Extending the issue of the species differences the

Extending the issue of the species differences, the role of neuroestradiol in the preovulatory GnRH/LH surge might be specific to primates or species with a luteal phase. For example, animals with a true luteal phase, such as monkeys and sheep, exhibit a long preovulatory GnRH surge, lasting well after the end of the LH surge (Levine et al., 1985; Xia et al., 1992; Moenter et al., 1990). By Baricitinib in rats, which lack the luteal phase, the preovulatory GnRH surge terminates at the same time as the LH surge (Sarkar et al., 1976). Moreover, in OVX monkeys letrozole greatly attenuates the E2-induced GnRH and LH surges (Kenealy et al., 2017), whereas in OVX aromatase-deficient mice E2 or E2 plus progesterone readily induces LH surges (Szymanski and Bakker, 2012). It is speculated that the prolonged GnRH surge is a result of neuroestradiol and that it might be required for the establishment of the corpus luteum.
Conclusions and perspectives In this review article, I summarized our findings during the past ~15 years showing that E2 rapidly and directly stimulates GnRH neuronal activity and this rapid action of E2 has an important implication in the release of GnRH as well as in the local synthesis of E2 (neuroestradiol) in the hypothalamus. It turns out that neuroestradiol is released in the median eminence and this neuroestradiol release plays an important role in the regulation of pulsatile GnRH release as well as during the estrogen-induced GnRH surge (i.e., preovulatory GnRH surge). Because the preovulatory GnRH surge is the key event for successful pregnancy and contraception, the findings on the role of neuroestradiol in the preovulatory surge potentially open up a new avenue for treatments of fertility and sterility. In fact, brain-specific exon 1 of the human aromatase gene has been reported (Honda et al., 1994). The investigation of neuroestradiol in the regulation of reproductive function is just beginning and many questions remain to be answered. Does the release of neuroestradiol in the hypothalamus switch estrogen's action from the negative feedback effect to the positive feedback effect? Is the role of neuroestradiol in the regulation of GnRH release limited to females, given that the male brain generally expresses a higher level of aromatase than the female brain (Roselli and Resko, 1997)? We previously postulated that neuroestradiol may be a substrate for the “Prepubertal Central Inhibition”, as release of neuroestradiol in the median eminence in prepubertal female monkeys is higher than that in early pubertal female monkeys (Kenealy et al., 2016), but how does neuroestradiol play a role in the suppression of GnRH release? Does neuroestradiol play any role in Alzheimer's disease, as aromatase expression in the hypothalamus in Alzheimer patients is lower than in the age-matched control hypothalamus (Ishunina et al., 2005). Is neuroestradiol synthesized in neurons, glia, or both? If synthesized in neurons, what is their cell type? We have no data regarding receptors mediating neuroestradiol action in vivo. Unlike genomic estrogen actions mediated through ESR1, rapid actions of E2 occur through membrane associated estrogen receptors, such as GPER1 (GPR30) (see Terasawa and Kenealy, 2012), but these studies were conducted in vitro. Finally, why did such a complicated system evolve in primates including actions of E2 not only from the ovary but also from the brain? As stated in the Introduction, the role of neuroestadiol has been described for learning and memory, stroke, and in behavioral contexts, such as sex behaviors. Together with current findings on the role of neuroestradiol in the regulation of GnRH release, we are still in the early stages of understanding the role of neuroestradiol in the brain.
Conflict of interest
Funding Supported by NIH grants: R21HD077447 and R01HD015433 to ET. The work was made possible by support (OD011106) for the Wisconsin National Primate Research Center.