FREE ESTRADIOL IN SERUM AND BRAIN UPTAKE OF ESTRADIOL DURING FETAL AND NEONATAL SEXUAL-DIFFERENTIATION IN FEMALE RATS

Circulating estradiol is assumed not to contribute to sexual different iation of the brain or other estrogen target tissues, The only estradi ol available for binding to estrogen receptors is thought to be produc ed within brain cells by the aromatization of testosterone to estradio l as part of the action of androgen in the brain. However, we report t hat the concentration of free, biologically active serum estradiol (th e concentration not bound to plasma proteins) was 0.54-2.17 pg/ml duri ng the fetal and early neonatal period of sexual differentiation, Thes e values were within the same concentration range for free estradiol o bserved in adult female rats throughout the estrous cycle (diestrus = 0.53 pg/ml; proestrus = 2.26 pg/ml), and estradiol clearly has physiol ogical effects during diestrus as well as proestrus in adult females. When a stable, physiological blood concentration of [H-3]estradiol of 49 pg/ml total (0.61 pg/ml free) was achieved with Silastic capsules i n P-day-old female pups, [H-3]estradiol was recovered specifically bou nd to brain cell nuclei at approximately 2.7 fmol per pup brain or 12. 4 fmol/mg DNA. The finding of brain uptake of circulating estradiol is contrary to current hypotheses, These findings suggest that estradiol in the fetal and neonatal circulation may be able to interact with te stosterone and its metabolites to regulate sexual differentiation of t he brain and other estrogen target tissues.