We report the first detailed study of the pharmacological effects of exemestane in male subjects. Doses of 25 and 50 mg were comparable in suppressing all circulating estrogens and had similar effects of increasing serum androstenedione and testosterone concentrations. There were 38%, 71%, and 45% decreases in estradiol, estrone, and estrone sulfate concentrations, respectively, after 10 d, approximately 24 h after administration of the last dose of 25 mg exemestane, coupled with 60% and 32% increases in testosterone and androstenedione concentrations. The rise in the aromatase substrates, testosterone and androstenedione, is probably secondary to substrate accumulation and/or to the feedback increase in gonadotropins caused by aromatase blockade. The 21% decrease in SHBG concentrations caused by 25 mg exemestane confirms the observation in postmenopausal women (20).
The maximum plasma concentration, time to achieve maximal concentrations and oral clearance for exemestane after oral administration of a single dose of 25 mg in the present study of males were similar to those reported for females (21–23). The terminal half-life in the present study (8.9 h) was considerably shorter than the published value of 27 h (23). The reason for this difference is not clear, but may be related to a true gender dependency possibly involving the volume of distribution (lower in males than females) and plasma or tissue protein binding (respectively, higher and lower in males). This finding may also be due to the lower sensitivity of the analytical methodology used in the previous studies (14 pg/ml by HPLC/RIA) (21).
The maximal suppression evoked by exemestane at the single dose of 25 mg in the present study was similar to published results in postmenopausal women, but the time course differed (24). Evans et al. (24) reported that a single 25-mg oral dose of exemestane maximally suppressed estradiol concentrations by 72% 3 d after administration, and estradiol levels returned to baseline only 8–11 d after drug administration. In the present study maximal suppression of estradiol of 62% was observed 12 h after exemestane administration and returned to baseline 3–6 d after administration. The reason for this difference is not clear, but may be related to the shorter half-life of exemestane in males, the lower exposure to exemestane, and the higher levels of the aromatase substrates androstenedione (∼1 ng/ml in young males vs. ∼0.5 ng/ml in postmenopausal women), particularly the much higher testosterone concentrations in young males than in postmenopausal women (∼700 ng/dl vs. ∼20 ng/dl, respectively) (25). This is supported by the observation that in the 10-d studyin young males reported here, the suppression of estradiol is weaker (due to the very high levels of the precursor testosterone) than that of estrone(due to androstenedione levels not very different from those in postmenopausal women). A limited suppression of circulating estradiol (∼50%) has been reported in a similar study in young males treated with 1 mg daily anastrozole (7), a dose that reduces estradiol by 85% in postmenopausal women (23).
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