| Autor: |
Prahalada, S., Tarantal, A.F., Harris, G.S., Ellsworth, K.P., Clarke, A.P., Skiles, G.L., MacKenzie, K.I., Kruk, L.F., Ablin, D.S., Cukierski, M.A., Peter, C.P., vanZwieten, M.J., Hendrickx, A.G. |
| Zdroj: |
Teratology; February 1997, Vol. 55 Issue: 2 p119-131, 13p |
| Abstrakt: |
In genetic male fetuses, dihydrotestosterone (DHT) plays an important role in normal prostatic and external genital differentiation. The enzyme steroid 5-alpha reductase (5αR) catalyzes the conversion of testosterone (T) to DHT. The importance of 5αR in sexual differentiation is evident from the study of human genetic males who congenitally lack this enzyme and consequently develop ambiguous genitalia. These individuals are specifically deficient in the type 2 isozyme, whereas the normal type 1 isozyme activity has been found. The purpose of this study was to determine 1) the suitability of the rhesus monkey for testing the safety of 5αR inhibitors when administered during pregnancy and 2) the potential risk of administering a known type 2 5αR inhibitor, finasteride, during the critical period of internal and external genital differentiation in rhesus monkeys. In vitro studies were also performed on selected rhesus monkey tissues to determine the distribution of the 5αR isozymes. Gravid monkeys were treated once daily from gestational days (GD) 20 to 100. Sonographic monitoring 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 5αR results in specific external genital abnormalities in male fetuses. Thirty-two pregnant monkeys were administered an intravenous (IV) formulation of finasteride at doses of 8, 80, or 800 ng/day. The highest IV dose selected was at least 60750 times the semen levels of finasteride in man given orally 5 or 1 mg/day, respectively. Seventeen vehicle-control pregnant monkeys were also included. Administration of a high oral dose (2 mg/kg/day) of finasteride resulted in external genital abnormalities characterized by hypospadias, preputial adhesions to the glans, a small underdeveloped scrotum, a small penis, and a prominent midline raphe in male fetuses; however, no developmental abnormalities were seen in female fetuses. Similarly, no abnormalities 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 utero sonographic findings in fetuses correlated with the gross findings at term. These studies have shown that external genital abnormalities can be produced in male monkey fetuses when exposed to a high oral dose (2 mg/kg/day) of finasteride, whereas no abnormalities were observed in fetuses exposed to the IV formulation of finasteride. Detailed in vitro studies demonstrated that the rhesus monkey also has two 5αR isozymes (types 1 and 2) with a tissue distribution similar to that seen in man and, furthermore, that finasteride is a potent, mechanism-based inhibitor with selectivity for both human and rhesus type 2 5αR. These studies have demonstrated that the monkey is a suitable model for assessing the safety of 5αR inhibitors administered during pregnancy. Teratology 55:119131, 1997. © 1997 Wiley-Liss, Inc. |
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