Androgens in Health and Disease.pdf - E Library

322 Matsumoto
dosage is increased gradually to 50–100 mg im every 2 wk, and then to full adult replacement
doses, over the next several years. By avoiding intramuscular injections,
transdermal T patches or gels would provide potentially very useful alternatives for the
treatment of prepubertal androgen deficiency. However, these T formulations have not
been tested and are not approved for use in prepubertal boys.
Transdermal T Formulations
Three transdermal T patches and a transdermal T gel are available as safe and effective
alternatives to T esters for T-replacement therapy in hypogonadal men (see Table 1)
(16,31). They are useful in men who prefer to avoid or are unable to tolerate or administer
intramuscular T ester injections. In contrast to T ester injections, T patches produce
physiological T levels that exhibit a normal circadian variation, and T gel produces
steady-state physiological T concentrations. However, all of these transdermal T delivery
systems require daily application, are more expensive than androgen-replacement
therapy using T ester injections, and possess some limitations (e.g., scrotal application
site, skin irritation, poor skin adherence or absorption, limited dose flexibility, and
potential for contact transfer). Many of these limitations are a consequence of the need
to deliver relatively large amounts (5–10 mg) of T through skin that requires a thin,
vascular area of skin (e.g., scrotal skin), a large patch or skin surface area of application,
or solvents (e.g., alcohol) and permeation-enhancing agents. In some men, inherent skin
sensitivity is also factor that may limit the use of some transdermal T formulations.
A scrotal T patch (Testoderm; Alza, Palo Alto, CA) was the first transdermal T
delivery system available for T replacement in hypogonadal men (32–34). This system
contains T within the matrix of the patch, and because it is applied to the thin, highly
vascular skin of the scrotum, it does not require permeation-enhancing agents. Scrotal
T patches are available in two sizes that deliver either 6 mg (60 cm2 ) or 4 mg (40 cm2 )
of T daily. Long-term daily morning application of the Testoderm patch maintains
normal physiological T levels that mimic the circadian variation of endogenous T and
improves clinical manifestations of androgen deficiency (35–37). After 3–4 wk of
daily use, serum T levels are measured 2–4 h after application of the patch in order to
assess the adequacy of T delivery. This patch requires application on an adequate size,
clean, dry, and, preferably, shaven scrotum and the use of brief-type underwear for
optimal adhesion. These requirements may not be acceptable to some hypogonadal
men. Because of poor adherence to scrotal skin, thin adhesive strips were added to a
subsequent version of this patch. Some men may experience skin irritation and itching.
Serum levels of dihydrotestosterone (DHT), a more potent androgen than T, increase
to above the normal range as a result of the high 5α-reductase activity in scrotal skin.
The clinical significance of chronic exposure to high circulating DHT levels in androgen-responsive
organs such as the prostate is unclear, but careful monitoring for the
development of adverse androgenic effects should be performed. No increase in prostate
disease was observed in small, short-term controlled studies of older men treated
with the Testoderm patch (35–37) or DHT gel formulations (38–40), but these studies
do not address potential long-term risks. The subsequent availability of nonscrotal T
patches (see the following paragraph) has supplanted the use of the scrotal T patch for
androgen-replacement therapy.
A permeation-enhanced, nonscrotal T patch (Androderm, Watson, Corona, CA) that
is composed of a central reservoir containing T and permeation enhancers in an alcohol-