[Experimental studies of the significance and mechanism of desensitization to the gonadotropin-inhibiting effect of estrogen. 2. Detection and mechanisms of preovulatory desensitization in the ovarian cycle].

It has recently been demonstrated in women and several mammalian species that the basal LH secretion increases prior to the ovulation-inducing LH surge in spite of a simultaneous rise of the estrogen level in the blood. The temporary relative inefficiency of estrogen in its negative feedback action may be necessary to make adequate gonadotrophic support of final preovulatory follicle maturation possible. To study the mechanisms underlying this phenomenon, the gonadotrophic response to a single injection of estradiol benzoate (EB) was evaluated in acutely ovariectomized adult rats during the different stages of a 4-day ovarian cycle. The results showed that the sensitivity to the gonadotrophin-inhibiting effect of EB is high during late estrus and early metestrus. Between metestrus and diestrus it suddenly declines, and EB did not inhibit the hypophysial gonadotrophin secretion from diestrus through the morning of the subsequent estrus. The cyclic variation of the sensitivity to the negative estrogen feedback is probably not based upon an endogenous rhythm that is independent of the ovarian hormone secretion, because similar variability of the gonadotrophic response to estrogen was not found in rats that had been castrated three days before the injection of EB. A further experiment demonstrated that bilateral implants of EB placed in the medial preoptic area (MPOA) of ovariectomized rats significantly reduced the gonadotrophin-inhibiting effect of s. c. injected estradiol, whereas similar implants located in the mediobasal hypothalamus were completely ineffective in this regard. Since bilateral lesioning of the MPOA in long-term ovariectomized females also lowered the sensitivity to estrogen, the conclusion may be drawn that preovulatory desensitization to the negative estrogen feedback is probably induced in cyclic female rats by an inhibitory effect on medial preoptic neurones of the increase of circulating estrogen recorded in metestrus. In accordance with this assumption, imitation of the periovulatory diminution of estrogen action on the MPOA of intact rats by the removal of medial preoptic EB implants in castrated females during the afternoon of proestrus, resulted in high sensitivity to estrogen during estrus and metestrus. The possible clinical significance of the hitherto not described preovulatory desensitization is briefly discussed.