Androgens in Health and Disease.pdf - E Library

142 Wang and Swerdloff
PHARMACOLOGY OF ANDROGENS
Testosterone is the major androgen produced by the Leydig cells of the testis and acts
directly or through its conversion to 5α-dihydrotestosterone (DHT) on androgen receptors
present in reproductive and nonreproductive tissues. The major target organs for
testosterone include the testis, derivatives of the wolffian ducts (epididymis, seminal
vesicles), muscle, liver, bone marrow, and, possibly, bone and brain. Some tissues (e.g.,
prostate, external genitalia, and skin) have high levels of the 5α-reductase enzyme and
greater specificity for DHT. Alternatively, testosterone is converted to estradiol (E 2)
both in the testis and peripherally via the aromatase enzyme and acts through interaction
with estrogen receptors. The presumptive target organs of E 2 include the liver, brain,
adipose tissue and bone and the accessory reproductive organs (efferent ducts).
In androgen-deficiency states, it is desirable that the androgen be aromatizable to
estrogens to achieve the full beneficial effects on bone and lipoproteins. In animals,
estrogens are necessary for sexual dimorphic behavior, with androgenic effects mediated
through aromatization to estradiol in the brain. In humans, there is little evidence
that conversion of testosterone to E2 is required for sexual function and male behavior.
Although conversion of testosterone to DHT is important for male external genitalia
development, DHT is not required in adult man to maintain external genitalia or sexual
function. Recent studies demonstrating low bone mass and severe osteoporosis in male
patients with estrogen-receptor or aromatase enzyme gene mutations suggest the important
role of estrogens in attaining and maintaining peak bone mass in men (5–7). There
are no data to indicate that estrogens are required to maintain bone mass in adult or
elderly men. Correlation studies suggest, however, that serum bioavailable estradiol
concentrations show the better correlation with bone mineral density than serum totalor
bioavailable-testosterone levels in elderly men (8,9).
Natural testosterone is available in several formulations for therapeutic use:
transdermal patch or gel, implants, bioadhesive tablets, or as cyclodextrins. Testosterone
esters such as testosterone enanthate, cypionate, decanoate, or undecanoate are synthesized
by esterification at the 17β position with fatty acids of varying lengths. The duration
of the testosterone ester depends on the length and type of the fatty acid. These
17β-testosterone esters are rapidly metabolized by the liver to release both testosterone
and the fatty acid side chain. Further modifications of the 17β-testosterone esters with
addition of a methyl group at the 19 position produces long-acting 19 nor-testosterone
esters such as nandrolone decanoate or phenylproprionate. These testosterone esters are
aromatizable to estrogens and can be reduced by the 5α-reductase enzyme. Modification
of the testosterone molecule with a 17α-methyl group led to the synthesis of orally active
methyltestosterone. Other 17α-alkyl testosterone derivatives include fluoxymesterone,
oxandrolone, stanozole, and danazole. These 17α-alkyl derivatives of testosterone are
not aromatizable to estrogens and not converted to testosterone. A derivative of DHT
(mesterolone) is a weak androgen but is orally active. All of these derivatives are synthesized
based on modification of the testosterone molecule.
ANDROGEN PREPARATIONS AND DELIVERY SYSTEMS (SEE TABLE 1)
Oral Preparations
When administered orally, nonmodified testosterone is absorbed by the gastrointestinal
tract but is very rapidly cleared and metabolized by the liver. For this reason,