Aromatase inhibitors
Aromatase, also known as estrogen synthetase, is an enzyme complex present in brain, muscle, adipose tissue, gonads, skin, bone, liver and a variety of other tissues [29,30]. It represents a complex of a microsomal cytochrome P-450 enzyme and a NADPH-dependent cytochrome reductase [31,32]. This enzyme is responsible for converting testosterone to estradiol and the weak adrenal and testicular androgen, androstenedione, to estrone. Aromatase inhibitors would be expected to reduce gynecomastia by decreasing the peripheral aromatization of androgens to estrogens.
The first aromatase inhibitor to be used in the treatment of gynecomastia was testolactone. In an open labeled study of 22 pubertal males, Zachman et al administered 450 mg of the drug orally for 2 to 6 months and noted that gynecomastia had significantly decreased. Mean breast diameter decreased from 4.4 cm to 3.2 cm to 1.7 cm at 2, 4 and 6 months, respectively [33•]. There were no relapses following discontinuation of treatment. We examined the effect of testolactone on four patients with long standing, idiopathic gynecomastia who received escalating doses of the drug up to 750 mg over 6 months. In this prospective study, mean breast size decreased by 28, 32 and 47% at two, four and six months (p < 0.05), respectively. However, only one man had a complete resolution of gynecomastia.
There have been no systematic studies of the use of the second or third generation aromatase inhibitors such as fadrozole (Novartis), formestane (Novartis), exemestane (Pharmacia), letrozole (Novartis), anastrazole (AstraZeneca) or vorozole (Janssen) for the treatment of gynecomastia. However, anastrazole has successfully been used in three patients with gynecomastia due to aromatase excess mechanisms as described by Bulun [34]. A double-blind, prospective, placebo-controlled trial with anastrazole in 60 adolescents with pubertal gynecomastia is currently underway by AstraZeneca.
