EFFECTS OF FINASTERIDE, A TYPE-2 5-ALPHA REDUCTASE INHIBITOR, ON FETAL DEVELOPMENT IN THE RHESUS-MONKEY (MACACA-MULATTA)

In genetic male fetuses, dihydrotestosterone (DHT) plays an important role in normal prostatic and external genital differentiation. The enz yme steroid 5-alpha reductase (5 alpha R) catalyzes the conversion of testosterone (T) to DHT. The importance of 5 alpha R in sexual differe ntiation is evident from the study of human genetic males who congenit ally lack this enzyme and consequently develop ambiguous genitalia. Th ese individuals are specifically deficient in the type 2 isozyme, wher eas the normal type 1 isozyme activity has been found. The purpose of this study was to determine 1) the suitability of the rhesus monkey fo r testing the safety of 5 alpha R inhibitors when administered during pregnancy and 2) the potential risk of administering a known type 2 5 alpha R inhibitor, finasteride, during the critical period of internal and external genital differentiation in rhesus monkeys. In vitro stud ies were also performed on selected rhesus monkey tissues to determine the distribution of the 5 alpha R isozymes. Gravid monkeys were treat ed once daily from gestational days (GD) 20 to 100. Sonographic monito ring was performed during the course of gestation to monitor viability , growth, and organ system development. Detailed fetal evaluations for developmental abnormalities were performed at term (GD 152 +/- 2). A group of 13 pregnant monkeys (''positive control'') were given a high oral dose (2 mg/kg/day) of finasteride to demonstrate that inhibiting type 2 5 alpha R results in specific external genital abnormalities in male fetuses. Thirty-two pregnant monkeys were administered an intrav enous (IV) formulation of finasteride at doses of 8, 80, or 800 ng/day . The highest IV dose selected was at least 60-750 times the semen lev els of finasteride in man given orally 5 or 1 mg/day, respectively. Se venteen vehicle-control pregnant monkeys were also included. Administr ation of a high oral dose (2 mg/kg/day) of finasteride resulted in ext ernal genital abnormalities characterized by hypospadias, preputial ad hesions to the glans, a small underdeveloped scrotum, a small penis, a nd a prominent midline raphe in male fetuses; however, no developmenta l abnormalities were seen in female fetuses. Similarly, no abnormaliti es were observed in either male or female fetuses of mothers given IV doses (8, 80, or 800 ng/day) of finasteride during pregnancy. The in u tero sonographic findings in fetuses correlated with the gross finding s at term. These studies have shown that external genital abnormalitie s can be produced in male monkey fetuses when exposed to a high oral d ose (2 mg/kg/day) of finasteride, whereas no abnormalities were observ ed in fetuses exposed to the IV formulation of finasteride. Detailed i n vitro studies demonstrated that the rhesus monkey also has two 5 alp ha R isozymes (types 1 and 2) with a tissue distribution similar to th at seen in man and, furthermore, that finasteride is a potent, mechani sm-based inhibitor with selectivity for both human and rhesus type 2 5 alpha R. These studies have demonstrated that the monkey is a suitabl e model for assessing the safety of 5 alpha R inhibitors administered during pregnancy. (C) 1997 Wiley-Liss, Inc.