Inhibition of P450 aromatase enhances gonadotropin secretion in early and midpubertal boys: Evidence for a pituitary site of action of endogenous E

In early pubertal boys, E concentrations are very low. We studied the role and site of action of endogenous E in the regulation of gonadotropin secret ion in early and midpubertal boys by inhibiting the action of E with a pote nt and specific P450 aromatase inhibitor, letrozole. A total of 35 boys who were referred to us because of suspicion of delayed puberty were included in the study. The boys were in either early or midpuberty, and they compose d 3 groups: 10 boys did not receive any treatment, 12 boys received T alone , and 13 boys received T and letrozole. In the untreated group during the 5 -month follow-up, no changes were observed in 17 beta -E2, T, basal gonadot ropin, or inhibin B concentrations or in the GnRH-induced gonadotropin resp onses. In the T-treated group during the 5-month treatment, the T concentration in creased by 55% (P < 0.05), and the 17<beta>-E2 concentration increased by 1 30% (P < 0.02). Concurrently, basal gonadotropin concentrations were suppre ssed, but the GnRH-induced gonadotropin responses and the inhibin B concent ration remained unchanged. In the T-plus letrozole-treated group during the 5-month treatment, an increase in T concentration of 606% was observed (P < 0.001), but the 17 beta -E2 concentration remained unchanged. The changes in the 17 beta -E2 concentration within 5 months in the untreated and the T- plus letrozole-treated groups were different (P < 0.02), indicating sign ificant inhibition of endogenous E synthesis during letrozole treatment. Du ring the T plus letrozole treatment, basal gonadotropin concentration, the GnRH-induced LH response, and inhibin B concentration increased, and the Gn RH-induced FSH response did not change significantly. Serum nocturnal gonad otropin pulses were determined in 5 boys treated with T and in 5 boys treat ed with T plus letrozole. In the T- plus letrozole-treated group, the noctu rnal LH pulse amplitude increased, and the LH pulse frequency and interpuls e interval remained unchanged. In conclusion, in early and midpubertal boys, suppression of the action of E by the P450 aromatase inhibitor increased LH concentration, LH pulse ampl itude, and the GnRH-induced LH response, which indicates that in boys durin g early and midpuberty, endogenous E regulates LH secretion at the site of the pituitary.