ANDROGENS

BY DR.NAAZIA

HISTORY
Endocrine function of testes established by Berthold 1849. Androsterone isolated from male urine by Butenandt 1931. Testosterone isolated, structure worked out and synthesised by 1935.

INTRODUCTION
Natural and synthetic steroids. Masculanising and anabolic actions. Natural androgens testosterone,5 alpha dihydrotestosterone. Structure cyclopentanoperhydrophenanthrene ring

 Leydig cells testosterone Sertoli cells spermatogenesis ,inhibin-B, activin. Inhibin-B has ve feedback on FSH, no effect on GnRH, LH. Activin - +ve feedback on FSH.

PHYSIOLOGICAL REGULATIONS OF TESTICULAR FUNCTIONS

STEROIDOGENESIS
19 C steroid hormone. In leydig cells,adrenal cortex ,theca cells of ovary. Precursor cholesterol mitochondria by STAR protein cleavage of cholesterol side chain by lyase pregnenolone cytoplasm testosterone.

PERIPHERAL CONVERSION OF TESTOSTERONE

Testosterone dihydrotestosterone , estradiol by 5-alpha reductase. Both on androgen receptor. 5-alpha reductase non genital skin, liver,urogenital tissue in men and genital skin of both sexes. Testosterone and androstenedione by aromatase estrodiol in liver,adipose.

ANDROGEN PRODUCTION BY ADRENAL GLANDS

DHEA, Androstenedione are weak androgens. Support androgen dependant pubertal changes. DHEA may prolong life span in rabbits. In men improve quality of life , prevent atherogenesis.

SEX HORMONE BINDING PROTEINS

Sertoli cells androgen binding proteins. Circulation sex hormone binding protein 58%, albumin 40%. SHBG increased by estrogens , thyroid hormone, cirrhosis of liver. Decreased by androgens , growth hormones ,obese persons.

MECHANISM OF ACTION
Testosterone and DHT bind to intracellular androgen receptor. Androgen receptor complex confirmation of receptor altered bind to DNA response elements transcription of m RNA tissue specific proteins.

PHARMACOKINETICS
Testosterone orally inactive . First pass metabolism Half life 15 min. Testosterone enanthate sustained release for 1-2 weeks. Other forms- transdermal patches , pellets , buccal tablets , biodegradable microspheres.

 Metabolites androsterone , etiocholanolone. Excreted in urine as glucuronic acid or sulfate metabolites.

PHYSIOLOGICAL ACTIONS
1. Male reproductive system : sexual differentiation in fetus; penile ,scrotal , prostate, seminalvesicles growth. 2. Secondary sex characteristics : pubertal changes; growth of pubic,axillary and beard hair ; thickening of vocal cords.

 3. CNS: feedback control of FSH,LH. 4. ANABOLIC ACIONS : Increase in protein synthesis sodium and water retention increased bone density,muscle mass haeme synthesis.

 5.Metabolic effects: increased clotting factors,lipase,alpha-1 antitrypsin,haptoglobin, erythropoietin. decrease in HDL. 6.Others : Bones linear skeletal growth increased bone density skin thick, oily skin.

 7. In females: hirsutism,frontal baldness,enlargement of clitoris, prominent musculature, deepening of voice, suppression of ovulation and menstruation.

 1. Replacement in hypogonadism: primary elevated FSH,LH Secondary low FSH,LH end organs to be sensitive to androgens. IM testosterone enanthate,cypionate-effective oral methyl testosterone,fluoxymestrone incomplete drug absorption.

THERAPEUTIC USES OF ANDROGENS AND ANABOLIC STEROIDS

Increases libido and sexual performance in men. 2. Treatment of anaemia : stimulate erythrocyte production used in refractory anaemia. 3.Osteoporosis: androgens reduce calcium ions excretion.

4. Growth stimulators: linear growth epiphyseal closure on vigorous treatment 5. Protein anabolic agents: Methandienone, nandrolone, oxandrolone, oxymetholone, stanozolol have high degree of anabolic to androgen ratio.

 Increase protein synthesis, muscle mass,weight gain and sense of well being. Recover protein loss after trauma , surgery , cancer. Improves weakness,muscle wasting in AIDS patients with low testosterone levels. Methyltestosterone ,stanozolol prevent hereditary angioneurotic oedema by increasing complement c-1 esterase inhibitor.

 6. Anabolic steroid abuse in sports: Used by athletes to increase muscle mass , strength and performance. dose taken is about 25-30 times the normal therapeutic dose. adverse effects outweigh benefit

 In males testicular atrophy , sterility and gynaecomastia. In females inhibition of ovulation , hirsutism, frontal baldness,acne,deepening of voice. Increased aggressiveness ,psychotic symptoms Increased risk of coronary artery disease. Oxymetholone , stanozolol produce cholestatic jaundice,worsen lipid profile.

 Anabolic steroids included in dope test for athletes. 7. Androgens in females : A. Female hypogonadism: in prepubertal females with hypopituitarism. Combination of methyl testosterone and diethylstilbesterol induce secondary sexual characteristics.

 B. Low dose of androgens with estrogen replacement therapy improve libido in postmenopausal women. C. With estrogens reduce postpartum breast engorgement. Virilising side effects limit their use.

ADVERSE EFFECTS
1. Toxicity in men: A. Inhibit FSH,LH oligozoospermia and infertility. B. Peripheral conversion of testosterone to estrogen gynaecomastia C. Stimulate growth of prostatic neoplasm in elderly.

 2. Toxicity in women: Masculinisation , virilisation , shrunken breasts , enlarged clitoris , frontal alopecia , hirsutism. In pregnant women pseudohermaphroditism in genetically female fetus.

 3.Toxicity in either sex : fluid retention , erythrocytosis, cirrhosis of liver , acne , decreased HDL , increased LDL. Methyltestosterone,fluoxymestrone cholesta tic jaundice , benign liver tumors. Precocious puberty and shortening of stature. Anabolic steroids increased aggressiveness

CONTRAINDICATIONS
Pregnancy Carcinoma prostate and breast Liver and kidney disease Hypertension Congestive heart failure Nephrotic syndrome diabetes

ANTIANDROGENS
Sites of action : 1. gonadotrophin suppression 2.inhibition of testosterone synthesis 3.inhibition of conversion of testosterone to DHT 4. androgen receptor blockade

USES : Precocious puberty Hirsutism Acne Testicular and prostatic tumors

 GnRH analogues : Drugs leuprolide,nafarelin , buserelin , goserelin , desorelin. MOA : initially increase FSH ,LH secretion but on prolonged use cause downregulation of GnRH receptors. Uses : precocious puberty , polycystic ovarian disease, prostatic carcinoma.

 Used with androgen antagonists flutamide Preparations i.m , s.c , nasal GnRH antagonists cetrorelix , ganirelix (abarelix,degarelix cause anaphylactoid reactions) do not cause initial flare up. Used in prostatic carcinoma

 Androgen synthesis inhibitors : Ketoconazole inhibitor of adrenal and gonadal steroid synthesis. Used in prostatic carcinoma at high doses (800-1600 mg) Hepatotoxicity Gynaecomastia due to high estrogen:testosterone ratio.

 5 alpha reductase inhibitor : Finasteride blocks conversion of testosterone to dihydrotestosterone . Used in DHT mediated prostatic tumor and BPH. Dose 5mg/day orally Response take 6-12 months Used with alpha 1 adrenoceptor antagonists

Used in male pattern baldness Dose 1mg/day Response seen in about 3 months Dutasteride inhibitor of 5 alpha reductase type 1&2 . Response is faster

Others turosteride ,bexlosteride, izonsteride Adverse effects : Decreased libido, volume of ejaculate Skin rashes , swollen lips

 Androgen receptor antagonists : Flutamide inhibits testosterone and DHT binding to androgen receptor Used in prostatic carcinoma along with GnRH analogue (leuprolide) Dose 250 mg TDS orally Also in frontal baldness and hirsutism

 Adverse effects hepatotoxicity, gynaecomastia Bicalutamide (150mg/day) , nilutamide(150mg/day) Cyproterone acetate competitive antagonist at androgen receptor progestational effect at hypothalamus

 Uses prostatic carcinoma ,hirsutism ,acne precocious puberty in boys Orphan drug status limits its use. Spironolactone competes for androgen receptors dose 50-200mg/day orally side effect hyperkalaemia Others -progesterone

 Danazol : suppresses gonadotrophin release in both sexes. mild anabolic ,androgenic ,progestational activity. dose 200mg/day orally

Uses endometriosis,fibrocystic breast

Hereditary angioneurotic edema Haemophiliacs Rebound infertility Side effects hot flushes,loss of libido,virilism

ERECTILE DYSFUNCTION
ETIOLOGY : Vascular , neurological , hormonal , psychogenic Secondary arteriosclerosis , hypertension , diabetes Drugs antiandrogens , estrogens , betablockers , clonidine , phenothiazines , alcohol,nicotine.

PHYSIOLOGY OF PENILE ERECTION

Complex interaction of ANS,CNS,physical factors. NO is principal modulator NO activates guanylate cyclase inccreased cGMP reduced cytosolic calcium relaxation of smooth muscle. cGMP GMP by PD 5 DA,5 HT, ACTH ,prolactin also play a role.

ORAL THERAPY
Sildenafil inhibits PD -5 Taken 1 hr before intercourse. Oral bioavailability 40% PPB 95% N-desmethyl sildenafil metabolite Biliary excretion Dose 25-50mg Used in pulmonary hypertension

Adverse effects : Nasal congestion , fall in BP. Loss of bluegreen discrimination Concurrent use of organic nitrates contraindicated Enzyme inhibitors increase and enzyme inducers decrease sildenafil levels.

Tadalafil 5-20mg Vardenafil 5-20mg Other drugs Yohimbine alpha2 antagonist Phentolamine alpha blocker Apomorphine dopamine agonist Trazodone antidepressant L-Arginine precursor of NO

INTRACAVERNOSAL INJECTION THERAPY

Alprostadil : PGE1 analogue In patients not responding to sildenafil Triple therapy of alprostadil ,papaverine , phentolamine effective Papaverine : Nonselective PDE inhibitor

 Aviptadil smooth muscle relaxant , vasodilator Ketanserin 5HT2 , alpha 1 antagonist Thymoxamine vasodilator property DISADVANTAGES Painful , fibrosis

 Transcutaneous delivery : Creams or gels of glyceryl trinitrate,papaverine,minoxidil, alprostadil Herbal : Ginseng , kava , ginkgo biloba.

SELECTIVE ANDROGEN RECEPTOR MODULATORS

Developed since 2003 and are undergoing clinical trials Ostarine in osteoporosis S -4503 under trials Androgen receptor ligands Selective anabolic effect in bones,muscles Anabolic to androgen effect 10:1 Hershberger assay.

FUTURE PROSPECTS
Topical preparation of flutamide less risk of hepatotoxicity Naltrexone restores erectile dysfunction in abuse of opiods Testosterone gels effective over i.m since sustained release of drug.

THANK YOU