ANDROGENS,ANTIANDROGENS &
ANABOLIC STEROIDS
Dr. Ch.Anil
Asst. Professor
Dept. of Pharmacology
ANDROGENS
• Substances which cause development of
secondary sex characters in castrated male
• Includes all natural & synthetic steroidal drugs
having musculinising properties
• Testosterone – isolated as testicular hormone –
synthetically prepared by 1935
CLASSIFICATION
Natural Androgens:
• From Testes: Testosterone (5-12 mg daily)
• Part of which is converted in extraglandular
tissues to more active Dihydrotestosterone by
enzyme 5 – α reductase
• Adrenal cortex produces small quantities of
dehydroepiandrosterone and androstenedione
(weak androgens)
• Females - testosterone: 0.25 – 0.5 mg/day
(ovary+ adrenals)
• Androsterone – metabolite of testosterone with
1/10 activity of testosterone
Synthetic androgens:
- Methyltestosterone
- Fluoxymesterone
- Testosterone undecanoate
- Mesterolone
TESTOSTERONE
• Testosterone is secreted by interstitial cells of
testis (Leydig) under the influence of LH from
pituitary
• FSH – Spermatogenesis in tubular (sertoli) cells
• Reduced by 5 α-reductase to the more potent,
Dihydrotestosterone (DHT), which is responsible
for many of the differentiative,growth promoting,
secondary male sexual characteristics
• Also converted to estradiol by aromatase enzyme
in extraglandular tissue (liver,adipose tissue)
REGULATION OF SECRETION
TESTOSTERONE – ACTIONS
Sex organs and secondary sexual characters:
• Growth of genitals – penis,scrotum,seminal
vesicles,prostate
• Growth of hair – pubic,axillary,beard,moustache
• Thickening of skin – greasy due to proliferation &
↑activity of sebaceous glands – face
• Larynx grows & voice deepens
• ↑physical vigour,aggressiveness,penile erections
• Intrauterine development – male phenotype
Anabolic actions:
• Pubertal spurt of growth in boys
• Rapid bone growth(thickness & length)
• Promotes muscle building if aided by exercise
• ↑protein synthesis &↓ protein breakdown
• Sodium & water retention
Erythropoiesis:
• accelerates erythropoiesis by increasing
erythropoietin production & haeme synthesis
MECHANISM OF ACTION
• Testosterone or DHT – bind to cytoplasmic
androgen receptor (AR) and the complex
combines with androgen responsive elements of
target genes
• DNA transcription is enhanced/repressed with
the help of coactivators/corepressors
• Effects expressed through modification of
protein synthesis
PHARMACOKINETICS
• Orally ineffective - high first pass metabolism
• Slowly absorbed esters of testosterone are used
• Highly protein bound (98% - SHBG, albumin)
• Major metabolites: androsterone &
etiocholanolone
• excreted in urine after conjugation with sulfate &
glucuronic acid
• small quantity of estradiol produced from
testosterone - aromatization
TESTOSTERONE PREPARATIONS
• Testosterone propionate IM
• Testosterone enanthate IM
• Testosterone cypionate IM
• Methyl testosterone ORAL
• Mesterolone ORAL
• Fluoxymesterone ORAL
• Transdermal androgen
• Gel formulation - once daily application
THERAPEUTIC USES - ANDROGENS
1. Androgen replacement therapy (ART) –primary
and secondary testicular failure(hypogonadism)
2. AIDS related muscle wasting
3. Hypopituitarism
4. Hereditary angioneurotic edema -17α-alkylated
compounds
5. Ageing
6. Postmenopausal hormonal replacement
7. Idiopathic male infertility
8. Refractory anemia
9. osteoporosis
ANDROGENS – ADVERSE EFFECTS
• Virilization, excess body hair and menstrual
irregularities in women
• Acne
• Frequent, sustained &often painful erections in males
• Oligozoospermia,testicular atrophy
• Precocious puberty, premature sexual behaviour, and
stunting of stature
• Salt retention and edema
• Cholestatic Jaundice - 17-alkyl compounds
• Hepatic carcinoma
• Gynaecomastia
• Lowering of HDL & rise in LDL
ANABOLIC STEROIDS
• Synthetic androgens – higher anabolic and
lower androgenic activity (3:1 to 10:1 ratio)
• mediated through the same receptor as the
androgenic effects
• Were developed to avoid virilizing A/E of
androgens while retaining anabolic effects
• Ex:
– Nandrolone
– Oxymetholone
– Stanozolol
– Methandienone
PHARMACOLOGICAL ACTIONS
• Protein anabolism:↑muscle mass & body weight
• Anticatabolic effects: Positive nitrogen balance in
individuals on prolonged glucocorticoids
• Progestational effects
• Reduce bone resorption
A/E: Similar to testosterone (androgenic action)
• In pregnancy - virilization of foetus
• Orally active anabolic steroids - cholestatic
jaundice,liver damage
• Sodium & water retention
THERAPEUTIC USES
• Catabolic states: Chronic illness, severe trauma,
major surgery, HIV cachexia - to improve appetite
& sense of well being
• Suboptimal growth in boys-hypogonadal children
• Anaemia –Hypoplastic,hemolytic,malignancy
associated
• Osteoporosis
• Renal failure along with protein restriction
To enhance physical ability in athletes -↑ strength
of exercised muscles - Considered illegal
DOPE TEST - included
ANTI-ANDROGENS
• Any compound which antagonises with action of
androgens at tissue level
Androgen receptor antagonists –
Flutamide,Bicalutamide,Nilutamide,Cyproterone
acetate, spironolactone
GnRh anlogues –
Agonists – Leuprolide,Goserelin,Nafarelin
Antagonists – Cetrorelix,Ganirelix
5 α reductase inhibitors – Finasteride,Dutasteride
Androgen synthesis inhibitor - Ketoconazole
Others – Danazol
DANAZOL
• Orally active ethisterone derivative
• Weak androgenic, anabolic, progestational &
glucocorticoid activity
• Labelled as impeded/attenuated androgen -
Induces some androgen specific RNA production
• Suppresion of Gn secretion from Pituitary in both
men & women – inhibition of testicular/ovarian
function
• Results in endometrial atrophy and
ammenorrhoea
DANAZOL
• Uses: • Side effects: Dose
– Endometriosis related
• Amenorrhea (High
– Menorrhagia doses)
– Fibrocystic breast • Androgenic effects
disease - Decreased breast
– Hereditary size, hirsutism,
angioneurotic weight gain etc.
oedema • Hot flashes, night
– Infertility in women sweating, cramps
CYPROTERONE ACETATE
• Inhibits LH release by its progestational activity
• Lowers serum testosterone( LH inhibition) –
direct antiandrogenic action
Uses:
• Precocious puberty in boys
• Inappropriate sexual behaviour in men
• Acne & hirsutism in women(with oestrogen)
• With ethinylestradiol – contraceptive in women
• Prostatic carcinoma
FLUTAMIDE
• Non-steroidal AR antagonist with no other
hormonal activity
• Active metabolite “2-hydroxyflutamide” causes
competitive block of androgen action on
accessory sex organs & Pituitary
Uses:
• Metastatic carcinoma of prostate along with
GnRH agonist - preferably started 3 days before
the GnRH agonist to block the initial flare up
• Female hirsutism – with Oral Contraceptives
FINASTERIDE
MOA:
• Competitive inhibitor of 5 α-reductase, which
converts testosterone to more active DHT
• Selective for 5 α-reductase type - 2 isoenzyme
• Male urogenital tract – Circulating and prostatic
DHT concentration are lowered
Uses:
Benign prostatic hypertrophy
• ↓Prostatic size and↑ peak urinary flow rate
• Beneficial effects delayed – 6 months
• Primarily reduces static component of obstruction
Male pattern baldness
Kinetics:
• Effective orally
• metabolized in liver
A/E:
• decreased libido
• Impotence
• decreased volume of ejaculate
DRUGS FOR ERECTILE DYSFUNCTION
• PDE-5 Inhibitors: Sildenafil, tadalafil,Vardenafil
SILDENAFIL
• Orally active for treatment of erectile
dysfunction
• Inhibits PDE-5 in the corpus cavernosum
• 50mg 1 hr before intercourse
• Potentiate nitrate’s hypotensive activity –(nitrates be
avoided for 24 hrs)
• CYP3A4 inhibitors like ketoconazole, erythromycin,
Verapamil potentiate its action
A/E:
• Headache, flushing, fall in BP, dyspepsia, nasal
congestion,impairment of colour vision(blue-
green discrimination),sudden loss of vision due to
non arteritic ischaemic optic neuropathy(NAION)
• Contraindicated in coronary heart disease
• Caution – liver, kidney disease
• Other Uses: Pulmonary hypertension
• Tadalafil – potent & longer acting congener
• Papaverine/ phentolamine induced penile
erection(PIPE) therapy – Injected into corpus
cavernosum
• Alprostadil (PGE1) – Injected into corpus
cavernosum
• Parenteral testosterone esters – ED due to
androgen deficiency
