Pharmacology of androgens and

other anabolic steroids

 Introduction
Three major categories of sex steroids:
1. Estrogens
2. Progestins
3. Androgens
How do they work?
All are steroids they will enter the cell bind
to a cytosolic receptor ligand-receptor
complex will then travel to the nucleus and
activate gene transcription
 The testis, like the ovary, has both
gametogenic and endocrine functions
The onset of gametogenic function of the
testes is controlled largely by the secretion of
FSH by the pituitary
With LH stimulation, testosterone is produced
by the interstitial or Leydig cells found in the
spaces between the seminiferous tubules.
 Androgens
Androgens are a group of 19-carbon steroids
derived from cholesterol
There are four androgens produced by the
testes
1. Testesterone (principal androgen)
2. Dihydrotestesterone
3. Dehydroepiandrosterone
4. Androstenedione
 Testesterone is produced in:
The testis, the adrenal gland, and (to a small
degree) the ovary
Precursors of testesterone:
Progesterone
dehydroepiandrosterone
 Physiologic effects of androgens
The androgens effects can be broken down into two
categories:
1. Anabolicincrease in muscle mass and red blood cell
production
2. Androgenicgrowth of the larynx and skeleton,
development of facial hair, darkening of skin
penile and scrotal growth.
appearance of pubic, axillary, and beard hair.
The sebaceous glands become more active, and the skin tends to become
thicker and oilier.
The larynx grows and the vocal cords become thicker, leading to a lower-
pitched voice.
Skeletal growth is stimulated and epiphysial closure accelerated.
growth of the prostate and seminal vesicles,
darkening of the skin, and increased skin circulation.
Androgens play an important role in stimulating and maintaining sexual
function in men.
Androgens increase lean body mass
 In some studies in animals, the anabolic effects of the compound
may be dissociated from the other androgenic effects.
This has led to the marketing of compounds claimed to have
anabolic activity associated with only weak androgenic effects.
Unfortunately, this dissociation is less marked in humans than in the
animals used for testing ( Table 405 ), and all are potent
androgens.
 Examples of synthetic androgens
Oxandrolone
Stanozolol
Fluoxymesterone
Oxymetholone
Nandrolone phenpropionate
 Clinical Uses
Androgen Replacement Therapy in Men
Androgens are used to replace or augment endogenous
androgen secretion in hypogonadal men
 Clinical Uses
Use as Protein Anabolic Agents
Androgens and anabolic steroids have been used in conjunction
with dietary measures and exercises in an attempt to reverse
protein loss after trauma, surgery, or prolonged immobilization
and in patients with debilitating diseases
Anemia Recombinant erythropoietin has largely replaced
androgens
Osteoporosisbisphosphonates have largely replaced
androgen use for this purpose
Use as Growth Stimulators
Stimulate growth in boys with delayed puberty
Anabolic Steroid and Androgen Abuse in Sports
The use of anabolic steroids by athletes has received worldwide
attention. Many athletes and their coaches believe that anabolic
steroids increase strength and aggressiveness, thereby improving
competitive performance
aging
decline in muscle mass, strength, and libido
 Toxicities of synthetic androgen treatment
Toxicity is mostly related to over masculinization
In women, excessive testesterone can lead to
hirsutism, depression of menses, acne, and
clitorial enlargment
Very rarely, hepatic carcinomas have been
reported
Cholestatic jaundice and prostatic hypertrophy
can also occur
Contraindication to androgen use is:
pregnancy
 Androgen antagonists
Four categories of androgen antagonists with
examples:
1. Gonadotropin-releasing analoguesleuprolide,
gonadorelin, goserelin, nafarelin, buserelin,
2. Receptor inhibitorscyproterone and flutamide
3. Steroid synthesis inhibitorsketoconazole,
spironolactone
4. 5-reductase inhibitorsfinasteride, dutasteride
 Uses
Androgen antagonists are used for:
Treatment of benign prostatic hyperplasia as well
as hirsutism (in women), (finasteride, cyproterone,
spiranolactone)
Prostatic cancer (leuprolide), and
cushings disease (ketokonazole)
 Ketoconazole, an antifungal imidazole
derivative, is a potent and rather nonselective
inhibitor of adrenal and gonadal steroid
synthesis.
This compound inhibits the cholesterol side-
chain cleavage, P450c17, C17,20-lyase, 3-
hydroxysteroid dehydrogenase, and P450c11
enzymes required for steroid hormone
synthesis
Spironolactone
a competitive inhibitor of aldosterone
is also an androgen antagonist
also competes with dihydrotestosterone for the androgen
receptors in target tissues
used in the treatment of hirsutism in women.
It also reduces 17-hydroxylase activity, lowering
plasma levels of testosterone and androstenedione.
It is used in dosages of 50200 mg/d in the treatment
of hirsutism in women and appears to be as effective
as finasteride,
flutamide, or cyproterone in this condition.
Dosages of 50200 mg/d cause a reduction in the density,
diameter, and rate of growth of facial hair in patients with
idiopathic hirsutism or hirsutism secondary to androgen
excess
 CHEMICAL CONTRACEPTION
IN MEN
GOSSYPOL
Extensive trials of this cottonseed derivative have
been conducted in China.
This compound destroys elements of the
seminiferous epithelium but does not
significantly alter the endocrine function of the
testis
Because of low efficacy and significant toxicity,
gossypol has been abandoned as a candidate
male contraceptive.