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© 1994 Oxford University Press

research-article

Leydig Cell Hyperplasia and Adenomas in Mice Treated with Finasteride, a 5{alpha}-Reductase Inhibitor: A Possible Mechanism

S. PRAHALADA, J. A. MAJKA, K. A. SOPER, T. M. NETT*, W. J. BAGDON, C. P. PETER, J. D. BUREK, J. S. MACDONALD and M. J. VAN ZWIETEN

Merck Research Laboratories, Merck & Company, Inc. West Point, Pennsylvania 19486 *Colorado State University Fort Collins, Colorado 80521

Received May 24, 1993; accepted September 28, 1993

Finasteride is a selective inhibitor of the enzyme 5{alpha}-reductase which is responsible for the conversion of testosterone (T) to dihydrotestosterone (DHT). Finasteride is indicated for the treatment of benign prostatic hyperplasia in man ({small tilde}0.1 mg/kg/day). The effect of long-term treatment was studied in mice given high doses (2.5, 25, and 250 mg/kg/day) of finasteride for 83 weeks. In finasteride-treated mice, increased incidences of testicular Leydig cell hyperplasia (52% compared to 24% in control group) at doses equal to or greater than 25 mg/kg/day and Leydig cell adenomas (32% compared to 0.5% in control group) at 250 mg/kg/day were observed. There were no drug-related effects on the seminiferous tubules. Since luteinizing hor mone (LH) is a trophic hormone for Leydig cells, short-term studies (5 to 14 weeks) were done to investigate the relationship between Leydig cell hyperplasia and serum LH levels in finasteride-treated mice. In these studies, there was a positive correlation between the drug-related increased incidence of Leydig cell hyperplasia and a statistically significant (p≤ 0.05) increase in serum LH levels in finasteride-treated (250 mg/kg/day) mice. Furthermore, studies in castrated male mice showed that the suppression of serum LH levels by T is reversible by inhibition of conversion of T to DHT with finasteride (250 mg/kg/day), supporting the hypothesis that DHT is involved in the regulation of LH release in mice. The data presented support the conclusion that the effects of finasteride on Leydig cells appear to be secondary to increased serum LH levels and that they occur only at very high doses when compared to the therapeutic dose (approximately 0.1 mg/kg/day) in man.


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