Androgens in Health and Disease.pdf - E Library

144 Wang and Swerdloff
The 17α-alkyl esters of testosterone were the first orally active forms of testosterone
to be synthesized. These 17α-alkyl derivatives are not converted to testosterone in the
body but fit the androgen receptor directly. Thus, monitoring of therapy requires the
measurement of the administered steroids by gas chromatograph–mass spectroscopy,
which is not generally available to clinicians. Methyltestosterone has been reported to
be associated with cholestatic jaundice. Other 17α-alkyl derivatives are used as “anabolic”
steroids for wasting diseases and, in the past, for the treatment of aplastic and
refractory anemias. When used in high doses, hepatic toxicity has been reported (15,16).
These modified orally active 17α-alkyl derivatives are not aromatized to estrogens. In
addition, because of the first-pass effect through the liver, these agents cause significant
increases in serum low-density lipoprotein (LDL)-cholesterol and decreases in highdensity
lipoprotein (HDL)-cholesterol (17). For the above reasons, 17α-alkyl androgens
are not often recommended for long-term androgen-replacement therapy. Despite concerns
about potential toxicity, these orally active steroids are commonly used by athletes
for bodybuilding and enhancing muscle strength.
Other non-17α-alkylated oral androgens are approved for use in the United States
and/or other countries. Mesterolone is an α-methyl derivative of DHT. Available in
Europe and Asia, mesterolone is a weak androgen and has not been found useful for
androgen-replacement therapy. Oral testosterone undecanoate has been marketed over
15 yr for clinical use in Europe, Asia, Australia, South America, and some countries in
North America (Mexico and Canada). This ester has a very long side chain and is
lipophilic. When administered orally, it is absorbed by the lymphatics and then to the
systemic circulation. Thus, the absorption of testosterone undecanoate may be affected
by the amount of fat in the diet. The peak serum testosterone levels in circulation occurred
4–5 h after administration and the levels gradually declined to baseline in 8–10 h (18,19).
There is very large variability in the time to achieve peak serum testosterone levels. The
serum DHT levels are relatively high after testosterone undecanoate oral administration.
The usual dose is 80 mg (two capsules) bid or tid and the preparation must be taken with
meals. Despite a high intrasubject and intersubject variation in serum testosterone levels
after oral testosterone undecanoate administration, the preparation is well accepted by
many patients. Long-term studies have demonstrated its safety as androgen replacement
for hypogonadal men (20). Because of the ease of administration, testosterone
undecanoate has also been used for the induction of puberty in boys with constitutional
delayed growth and development.
Injectables
Testosterone propionate maintains testosterone levels only for 2–3 d after an intramuscular
(im) injection and is impractical for androgen replacement. Testosterone
enanthate or cypionate are longer acting and have been widely used for androgenreplacement
therapy. The pharmacokinetics of testosterone enanthate are well defined
(21,22) (see Fig. 1, right panel). The usual recommended dose for testosterone replacement
in an adult man is 200 mg im every 2 wk (see Table 2). Peak serum testosterone
levels may reach above the physiological range 1–3 d after the injection and return to
baseline levels by 10–14 d. Some patients may experience fluctuations in mood and
energy with the peaks and troughs of serum testosterone. To lessen these complaints,
testosterone enanthate can be administered in lower doses more frequently (e.g., 100 mg
every 7–10 d). Testosterone enanthate has been administered to patients over a wide age