Androgens, anabolic steroids and antiandrogens

Androgens, anabolic steroids and antiandrogens

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  Dr. Ankita Bist AssistantProfessor Department of Pharmacology
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   Normally, testesare responsible for male sexual characters  Testes Functions: • Production of Androgenic hormones • Spermatogenesis occurring within the seminiferous tubules  Androgens are the substances which cause development of secondary sex characters in the castrated male.
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  Natural Androgens:  FromTestes: • Testosterone • Dihydrotestosterone (by 5 α-reductase) • Androsterone – metabolite of testosterone  From Adrenal cortex: (weak androgens) • Dehydroepiandrosterone • Androstenedione  Females : 0.25 – 0.5 mg/day (ovary + adrenals)  Synthetic androgens:  Methyltestosterone, Fluoxymesterone–17-alkyl substituted derivatives  Orally effective: Testosterone undecanoate and Mesterolone  Lipid soluble esters: Propionate, cypionate, enanthate salts etc.
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  Produced from cholesterol,primarily by Leydig cells in testes. Secreted at adult levels during 1st trimester, during neonatal life, continually after puberty. Converted by 5 α-reductase to the more potent, 5α-dihydrotestosterone (DHT), which is responsible for many of the responses to testosterone in the urogenital tract (e.g. prostate gland hyperplasia) Binds to and activates androgen receptors (AR) Androgen receptors are present in many tissues including reproductive tissue, skeletal muscle, brain, kidney etc.
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  Testosterone 17-alkyl substitution Methyltestosterone Fluoxymesterone • Allandrogens contain a Testosterone structures •Testosterone has 19-carbons and in general its a steroidal structure DIhydrotestosterone 5 –α reductase
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  •Testosterone secretion -Leydig`s cell of testes • Pulsatile LH – Pituitary • FSH – only Spermatogenesis • High testosterone – inhibits LH (atrophy) • Oestrogen – feedback inhibition • Inhibin – FSH inhibition • Plasma level of Testosterone: 0.3 to 1 mcg/dl (male) 20 to 60 ng/dl (female)
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  Androgenic Effects  Foetus:promotes development of male reproductive tract (sex differentiation).  During puberty, testosterone promotes development of : • primary sexual characteristics (e.g. enlargement of penis, scrotum and testes) • secondary sexual characteristics (e.g. male body shape, axillary/pubic hair, deeper pitch of voice, thickening of skin – greasy, loss of subcutaneous fat)  Adulthood: Male pattern baldness, BHP, Prostatic cancer. Testes: Normal spermatogenesis and maturation of sperm • Moderately high dose : testicular atrophy by inhibiting Gn secretion. • Higher doses: direct sustaining effect and less marked atrophy
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  Skeleton and musclesgrowthmuscle building, estrogen from testosterone leads to fusion of epiphysis and mineralization Positive nitrogen, minerals and water balance – increase in weight, edema Increase in appetite Acceleration of erythropoiesis
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  Androgen receptor: Testosterone isconverted to more active dihydrotestosterone by 5 –α reductase. It has 2 isoforms: •1 is present in genital skin and urogenital tract •2 has wider distribution and is less sensitive to finestride.  Both, testosterone and DH testosterone – act via Androgen receptors (AR) – nuclear receptor super family  Ligand binding and DNA binding domains  Mutations in AR: Incomplete sexual development.
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  • Absorption: Inactiveorally, undergoes high first pass metabolism. Therefore IM injections or synthetic, preparations are used • Transport: highly protein bound (98%) in plasma to albumin & sex hormone binding globulin (SHBG) • Metabolism: – by liver enzymes : converted to androsterone & etiocholanolone – excretion by urine after conjugation – small quantity of oestrogen also produced from testosterone, by aromatization of A ring. – Plasma t1/2 10-20 mins
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   Females: Virilization,menstrual irregularities may occur in women receiving relatively high doses for prolonged periods, such as for estrogen-dependent mammary carcinoma.  Acne  Cholestatic Jaundice: may be produced by steroids possessing a 17- alkyl substituted group  Priapism (sustained erection)  Precocious puberty and stunting stature  Oligozoospermia or testicular atrophy  Oedema--via promotion of salt and water retention  Hepatic carcinoma  Gynaecomastia
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  1. Androgen replacementtherapy (ART) Primary Androgen deficiency: underlying testicular disorders (high LH, but low testosterone levels), courses of 4-6 months at a time given. Secondary Androgen deficiency: hypothalamic-pituitary disorders (low LH and low testosterone levels) Mimic the normal testosterone concentration as closely as possible (serum concentration monitoring) If untreated, does not shorten life expectancy, but is associated with significant morbidity (ambiguous genitalia, delayed puberty & infertility) The aim is to restore tissue androgen exposure by using the natural androgen testosterone, rather than synthetic androgens, because they are safe, effective and easy to monitor.
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  2. Hypopituitarism: Monitoringat anticipated time of puberty, as hypogonadism is one of the factor 3. AIDS related muscle wasting 4. Hereditary angioneurotic edema (methyltestosterone) 5. Ageing Misuse: involves prescription with no acceptable medical indication. Examples of misuse include:  male infertility  male sexual dysfunction Contraindication: CA prostate, male breast, liver kidney and during pregnancy (virilization of female foetus)
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  • Synthetic androgens– higher anabolic but lower androgenic activity (1: 3 ratio) – decreased virilizing effect • Examples: Nandrolone, Stanazolol, Oxymetholone, Methandione • Similar anabolic effect, same receptors and same androgenic effects • Side effects and CI similar to testosterone.
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  1. Catabolic states:Acute illness, severe trauma, major surgery. These may produce transient response over short periods, but long term response is debatable. 2. Renal insufficiency 3. Osteoporosis: better drugs available 4. Suboptimal growth in boys 5. Anaemia: haemolytic and malignancy associated : better drugs available 6. Performance enhancement as in athletes but illegal.
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  • Superactive GnRHagonists • Danazol • Cyproterone acetate • Flutamide • Finasteride, Bicalutamide
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  Ethisterone derivative effectiveorally Weak androgenic, anabolic, progestational & glucocorticoid action Also Labeled as impeded/attenuated androgen:  Causes suppression of Gn secretion from Pituitary – FSH & LH release in both sexes decrease – inhibition of testicular/ovarian function directly by inhibition of steroidogenic hormones. • Uses: – Endometriosis : 3-6 months course – Menorrhagia – Fibrocystic breast disease – Hereditary angioneurotic oedema – Gynecomastia, Infertility
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  Direct antiantiandrogenic action Progesteronelike activity – inhibits LH causing antiandrogenic action Competes with dihydroteststerone for intracellular receptor Uses: Precocious puberty in Boys Virilization in women Limited use
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  Non-steroidal and noother hormonal activity Active metabolite “2-hydroxyflutamide” that competitively blocks Androgen action on accessory sex organs as well as Pituitary. Increased LH secretion by blocking feedback inhibition Plasma testosterone level may increase that partially overcomes the direct antiandrogenic effect, this limits monotherapy. Uses: Cancer of prostate along with GnRH agonist, Female hirusitism ADRs: Hepatotoxic potential, Gynaecomastia and breast tenderness. Dose: 250 mg tds. BICALUTAMIDE: more potent, longer acting (OD), less hepatotoxic
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  MOA: Competitive inhibitorof 5 α-reductase Selectively inhibits 5 α-reductase type-2 isoenzyme Uses:  Benign prostatic hypertrophy – decrease in prostate volume, improved urinary flow, reversion of disease progression Withdrawal results in regrowth – prolonged therapy needed, overcomes the static component of obstruction. (alpha 1 blockers needed for dynamic component)  Male pattern baldness Pharmacokinetics: effective orally, metabolized in liver (t1/2 – 4-6 hrs) Side effects: loss of libido, impotence, decreased ejaculation Doses: 5 mg OD (BHP) or 1 mg OD in baldness Dutesteride: Competitive inhibitor of both 5 α-reductases, approved for both BPH and Baldness.
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  PDE-5 Inhibitors: •Sidenafil, tadalafil •Nitricoxide (NO) pathway cGMP 5- GMP PDE-5
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  Absorbed orally andhalf-life is 4 Hrs Inhibits PDE5 in the corpus cavernosa Potentiate nitrate’s hypotension activity renal & hepatic disease increases its level Drug interactions •Ketoconazole, erythromycin, Verapamil increases its level – due to CYP3A4 inhibition •Fall in BP and precipitation of MI especially in patient with Nitrates for angina Side effects: headache, flushing, dyspepsia, myalgia, loose motion. Colour vision impairement and Norarteretic ischaemic optic neuropathy (NAION) (PDE6) Other Uses: Pulmonary hypertension
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  1. Testosterone –Pharmacological action, MOA, Pharmacokinetics, Uses and its preparations 2. Anabolic steroids and uses 3. Antiandrogens 4. PDE – 5 inhibitors, MOA and Adverse effects