CLINICAL PHARMACOLOGY
Estrogens: Estrogens are important in
the development and maintenance of the female reproductive
system and secondary sex characteristics. They promote
growth and development of the vagina, uterus, and fallopian
tubes, and enlargement of the breasts. Indirectly, they
contribute to the shaping of the skeleton, maintenance
of tone and elasticity of urogenital structures, changes
in the epiphyses of the long bones that allow for the
pubertal growth spurt and its termination, growth of axillary
and pubic hair, and pigmentation of the nipples and genitals.
Decline of estrogenic activity at the end of the menstrual
cycle can bring on menstruation, although the cessation
of progesterone secretion is the most important factor
in the mature ovulatory cycle. However, in the preovulatory
or nonovulatory cycle, estrogen is the primary determinant
in the onset of menstruation. Estrogens also affect the
release of pituitary gonadotropins.
The pharmacologic effects of esterified estrogens are
similar to those of endogenous estrogens. They are soluble
in water and are well absorbed from the gastrointestinal
tract.
In responsive tissues (female genital organs, breasts,
hypothalamus, pituitary) estrogens enter the cell and
are transported into the nucleus. As a result of estrogen
action, specific RNA and protein synthesis occurs.
Estrogen Pharmacokinetics
Metabolism and inactivation occur primarily in the liver.
Some estrogens are excreted into the bile; however they
are reabsorbed from the intestine and returned to the
liver through the portal venous system. Water soluble
esterified estrogens are strongly acidic and are ionized
in body fluids, which favor excretion through the kidneys
since tubular reabsorption is minimal.
Androgens: Endogenous androgens are
responsible for the normal growth and development of the
male sex organs and for maintenance of secondary sex characteristics.
These effects include the growth and maturation of prostate,
seminal vesicles, penis, and scrotum; the development
of male hair distribution, such as beard, pubic, chest,
and axillary hair, laryngeal enlargement, vocal cord thickening,
alterations in body musculature, and fat distribution.
Drugs in this class also cause retention of nitrogen,
sodium, potassium, phosphorus, and decreased urinary excretion
of calcium. Androgens have been reported to increase protein
anabolism and decrease protein catabolism. Nitrogen balance
is improved only when there is sufficient intake of calories
and protein. Androgens are responsible for the growth
spurt of adolescence and for the eventual termination
of linear growth which is brought about by fusion of the
epiphyseal growth centers. In children, exogenous androgens
accelerate linear growth rates, but may cause a disproportionate
advancement in bone maturation. Use over long periods
may result in fusion of the epiphyseal growth centers
and termination of growth process. Androgens have been
reported to stimulate the production of red blood cells
by enhancing the production of erythropoietic stimulating
factor.
Androgen Pharmacokinetics
Testosterone given orally is metabolized by the gut and
44 percent is cleared by the liver in the first pass.
Oral doses as high as 400 mg per day are needed to achieve
clinically effective blood levels for full replacement
therapy. The synthetic androgens (methyltestosterone and
fluoxymesterone) are less extensively metabolized by the
liver and have longer half-lives. They are more suitable
than testosterone for oral administration.
Testosterone in plasma is 98 percent bound to a specific
testosterone-estradiol binding globulin, and about 2 percent
is free. Generally, the amount of this sex-hormone binding
globulin in the plasma will determine the distribution
of testosterone between free and bound forms, and the
free testosterone concentration will determine its half-life.
About 90 percent of a dose of testosterone is excreted
in the urine as glucuronic and sulfuric acid conjugates
of testosterone and its metabolites; about 6 percent of
a dose is excreted in the feces, mostly in the unconjugated
form. Inactivation of testosterone occurs primarily in
the liver. Testosterone is metabolized to various 17-keto
steroids through two different pathways. There are considerable
variations of the half-life of testosterone as reported
in the literature, ranging from 10 to 100 minutes.
In many tissues the activity of testosterone appears
to depend on reduction to dihydrotestosterone, which binds
to cytosol receptor proteins. The steroid-receptor complex
is transported to the nucleus where it initiates transcription
events and cellular changes related to androgen action.
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