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 (E₂) results in GnRH and gonadotropin surges is a well-established principle. However, a series of studies investigating the rapid action of E₂ 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 E₂ induces rapid stimulatory action in GnRH neurons in vitro. Subsequently, we confirmed that a similar rapid stimulatory action of E₂ occurs in vivo. Unlike subcutaneous injection of E₂ 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 E₂ in a pulsatile manner, and the EB-induced GnRH and E₂ release is blocked by simultaneous infusion of the aromatase inhibitor, letrozole. This suggests that stimulated release of E₂ 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 E₂ on the GnRH/LH surge.