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

PHYSIOLOGICAL REGULATIONS OF TESTICULAR

FUNCTIONS• 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.

•

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.

THERAPEUTIC USES OF ANDROGENS AND ANABOLIC

STEROIDS• 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.

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 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