Androgens like testosterone are responsible for male sexual characteristics. Testosterone is produced primarily in the testes and stimulates the development of male sex organs and secondary sex characteristics at puberty. It also has anabolic effects like promoting muscle and bone growth. Anti-androgens can inhibit androgen production or block their effects, and are used to treat conditions like prostate cancer and excess hair growth in women. Common side effects of androgens and anti-androgens include sexual dysfunction and breast changes.

1. ANDROGENS

2. INTRODUCTION
• An androgen, or male sex hormone, is defined as a substance capable of developing and
maintaining masculine characteristics in reproductive tissues (notably the genital tract,
secondary sexual characteristics, and fertility) and contributing to the anabolic status of somatic
tissues.
• Testosterone together with its potent metabolite, dihydrotestosterone (DHT), are the principal
androgens in the circulation of mature male mammals.
• The Leydig cells (located in the interstitium of the testis between the seminiferous tubules)
synthesize the majority of testosterone. In women, testosterone also is probably the principal
androgen and is synthesized both in the corpus luteum and the adrenal cortex by similar pathways.
(However, estradiol and progesterone, not testosterone, are the principal inhibitors of LH
secretion in women)
• The testosterone precursors androstenedione and dehydroepiandrosterone are weak androgens
that can be converted peripherally to testosterone. Testosterone is converted to DHT by 5-α
reductase and to estradiol by aromatase.
• In men, approximately 8 mg of testosterone is produced daily. About 95% is produced by the
Leydig cells and only 5% by the adrenals. Plasma levels of testosterone in males are about 0.6
mcg/dL after puberty and appear to decline after age 50. Plasma conc. of testosterone in women
in concentrations of approximately 0.03 mcg/dL and is derived in approximately equal parts from
the ovaries and adrenals.

3. BIOSYNTHESIS AND METABOLISMOF ANDROGENS
Metabolism
In Leydig cells, the 11 and 21
hydroxylases (present in adrenal cortex)
are absent but 17 α-hydroxylase is
present. Thus androgens and estrogens
are synthesized; corticosterone and
cortisol are not formed. Bold arrows
indicate favored pathways.
Synthesis

4. MECHANISM OF ACTION

5. ACTIONS
1. Sex organs and secondary sex characters (Androgenic): Responsible for all changes that
occur in a boy at puberty: Growth of genitals (penis, scrotum, seminal vesicles, prostate);
Growth of hair (pubic, axillary, beard, moustache, body hair and male pattern of its
distribution); Thickening of skin which becomes greasy (due to proliferation and increased
activity of sebaceous glands especially on the face); acne (duct often gets blocked and
infection occurs). Veins look prominent (subcutaneous fat is lost) and Larynx grows and voice
deepens. Behavioral effects are (↑↑physical vigor, aggressiveness, penile erections). Male
libido appears to be activated by testosterone directly, and probably to a greater extent by
estradiol produced from testosterone.
2. Testes: Moderately large doses cause testicular atrophy by inhibiting Gn secretion from
pituitary. Still larger doses have a direct sustaining effect and atrophy is less marked.
Testosterone →high concentration of testosterone is attained locally in the spermatogenic
tubules by diffusion from the neighboring Leydig cells →stimulates spermatogenesis and
maturation of spermatozoa.

6. ACTIONS
3. Skeleton and skeletal muscles (Anabolic): Responsible for the pubertal spurt of
growth in boys and to a smaller extent in girls. There is rapid bone growth, both in
thickness as well as in length. After puberty, the epiphyses fuse and linear growth
comes to a halt. Estradiol, is responsible for fusion of epiphyses in boys as well as in
girls. Moreover, estradiol largely mediates the effect of testosterone on bone
mineralization. Testosterone also promotes muscle building, especially if aided by
exercise. There is accumulation of nitrogen, minerals (Na, K, Ca, P, S) and water—
body weight increases rapidly, more protoplasm is built. Appetite is improved and a
sense of well being prevails. Testosterone given to patients prone to salt and water
retention may develop edema.
4. Erythropoiesis: Testosterone accelerates erythropoiesis by increasing
erythropoietin production and probably direct action on haeme synthesis. Men
have higher hematocrit than women.

7. → Testosterone is inactive orally due to high first pass metabolism in liver.
→ The duration of action after i.m. injection is also very short. Therefore, slowly
absorbed esters of testosterone are used by this route—are hydrolysed to the
active free form.
→ Testosterone in circulation is 98% bound to sex hormone binding globulin (SHBG)
and to albumin. The SHBG bound testosterone is unavailable for action due to tight
binding.
→ The major metabolic products of testosterone are androsterone and
etiocholanolone which are excreted in urine, mostly as conjugates with glucuronic
acid and sulfate.
→ Plasma t½ of testosterone is 10–20 min.
PHARMACOKINETICS

9. TESTOSTERONE PREPARATIONS
Testosterone:
This agent is ineffective orally because of inactivation by first-pass metabolism. As with the other sex steroids,
testosterone is rapidly absorbed and is metabolized to relatively or completely inactive compounds that are
excreted primarily in the urine.
C17-esters of testosterone (for example, testosterone cypionate or enanthate) are administered
intramuscularly. [Note: The addition of the esterified lipid makes the hormone more lipid soluble, thereby
increasing its duration of action.]
Transdermal patches, topical gels, and buccal tablets of testosterone are also available.
Testosterone and its esters demonstrate a 1:1 relative ratio of androgenic to anabolic activity.
Testosterone derivatives:
Alkylation of the 17α position of testosterone allows oral administration of the hormone.
Fluoxymesterone: longer half-life than that of the naturally occurring androgen. It is effective when given
orally. It has a 1:2 androgenic-to-anabolic ratio.
Oxandrolone: Orally active testosterone derivative with anabolic activity 3 to 13 times that of testosterone.
Hepatic adverse effects have been associated with the 17α-alkylated androgens.
Mesterolone: Causes less feedback inhibition of Gn secretion and spermatogenesis, and has been promoted
for treatment of male infertility

10. TESTOSTERONE PREPARATIONS
Therapeutic uses
 Androgenic steroids are used for males with primary hypogonadism (caused by testicular dysfunction) or
secondary hypogonadism (due to failure of the hypothalamus or pituitary).
 Anabolic steroids can be used to treat chronic wasting associated with human immunodeficiency virus or cancer.
Testosterone therapy has been shown to improve weakness and muscle wasting in AIDS patients with low
testosterone levels.
 An unapproved use of anabolic steroids is to increase lean body mass, muscle strength, and endurance in
athletes and body builders.
 DHEA (a precursor of testosterone and estrogen) has been touted as an antiaging hormone as well as a
“performance enhancer.” Because testosterone levels decline in old age, it has been administered to elderly
males to improve bone mineralization and muscle mass. However, safety of such therapy in terms of metabolic,
cardiovascular and prostatic complications is not known.
 Idiopathic male infertility: Since high intratesticular level of testosterone is essential for spermatogenesis, it is
presumed that exogenous androgens will stimulate spermatogenesis or improve sperm maturation in epididymis.
On the other hand, androgens can adversely affect spermatogenesis by suppressing Gn secretion. Since
mesterolone causes less feedback inhibition of Gn (probably due to restricted entry into brain) it is believed that
moderate doses will predominantly stimulate testis directly.

11. TESTOSTERONE PREPARATIONS
ADVERSE EFFECTS:
1. In females: Androgens can cause masculinization, acne, growth of facial hair,
deepening of the voice, male pattern baldness, and excessive muscle
development. Menstrual irregularities may also occur. Testosterone should not be
used by pregnant women because of possible virilization of the female fetus.
2. In males: Excess androgens can cause priapism, impotence, decreased
spermatogenesis, and gynecomastia. Cosmetic changes such as those described
for females may occur as well. Androgens can also stimulate growth of the
prostate.
3. In children: Androgens can cause abnormal sexual maturation and growth
disturbances resulting from premature closing of the epiphyseal plates.
4. General effects: Androgens can increase serum LDL and lower serum high-density
lipoprotein levels. Whether these changes in the lipid profile predispose patients
to heart disease is unknown. Androgens can also cause fluid retention, leading to
edema.
5. In athletes: Use of anabolic steroids (for example, DHEA) by athletes can cause
premature closing of the epiphysis of the long bones, which stunts growth and
interrupts development. High doses taken by young athletes may result in
reduction of testicular size, hepatic abnormalities, increased aggression (“roid
rage”), major mood disorders, and other adverse effects described above.
Contraindications
Androgens are contraindicated in
carcinoma of prostate and male breast,
liver and kidney disease and during
pregnancy (masculinization of female
foetus). They should not be given to
men aged >65 years, and to those with
coronary artery disease or CHF.
Androgen therapy can worsen sleep
apnoea, migraine and epilepsy.

12. ANABOLICSTEROIDS
• These are synthetic androgens with supposedly higher anabolic and lower androgenic activity.
• Drugs are Nandrolone, Oxymetholone, Stanozolol and Methandienone.
• The anabolic effects are similar to that of testosterone and are mediated through the same receptor as the
androgenic effects.
Side effects Anabolic steroids were developed with the idea of avoiding the virilizing side effects of androgens
while retaining the anabolic effects. But the same adverse effect profile applies to these compounds. The 17-
alkyl substituted compounds oxymetholone, stanozolol, can produce jaundice and worsen lipid profile.
Contraindications are same as for testosterone.
Uses Osteoporosis In elderly males and that occurring due to prolonged immobilization may respond to anabolic steroids, but
bisphosphonates are more effective and are the preferred drugs.
Suboptimal growth in boys Use is controversial; somatropin is a better option. Brief spurts in linear growth can be induced by
anabolic steroids, but this probably does not make a difference in the final stature, except in hypogonadism. Use for more than 6
months is not recommended—premature closure of epiphyses and shortening of ultimate stature may result.
Hypoplastic, haemolytic and malignancy associated anaemia Majority of properly selected patients respond to anabolic
steroids/androgens by an increase in RBC count and Hb%. However, erythropoietin therapy is more effective.
To enhance physical ability in athletes When administered during the period of training androgens/anabolic steroids can increase
the strength of exercised muscles. However, effects are mostly short-lived and the magnitude of improvement in performance is
uncertain except in women. This is considered illegal and anabolic steroids are included in the list of ‘dope test’ performed on
athletes before competitive games.

13. ANTI ANDROGENS
Drugs in this group can act by inhibiting the synthesis, activation or action of androgens.
• Danazol, a weak androgen, is used in the treatment of endometriosis (ectopic growth of the endometrium) and
fibrocystic breast disease. [Note: Danazol also possesses antiestrogenic activity.] Weight gain, acne, decreased breast
size, deepening voice, increased libido, and increased hair growth are among the adverse effects.
• Steroid synthesis inhibitors:
Abiraterone is a newer orally acting inhibitor of 17-α-hydroxylase. It reduces the synthesis of cortisol and androgens,
and is approved for castration resistant refractory prostate cancer.
• 5-α reductase inhibitors: Most of the actions of testosterone are mediated by its conversion to DHT by 5-α
reductase. Important amongst these are growth of prostate, male pattern baldness and hirsutism in females.
Finasteride, a steroid like inhibitor of this enzyme, is orally active and causes a reduction in DHT levels. Onset of
action: within 8 hours after administration; Duration of action: ~24 hours. The half-life is about 8 hours (longer in
elderly individuals). It has been reported to be moderately effective in reducing prostate size in men with benign
prostatic hyperplasia and is approved for this use in the USA. The dosage is 5 mg/d.
Dutasteride is a similar orally active steroid derivative with a slow onset of action and a much longer half-life than
finasteride. The dosage is 0.5 mg daily. These drugs are not approved for use in women or children, although
finasteride has been used successfully in the treatment of hirsutism in women and early male pattern baldness in
men (1 mg/d).

15. ANTI ANDROGENS
• Androgen receptor inhibitors:
Cyproterone and cyproterone acetate are effective antiandrogens that inhibit the action of
androgens at the target organ. These compounds have been used in women to treat hirsutism and in
men to decrease excessive sexual drive.
Flutamide, a substituted anilide, is a potent antiandrogen that has been used in the treatment of
prostatic carcinoma. Although not a steroid, it behaves like a competitive antagonist at the androgen
receptor. It frequently causes mild gynecomastia (probably by increasing testicular estrogen
production) and occasionally causes mild reversible hepatic toxicity.
Bicalutamide, enzalutamide and nilutamide are other anti-androgens that act by same mechanism.
These are useful for the treatment of prostatic carcinoma. Bicalutamide is recommended for use in
combination with a GnRH analog (to reduce tumor flare) and may have fewer gastrointestinal side
effects than flutamide. A dosage of 150–200 mg/d (when used alone) is required to reduce prostate-
specific antigen levels to those achieved by castration, but, in combination with a GnRH analog, 50
mg/d may be adequate. Nilutamide is approved for use following surgical castration in a dosage of
300 mg/d for 30 days followed by 150 mg/d.
• Spironolactone, a competitive inhibitor of aldosterone, also competes with dihydrotestosterone for
the androgen receptors in target tissues. It also reduces 17α-hydroxylase activity, lowering plasma
levels of testosterone and androstenedione. It is used in dosages of 50–200 mg/d in the treatment of

16. Testosterone
INDICATIONS MOA Adverse Effects Misc.
Male hypogonadism
Direct agonism
of the AR
To restore testosterone
to the normal level
Contraindications:
Prostate cancer
High level of PSA
Untreated sleep apnea
Androgen Receptor
Antagonists
Flutamide
Bicalutamide
Nilutamide
Enzalutamide
Treatment of advanced
Prostate cancer
Used in combination
with androgen
deprivation therapy
(e.g. GnRH agonist/antagonist)
Flutamide also used
For treatment of
hyperandrogenism in women
Directly inhibits
action of testosterone
and
Dihydrotestosterone
at the AR
Men- typical effects
Of androgen deprivation
e.g. sexual dysfunction,
gynecomastia ,
vasomotor responses
Rare side effects:
1st Gen- Hepatotoxicity
2nd Gen-increased seizure risk
Abiraterone
Hormone-resistant
prostate cancer
Not responding to
androgen deprivation therapy
Inhibition of CYP17A1
Inhibits synthesis
of testosterone
(also effects corisol,
but not aldosterone)
Spironolactone
Treatment of women
with acne, hirsutism,
or androgenic alopecia
Antagonist/
weak partial agonist of AR
Also mineralocorticoid
receptor antagonist- used
as diuretic to treat HF
Menstrual irregularities
Breast tenderness
Orthostatic HTN
Contraindication:
Should not be used
in men with
prostate cancer
Acne
Increased risk prostate cancer
Increased risk BPH
Worsening of sleep apnea
Erythrocytosis
Increased risk VTE
Increased risk CVD
Hepatic dysfunction
Suppression of spermatogenesis
Adrenocorticol insufficiency
Mineralocorticoid excess
5a-reductase
Inhibitors
Finasteride
Dutasteride
BPH
Male pattern baldness
Female hirsutism
Inhibits peripheral conversion
of testosterone to
dihydrotestosterone
Male sexual dysfunction
Contraindication:
Pregnancy
SUMMARY