Androgens in Health and Disease.pdf - E Library

Chapter 16/Androgen Treatment of the Hypogonadal Male 325
initial hepatic inactivation, and is not associated with hepatotoxicity. Androgen replacement
usually requires high doses (80–240 mg daily) and administration in divided doses
(two to three times daily). Absorption of T undecanoate is quite variable and is dependent
on concomitant ingestion of a meal. Thus, serum T levels and clinical responses produced
are highly variable.
A new formulation of T undecanoate and a bioadhesive buccal T tablet, both administered
twice daily, are being tested for androgen replacement in hypogonadal men and
registration in the United States. In previous studies, T complexed to 2.5–5 mg
hydroxypropyl-β-cyclodextrin administered sublingually to hypogonadal men resulted
in a rapid increase in serum T levels that peaked in 20–40 min and lasted for only 2–
4 h (25,26,61). Despite these unfavorably pharmacokinetics, T cyclodextrin improved
sexual function, mood, and muscle strength and reduced markers of bone resorption,
supporting the notion that the biological actions of T may not be reflected by its serum
levels and that sustained physiological concentrations may not be necessary for some
clinical effects of T.
In some countries in Europe, a 2% hydroalcoholic DHT gel formulation is used for
androgen replacement therapy of young hypogonadal men (38). Recently, DHT gel
formulations have also been tested in older hypogonadal men (39,40,62). A rationale that
is proposed for the its use in treatment of hypogonadal men is that DHT administration
may suppress endogenous gonadotropins and T secretion, thereby lowering intraprostatic
T and DHT concentrations and preventing prostatic stimulation (63). Also, because it is
not aromatizable, DHT may not induce or worsen gynecomastia in hypogonadal men.
However, evidence for these potential advantages of DHT over T for androgen-replacement
therapy is lacking. As with T gel, there is concern regarding transfer of this more
potent androgen to females and children who come in contact with skin sites of application.
Furthermore, because DHT is not aromatizable and endogenous gonadotropin
and estrogen (E 2) secretion are suppressed, there is concern regarding the potential
consequences of estrogen deficiency produce in hypogonadal men treated with DHT
(e.g., on bone, brain, and lipids). Finally, other transdermal T-gel formulations and
patches are being developed for androgen-replacement therapy in hypogonadal men.
In addition to these short-acting androgen preparations, a number of long-acting
formulations are being developed that produce prolonged release of T and sustained
serum T levels in the normal range, both for use in androgen replacement in young
hypogonadal men and other potential uses such as hormonal male contraception. In
hypogonadal men, the 17β-hydroxyl esters, [T undecanoate formulated in castor or tea
seed oil (64,65) and T buciclate (66)] were administered im every 6–12 wk to maintain
serum T levels within the eugonadal range (the latter in the low-normal range). Also,
intramuscular or subcutaneous injections of T incorporated into biodegradable
microcapsules produce serum T concentrations in the eugonadal range for 10–11 wk
(67,68). Although these long-acting T preparations show promise, major limitations of
these formulations include the large (4 mL) injection volumes, which require two separate
injection sites and are often uncomfortable, and their highly variable bioavailability.
Finally, there is expanding interest in developing “designer” androgens that will
maintain the beneficial effects of T on muscle, bone, sexual function, behavior, mood,
cognition, and cardiovascular function but will have reduced adverse actions or protective
effects on the prostate gland, lipid profile, and cardiovascular risk. Based on the
knowledge that tissue-specific androgen action involves interactions among the andro-