The maturation of estradiol-negative feedback in female rats: Evidence that the resetting of the hypothalamic “gonadostat” does not precede the first preovulatory surge of gonadotropins

Several experiments were performed to study the changes in the negative feedback of estradiol on gonadotropin secretion around the time of puberty in the female rat. Ovariectomy of juvenile, first diestrus, or adult animals elevated FSH and LH levels 2 and/or 4 days later. Estradiol administered via Silastic capsules, at several dose levels, was much more effective in preventing the postcastration rise of gonadotropins in juvenile than in the older animals. A dose of estradiol that inhibited gonadotropin levels in juvenile rats, but not in adult animals, maintained preovariectomy serum estradiol levels more efficiently in the adult rats. Therefore, a more rapid removal of estradiol from the blood stream cannot explain its lower effectiveness in suppressing gonadotropin release in adult rats. Estradiol-negative feedback effectiveness remained maximal until the day of first proestrus and decreased markedly on the next day (first estrus), remaining low thereafter. “Resetting” of the gonadostat to estr diol negative feedback was advanced by inducing precocious puberty by means of hyperprolactinemia, but not by mimicking the periovulatory changes in serum estradiol and progesterone in the absence of an LH surge. Serum progesterone levels were much higher in postpubertal rats than in juvenile animals. Ovariectomy of juvenile rats slightly decreased the already low levels of serum progesterone, but it produced a striking progesterone decrease in postpubertal animals. Quantitative replacement of preovariectomy serum progesterone levels in adult rats, treated with an ineffective dose of estradiol, almost completely restored the prepubertal effectiveness of estradiol in inhibiting LH release and, to a lesser extent, release of FSH. The results indicate that 1) physiological levels of estradiol are much more effective in inhibiting gonadotropin Release in prepubertal than in postpubertal animals; 2) a major part of the change in sensitivity to estradiol-negative feedback occijrs within 24 h after the first preovulatory surge of gonadotropins; 3) although in prepubertal rats estradiol can suppress gonadotropin release in the presence of very low levels of progesterone, after the first ovulation estradiol effectiveness depends on the presence of elevated but physiological serum levels of progfesterone; 4) the abrupt, pubertal decline in sensitivity to estradiol-negative feedback appears to depend upon alterations that occur at both the central nervous system-pituitary unit and the gonads during the hours encompassing the first ovulation. It is postulated, therefore, that in the female rat the resetting of the gonadostat to estradiol-negative feedback is a consequence rather than the trigger of puberty.