K. Penile Erection Vasodilatation Muscarinic Receptors  Ca ++ ↑ NO GTP cGMP cAMP ATP ↑ VP AC GC 5’ GMP PDE V SILDENAFIL
    • 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.