Neuroestradiol in regulation of GnRH release.

Contribution to Special Issue on Fast effects of steroids. The concept that the positive feedback effect of ovarian estradiol (E) results in GnRH and gonadotropin surges is a well-established principle. However, a series of studies investigating the rapid action of E in female rhesus monkeys has led to a new concept that neuroestradiol, synthesized and released in the hypothalamus, also contributes to regulation of the preovulatory GnRH surge. This unexpected finding started from our surprising observation that E induces rapid stimulatory action in GnRH neurons in vitro. Subsequently, we confirmed that a similar rapid stimulatory action of E occurs in vivo. Unlike subcutaneous injection of E benzoate (EB), a brief (10-20 min), direct infusion of EB into the median eminence in ovariectomized (OVX) female monkeys rapidly stimulates release of GnRH and E in a pulsatile manner, and the EB-induced GnRH and E release is blocked by simultaneous infusion of the aromatase inhibitor, letrozole. This suggests that stimulated release of E is of hypothalamic origin. To further determine the role of neuroestradiol we examined the effects of letrozole on EB-induced GnRH and LH surges in OVX females. Results indicate that letrozole treatment greatly attenuated the EB-induced GnRH and LH surges. Collectively, neuroestradiol released from the hypothalamus appears to be necessary for the positive feedback effect of E on the GnRH/LH surge.