ANDROGENS

Testosterone is the main androgen produced in

testis by interstetial cells of Leydic under
influence of LH.
It is converted to the active dihydro-testosterone
in some tissues (in prostate, skin, brain) by
5--reductase 2 .

In plasma, about 65% bound to SHBG; most of
remainder is bound to albumin; only 2% is free
& active
It is metabolized in liver to weak products and is
also excreted in urine.
There are specific androgen receptors in
cytoplasm of target cell.



SHBG: Estrogen increases its production
, while testosterone decrease.
Actions :
Development of external genital organs and
secondary sex characters (voice, skin, hair) at
puberty in male

Testicular growth and stimulation of
spermatogenesis up to spermatid stage. Also
required for the activity and maturation of sperms.

Stimulation of anabolism : leading at puberty to
growth and muscle development (growth spurt ).
Positive nitrogen balance occur.

Bone maturation with fusion of epiphysis stop
linear growth .
CNS : change in behavior and sex attitude.





Negative feedback inhibition on ICSH (LH)
secretion directly on anterior pituitary and by
interfering with release of GnRH from
hypothalamus.

Preparations :
Testosterone : not given orally since
quickly destroyed by liver.
Aqueous inj. IM every 3 days.
Transdermal patch : slow release and long
acting.
Percutaneous gel also available


Testosterone esters in oil :
IM, slowly release the hormone for absorption, thus
longer acting.
Esterfication is done at 17-OH position.
T. propionate : every 1 week (~ 50 mg. i.e. ~ 10 mg/d)
T. enanthate : every 2 4 weeks (~100 - 200 mg)
T. cypionate : every 2 4 weeks

17-alkyl T. derivatives : Orally effective since
slowly metabolized in liver and thus have more
liver toxicity. e.g. Methyltestosterone (sublingual,
oral ) ; Fluoxymesterone (oral)



Main Theraputic uses :
1. Male hypogonadism : Chronic use
- Either primary testicular failure or secondary
to hypopituitarism.
Testosterone is used or its esters, sometimes
methyltestosterone. Treatment helps to
restore secondary sex characters and
psychological attitude but not fertility.

2. Sometimes used in cryptorchidism to
enhance descent of testis into scrotum in
boys 5 years of age. Short term use;
Testosterone IM is usually used for 6 weeks








3. Delayed puberty in boys :(max 16years)
short term use of Testosterone or
methyltestosterone or fluoxymesterone.

They stimulate development of secondary
sex characters and anabolic growth; these
would activate hypothalamic-pituitary-
gonadal axis.

4. Sometimes used by aging men.

Side effects of androgen therapy :
CNS : gonadotropin suppression, behavioral
effects.
Body habitus : hirsutism, virilization, acne

Bone : premature closure of epiphysis in
children
Metabolic : dyslipidemia (decrease HDL)

Hepatic : cholestatic jaundice, (hepatic
adenoma or CA esp. with 17 alkyli)
Hematologic : erythrocytosis

Genitourinary : prostate hypertrophy

Salt and water retention esp. in renal or
cardiac disease; hypertension

Others : gynaecomastia , testicular atrophy

Avoid in pregnancy : masculinization of
female foetus occurs
Avoid in young children: The main hazards
here are virilism & premature closure
of epiphysis leading to short stature.


due to Converting into estrogen

Anabolic less virilizing androgens :
they are 17a-alkyl derivatives of testosterone.
Some Preparations :
Nandrolone, Oxandrolone (both i.m.)
Oxymetholone, Stanozolol (both oral)

Special Uses :
Children with growth problems :
Given in short course (4 12 weeks) then stop 6
months to minimize androgenic side effects and
epiphyseal fusion.

Debilitated conditions with negative nitrogen
balance : e.g. cancer cachexia, CRF.
Nandrolone decanoate or oxandrolone used usually

Aplastic anemia : Oxymetholone was used
orally to stimulate erythropoietin production
by kidney and extrarenal tissue; less used now

Relieve itching of obstructive jaundice :
Norethandrolone is usually used

Used illicitly in sports by athletes to increase
muscle mass, strength, and performance (e.g. body
builders, heavy weight lifters)

Others : oral stanozolol for hereditary angioedema
due to deficiency of C1 inhibitor

Danazol :
Weak androgen derived from ethisterone. Also has
weak progestational activity. It inhibits many
CYP450 enzymes in synthesis of androgens or
glucosteroids. Eliminated by liver.
- Used to inhibit ovarian function by inhibiting
secretion of Gn especially LH surge in midcycle,
so ovulation and oestrogen and progesterone
production. Useful orally in :
Endometriosis , Dysfunctional uterine bleeding

S.E.: Menopausal symptoms : hot flushes
Weight gain .
Androgenic S.E: coarse voice, skin changes
Liver toxicity may occur

ANTI-ANDROGENS


Estrogen is physiological androgen antagonist

Pharmacological antagonists include :
1. GnRH analogues : e.g leuprolide, nafaralen,
buserelin, histrelin. They have higher affinity for
GnRH receptor in anterior pituitary than endogenous
GnRH
Administration SC or depot form of leuprolide IM
every 1-4 months will first stimulate, but then
desensitizes GnRH receptor causing secretion
of FSH and LH , so testosterone secretion in
men and estrogen secretion in women.

- May be used in palliative treatment of prostate
cancer(androgen-dependent), usually with androgen
receptor antagonist cyproterone or flutamide
effect of testosterone in enhancing growth of
prostate cancer
-may also be used in ovarian hyperstimulation
programs for anovulatory infertility to suppress
endogenous Gn production during administration of
exogenous Gonadotrophins, but pure GnRH
antagonists like Ganirelix or Cetorelix are
preferred since they act quickly.
These antagonists are also preferred to GnRH
analogues for treatment of endometriosis.

Prolonged use of GnRH analogues may produce
menopausal symptoms, and osteoporosis (if
used longer than 6 months)



2. Androgen receptor antagonists :
a. Steroidal :

1. Spironolactone : blocks T. receptors and also T.
synthesis by inhibiting 17-hydroxylase. Used for
Hirsutism; not effective in prostate CA or BPH

2. Cyproterone : blocks androgen receptors, and has
progestational activity which inhibits Gn release.

Used for Hirsutism if spironolactone fails.
(it may be used with the estrogen drug ethinyl
oestradiol in a combined tablet to enhance its
effect; this combined tablet is called Dianette
and is also a contraceptive & can also be used for
polycystic ovary syndrome or in resistant acne).



Sometimes cyproterone is used in prostate cancer
palliation.

b. Non-steroidal :
- Flutamide : used for palliation of prostate cancer.
Its continued use may lead to LH secretion which
testosterone synthesis, and may thus cause
therapeutic failure. So usually combined with GnRH
antagonist or cyproterone.
S.E.: vomiting, gynaecomastia,
reversible hepatic dysfunction.

- Bicalutamide has fewer GI side effects;
no liver toxicity



3. Synthesis inhibitors :
Ketoconazole : blocks many CYP450 enzymes in
gonads for synthesis of Testosterone. It was found
to be less effective anti-androgen in prostate cancer.
S.E.: gynaecomastia

4. 5-reductase inhibitors :
- Finasteride : blocks synthesis of DihydroT. from T.
in prostate and hair follicles by inhibiting the enzyme
5-reductase 2.

Used orally in :
Benign prostatic hyperplasia in elderly
(mildly effective; 20% reduction in prostate size
after 1 year of use); relief of obstructive and irritative
urinary bladder symptoms after first 6 months of use


.
Other uses of finasteride are :
Male pattern of baldness
Hirsutism

- Was not found useful in prostate cancer since
5-reductase 1 is still intact in other tissues e.g.
liver, skin fibroblasts

S.E: less likely to cause libido or impotence than
androgen receptor antagonist