Androgens in Health and Disease.pdf - E Library

148 Wang and Swerdloff
The steroid 7α-methyl-19 nor-testosterone (MENT) is also formulated as an implant.
This androgen is about 10 times as potent as testosterone in the suppression of gonadotropins
and maintenance of levator ani muscle but only 4 times as potent on testosterone in
promoting prostate growth in castrated rats (32). A reduced stimulation of prostate growth
relative to many other target organs has also been demonstrated in monkeys (33). The
prostate-sparing effects are explained by the demonstration that MENT is not reduced by
5α-reductase and thus have fewer androgenic effects on the prostate, hair follicles, and the
skin. MENT is being formulated as a subcutaneous implant inserted in the subcutaneous
tissue of the upper arm and also as a transdermal gel preparation. A two-center study
showed when administered as a subcutaneous implant, the MENT acetate (containing 115
mg active compound releasing 350–400 g/d MENT) had similar effects as testosterone
enanthate injections on restoration of sexual function and improvement of mood states in
hypogonadal men (34). Large-scale clinical studies have not yet been conducted.
TRANSDERMAL PREPARATIONS
In the mid-1990s, a transdermal scrotal patch releasing 6 mg testosterone per day
was developed. The application of the patch to scrotal skin required hair clipping or
shaving to optimize adherence. This daily patch (Testoderm) produced steady-state
serum testosterone levels in the lower normal range in hypogonadal men (35,36). The
use of the scrotal skin patch has been superseded by the development of nonscrotal skin
patches. The permeation-enhanced testosterone patch (Androderm) delivers 5 mg/d
testosterone and can be applied to the body (see Fig. 1, left panel). It produces serum
testosterone levels in the normal range, mimicking the diurnal variation of testosterone
(37,38). The application is associated with skin irritation in up to 60% of the subjects,
with 10–15% of users discontinuing application because of the skin irritation (39).
Preapplication of corticosteroid cream to the skin has been reported to decrease the
severity of the skin irritation. The other available nonscrotal patch (Testoderm TTS)
causes minimal skin irritation (about 12% itching and 3% erythema) but may have a
problem adhering to the skin. These transdermal testosterone patches provide steadystate
delivery of testosterone to the body and have been shown to reverse the signs and
symptoms of male hypogonadism and andropause (40,41).
Recently, a 1% hydroalcoholic gel (Androgel) containing 25 or 50 mg testosterone
in 2.5 or 5 g gel, delivering approx 2.5 or 5 mg testosterone to the body per day, has been
approved for clinical use in hypogonadism. The pharmacokinetic profile of serum
testosterone levels after application of 5–10 g of the testosterone gel compared to 5 mg
of a permeation-enhanced testosterone patch is shown in Fig. 3. After application of 5
or 10 g of gel containing 50 or 100 mg testosterone, serum testosterone levels rose
gradually and a steady state was achieved after 2–3 d. About 9–14% of the testosterone
in the gel is bioavailable (42). After long-term application, serum testosterone is maintained
in the mid-normal range with 5 g of gel and in the upper normal range with 10
g of gel. After testosterone gel application, dose-proportionate increases in serum DHT
and E 2 are observed (43). This testosterone-gel preparation has been demonstrated to
improve sexual function and lean body mass, muscle mass, and bone mineral density
while decreasing fat mass in hypogonadal men (44,45). The advantages of the testosterone
gel over the testosterone patch are the absence of skin irritation, the ease of application,
and the ability to deliver testosterone in the low, mid, or upper normal range. A
potential complication of testosterone-gel application is the transfer of testosterone to