Direct and indirect regulation of gonadotropin-releasing hormone neurons by estradiol

Estrogen signaling to GnRH neurons is critical for coordinating the preovulatory surge release of LH with follicular maturation. Until recently it was thought that estrogen signaled GnRH neurons only indirectly through numerous afferent systems. This minireview presents new evidence indicating that GnRH neurons are directly regulated by estradiol (E-2), primarily through estrogen receptor (ER)-beta, and indirectly through E-2-sensitive neurons in the anteroventral periventricular (AVPV) region. The data described suggest that E-2 generally represses GnRH gene expression but that this repression is transiently overcome by indirect E-2-dependent signals relayed by AVPV neurons. We also present evidence that the AVPV neurons responsible for relaying E-2 signals to GnRH neurons are multifunctional gamma aminobutyric acid-ergic/glutamatergic/neuropeptidergic neurons.