Androgen Suppression Androgen Suppression

& & AntiandrogensAntiandrogens

Male contraceptivesMale contraceptivesDr keliDr keli

Androgens supressionAndrogens supression

Androgens effects can be eliminated Androgens effects can be eliminated by Suppression of gonads byby Suppression of gonads by

Orchidectomy Orchidectomy Large doses of oestrogen !! Large doses of oestrogen !!

GynaecomastiaGynaecomastiaGnRH analogue adminstered GnRH analogue adminstered

contonouslycontonously

Anti-AndrogensAnti-Androgens

Compounds that block the synthesis or Compounds that block the synthesis or action of androgens.action of androgens.

They are useful in the management ofThey are useful in the management ofhyperplasia and carcinoma of the hyperplasia and carcinoma of the

prostate,prostate,acne,acne,male-pattern baldness,male-pattern baldness,virilizing syndromes in women virilizing syndromes in women precocious puberty in boys precocious puberty in boys To inhibit of sex drive in menTo inhibit of sex drive in men

Modes of Antiandrogens Modes of Antiandrogens effectseffects

1. Steroid synthesis inhibition ketoconazole

It inhibits adrenal and gonadol steroid synthesis

it does not affect the ovarian aromatase but affects the

placental aromatase activity

• Not usefull in women due to its toxcity

• Experimetal rx of prostatic ca

It causes gynaecomastia in men due to increased ratio

ofesradiol:testosterone

AntiandrogensAntiandrogens• Androgen Receptor inhibitorsAndrogen Receptor inhibitors

1. Cyproterone and Cyproterone1. Cyproterone and Cyproterone acetateacetate

inhibit androgens at their target organsinhibit androgens at their target organs

Use hirsutism has contraceptive effects, to reduce Use hirsutism has contraceptive effects, to reduce

excessive sexual drive in menexcessive sexual drive in men

2. Flutamide NSAID Rx of ca prostrate behaves like 2. Flutamide NSAID Rx of ca prostrate behaves like

a competitive antagonist of androgen receptors a competitive antagonist of androgen receptors

Ae mild gynaecomastia mild hepatotoxicity ? Mx Ae mild gynaecomastia mild hepatotoxicity ? Mx

of excess androgens in womenof excess androgens in women

Androgen receptor inhibitors3.3. Bicalutamide Nilutamide potent ant Bicalutamide Nilutamide potent ant

androgens for Rx of metastatic androgens for Rx of metastatic

prostrate ca use with GnRH prostrate ca use with GnRH

analogues to reduce tumour flareanalogues to reduce tumour flare

4. Spironolactone competes for 4. Spironolactone competes for

androgen receptors with androgen receptors with

dihydrotestosterone reduces 17 a dihydrotestosterone reduces 17 a

hydroxylase activity lowering hydroxylase activity lowering

testosterone and androstenedione testosterone and androstenedione

Rx of hirsutim in women Rx of hirsutim in women

Conversion of steroid precursors to androgens

This occurs via Inhibition of the conversion of This occurs via Inhibition of the conversion of

progesterone or pregnelone to androgens via progesterone or pregnelone to androgens via

inhibition of 17 hydroxylase by inhibition of 17 hydroxylase by Abiraterone and Abiraterone and

DutasterideDutasteride

Inhibition of 5 a reductase, reduces the levels of Inhibition of 5 a reductase, reduces the levels of

dihydrotestosterone an androgen in the prostratedihydrotestosterone an androgen in the prostrate

Finasteride Rx of prostrate ca Finasteride Rx of prostrate ca Dutasteride Slow OOA & longer DOASlow OOA & longer DOA

Dose 5mg/dDose 5mg/d

Both not approved for use in women or childrenBoth not approved for use in women or children

Receptor inhibitors

Cyproterone Cyproterone acetateFlutamideBicalutamide NilutamideSpironolactone

Spironolactone

A competitive inhibitor of aldosteroneA competitive inhibitor of aldosterone Also competes with DHT for androgen Also competes with DHT for androgen

receptors in target tissuesreceptors in target tissues Also reduces 17Also reduces 17 hydroxylase activity, hydroxylase activity,

lowering plasma levels of testosterone & lowering plasma levels of testosterone & androstenedioneandrostenedione

Treatment of hirsuitism in womenTreatment of hirsuitism in women As effective as other finasteride, As effective as other finasteride, Cyproterone

& Flutamide Dose: 50-200mg/dDose: 50-200mg/d

DanazolDanazol

Uses:Uses:EndometriosisEndometriosisMenorrhagiaMenorrhagiaFibrocystic breast diseaseFibrocystic breast diseaseHereditary angioneuroticHereditary angioneurotic

oedemaoedemaGynecomastiaGynecomastiaInfertilityInfertility

Side effects:Side effects:

Dose related Dose related

Amenorrhea (High doses)Amenorrhea (High doses)

Androgenic side effectsAndrogenic side effects

• FSH & LH release in both sexes

• Binding of steroids to receptors

• Enzymes needed for steroid synthesis

• Weak androgenic, anabolic, progestational & glucocorticoid action

SILDENAFILSILDENAFIL

Parasympathetic Sympathetic

Acetyl cholineNoradrenaline

Hypothalamus

ANS

Muscarinic Receptors

vasoconstriction

Penile flaccidityPenile erection

SildenafilSildenafil

Inhibits PDE5 in the corpus cavernosa of the Inhibits PDE5 in the corpus cavernosa of the penispenis

50mg, p.o. 1 h before sexual activity50mg, p.o. 1 h before sexual activity potentiate nitrate’s hypotension activitypotentiate nitrate’s hypotension activity ketoconazole & erythromycin increases its levelketoconazole & erythromycin increases its level renal & hepatic disease increases its levelrenal & hepatic disease increases its level Side effects: Side effects:

headache, flushing, dyspepsia, myalgiaheadache, flushing, dyspepsia, myalgia

MALE CONTRACEPTIONMALE CONTRACEPTION CondomCondom VasectomyVasectomy Male oral contraception with androgensMale oral contraception with androgens

and with cotton seed oiland with cotton seed oil Immunological contraception Immunological contraception

Still at Still at investigative investigative stage.stage.

Do men want new Do men want new options?options?

Over 40% of US couples rely on the Over 40% of US couples rely on the currently available male contraceptivescurrently available male contraceptives

Source: CDC (2006) Health, United States

Chemical Contraception in Chemical Contraception in MenMen

Testosterone and testosterone Testosterone and testosterone enanthate in a dose of 400 mg a enanthate in a dose of 400 mg a monthmonth

Testosterone + Danazole well Testosterone + Danazole well tolerated but not more effective than tolerated but not more effective than testosterone enathatetestosterone enathate

Testosterone enanthate 100 mg Testosterone enanthate 100 mg weekly + levonorgestrel 500 mg weekly + levonorgestrel 500 mg daily produce azoospermiadaily produce azoospermia

Under investigationUnder investigation

Gossypol a cottonseed derivative it Gossypol a cottonseed derivative it destroys semineferpous epithelium destroys semineferpous epithelium

AE Hypokalemia AE Hypokalemia Has been tried as an intravaginal Has been tried as an intravaginal

contraceptivecontraceptiveRisk of lack of normal near normal Risk of lack of normal near normal

reversibility of sperm amountsreversibility of sperm amounts

Cotton seedsCotton seeds

Cotton plantCotton plant