Prq, NeumPsychophamu~~~L & BbL Psychiat zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGF 1993. Vol. 17. pp. 991-1003 0278 - 5846/93 $24.00 Printed in Great Ekftah. Au rights reserved o 1993 ~egamon Press Ltd zyxwvut ALTERED BRAIN AND PITUITARY ANDROGEN METABOLISM BY PRENATAL, PERINATAL OR PRE- AND POSTNATAL FINASTERIDE, FLUTAMIDE OR DIHYDROTESTOSTERONE TREATMENT IN JUVENILE MALERATS EDWIN D. LEPHARTr and DOUGLAS A. HUSMANN;? The Cecil H. & Ida Green Center for rReproductive Biology Sciences and The Departments of tBiochemistry and IObstetrics and Gynecology The University of Texas Southwestern Medical Center Dallas, Texas, U.S.A. and The 2De The Mayo Clinic, Rochester, J artment of Urology mnesota, U.S.A. (Final form, September 1992) Abstract Lephart, Edwin D. and Douglas A. Husmann: Altered brain and pituitary androgen metabolism by prenatal, perinatal or pre- and postnatal finasteride, flutamide or dih drotestosterone treatment in juvenile male rats. Prog. Neuro-Psychopharmacol. & Biol. Psychiat. 1B 93, 17(6): 991-1003. 1. The authors investigated the administration of finasteride, a Sa-reductase inhibitor; flutamide, an androgen receptor blocker and; exogenous dihydrotestosterone (DHT) during intervals covering different portions of the “critical period” of neural development (Le. prenatal, perinatal or pre- and postnatal development) to determine the long-term effects of these agents on altering androgen metabolism in hypothalamic and pituitary tissue of juvenile (30 day-old) male rats. 2. The efficacy of the treatments and hypothalamic-pituitary axis function was monitored by measuring luteinizing hormone levels by radioimmunoassay. Sa-Reductase and aromatase 3. 4. activity was determined in hypothalamic and pituitary tissue. Significant alterations in pituitary So-reductase activity was detected in DHT-treated animals, whereas, hypothalamic Sa-reductase activity was significantly decreased by finasteride treatment and significantly increased by DHT treatment. was significantly decreased in flutamide-treated animals. Hypothalamic aromatase activity These results suggest that: a) prenatal exposure to exogenous DHT stimulates hypothalamic (but inhibits pituitary) Sa-reductase activity long-term and b) basal Sa-reductase activity levels can be inhibited by finasteride treatment in hypothalamic but not in pituitary tissue, suggesting that a different regulatory mechanism exists for So-reductase in hypothalamic verses pituitary tissue. Kev Words: aromatase, development, hypothalamus, pituitary, rat, Sa-reductase, reproductive behavior, sexual differentiation Abbreviations: aromatase cytochrome P450 (P450 ARoM),dihydrotestosterone (DHT), gestational day (GD), medial basal hypothalamus (MBH), preoptic area (POA), postnatal day (PND), testosterone (T) Introduction The current hypothesis regarding the sexual differentiation of the rodent brain is based upon evidence that certain neural structures are exquisitely sensitive to the organizational effects of the local conversion of testosterone to estrogen(s) (MacLusky and Naftolin 1981, Gorski 1989). Estrogens ik vitro can induce neural growth and aborization in perinatal hypothalamic explants (Toran-Allerand, 1976). Testosterone also stimulates neurite growth in hypothalamic explants in vitro via aromatization to estrogens, since DHT, a non-aromatizable androgen, does not increase neurite extension beyond that seen in control cultures (Toran-Allerand, 1976). These hypothalamic structures play important roles in brain differentiation (Toran-Allerand 1976, MacLusky and 991