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

Finasteride is a selective inhibitor of the enzyme 5-reductasewhich is responsible for the conversion of testosterone (T)to dihydrotestosterone (DHT). Finasteride is indicated for thetreatment of benign prostatic hyperplasia in man ({small tilde}0.1mg/kg/day). The effect of long-term treatment was studied inmice given high doses (2.5, 25, and 250 mg/kg/day) of finasteridefor 83 weeks. In finasteride-treated mice, increased incidencesof testicular Leydig cell hyperplasia (52% compared to 24% incontrol group) at doses equal to or greater than 25 mg/kg/dayand Leydig cell adenomas (32% compared to 0.5% in control group)at 250 mg/kg/day were observed. There were no drug-related effectson the seminiferous tubules. Since luteinizing hor mone (LH)is a trophic hormone for Leydig cells, short-term studies (5to 14 weeks) were done to investigate the relationship betweenLeydig cell hyperplasia and serum LH levels in finasteride-treatedmice. In these studies, there was a positive correlation betweenthe drug-related increased incidence of Leydig cell hyperplasiaand a statistically significant (p 0.05) increase in serum LHlevels in finasteride-treated (250 mg/kg/day) mice. Furthermore,studies in castrated male mice showed that the suppression ofserum LH levels by T is reversible by inhibition of conversionof T to DHT with finasteride (250 mg/kg/day), supporting thehypothesis that DHT is involved in the regulation of LH releasein mice. The data presented support the conclusion that theeffects of finasteride on Leydig cells appear to be secondaryto increased serum LH levels and that they occur only at veryhigh doses when compared to the therapeutic dose (approximately0.1 mg/kg/day) in man.