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Significant Role of 5α‐Reductase on Feedback Effects of Androgen in Rat Anterior Pituitary Cells Demonstrated With a Nonsteroidal 5α‐Reductase Inhibitor ONO‐3805

A 5α-reductase inhibitor with nonsteroidal structure, ONO-3805, has been used to study the role of 5α-reductase on positive and negative feedback effects of androgen on gonadotropin secretion in the rat anterior pituitary gland. Initially, the potential of ONO-3805 to inhibit the formation of 5α-dihydrotestosterone (DHT) was evaluated. The activity of 5α-reductase in rat anterior pituitary gland was approximately one-fourth of that in rat prostate gland or epididymis, with a Michaelis' constant (K m ) value for testosterone of 5-6×10 -7 M. When homogenates of rat anterior pituitary glands were incubated with 14 C-testosterone ( 14 C-T) in the presence of ≥10 -7 M ONO-38O5, the formation of labeled DHT and its metabolite 5α-androstane-3α,17β-diol was inhibited by >90%. The inhibition pattern was non-competitive, and the inhibition constant (Ki value) derived from Lineweaver-burk plots was 3.9×10 -11 M. Dispersed pituitary cells (1-2×10 5 /ml) were cultured for 48 hours and then further incubated with or without androgen and/or the inhibitor for 72 hours (basal secretion). After this incubation, the media were saved, and 10 nM of luteinizing hormone-releasing hormone (LH-RH) with the same concentration of androgen and/or the inhibitor as used in the 72-hour incubation was added to the cultures for 6 hours (LH-RH-induced secretion). Secreted follicle-stimulating hormone (FSH) and luteinizing hormone (LH) were assayed by radioimmunoassay (RIA). both testosterone M and DHT stimulated 72-hour basal FSH secretion from cultured pituitary cells in a dose-dependent fashion. T was less effective than DHT. The addition of inhibitor at >10 -9 M concentration significantly reduced the stimulating effect of T on basal FSH secretion. Basal LH secretion was not affected by either T or DHT with or without the inhibitor. In the presence of 10 nM LH-RH, 6-hour secretion of both FSH and LH was significantly reduced by the addition of T or DHT at a concentration of ≥100 pg/ml. T (10 ng/ml)-induced suppression of both FSH and LH was significantly but not completely returned by the addition of 10 -7 M of ONO-3805. These results strongly suggest a significant role of 5α-reductase on both positive and negative feedback effects of androgen in the rat anterior pituitary gland