Activation and differentiation of sexual behavior and translocation of hypothalamic estrogen receptors in rats by 6α-fluorotestosterone

Abstract

Androgens classified as nonaromatizable in placental assay systems typically do not mimic testosterone's effects on sexual behavior in rats. 6α-Fluorotestosterone is an exception. To pursue this challenge to the aromatization hypothesis, we compared several behavioral and neuroendocrine effects of 6α-fluorotestosterone propionate (6α-fluoro-TP) with those of testosterone propionate (TP). Even at a very low dose (6.25 μg/100 g/day), 6α-fluoro-TP maintained most aspects of male sexual behavior as well as TP. It was slightly less potent than TP for inhibiting gonadotropin secretion (testicular development) in prepubertal males. Given neonatally, these androgens were equally likely to induce anovulatory sterility. 6α-Fluoro-TP defeminized sexual development in females and neonatally castrated males half as effectively as TP based on lordosis:mount ratios following estrogen and progesterone therapy in adulthood. Neither androgen masculinized sexual behavior. The behavioral effects of 6α-fluoro-TP correspond to its ability to inhibit cell nuclear accumulation of 17β-[ 3H]estradiol in the hypothalamuspreoptic area. When injected on a schedule like that used to activate male sexual behavior, the two androgens reduced estrogen uptake equally. When injected into adult castrates on a schedule like that used to defeminize sexual development, 6α-fluoro-TP blocked estrogen uptake half as well as TP. 6α-Fluorotestosterone did not alter estrogen uptake when injected simultaneously with 17β-[ 3H]estradiol. These data suggest that 6α-fluorotestosterone activates male behavior and defeminizes development because it translocates estrogen receptors in the brain, probably via an aromatized metabolite. Hence androgen aromatizability in the placenta may not reflect neural metabolism and cannot predict the behavioral or neuroendocrine effects of androgens.