The Neurobiology of Preovulatory and Estradiol-Induced Gonadotropin-Releasing Hormone Surges

Ovarian steroids normally exert homeostatic negative feedback on GnRH release. During sustained exposure to elevated estradiol in the late follicular phase of the reproductive cycle, however, the feedback action of estradiol switches to positive, inducing a surge of GnRH release from the brain, which signals the pituitary LH surge that triggers ovulation. In rodents, this switch appears dependent on a circadian signal that times the surge to a specific time of day (e.g., late afternoon in nocturnal species). Although the precise nature of this daily signal and the mechanism of the switch from negative to positive feedback have remained elusive, work in the past decade has provided much insight into the role of circadian/diurnal and estradioldependent signals in GnRH/LH surge regulation and timing. Here we review the current knowledge of the neurobiology of the GnRH surge, in particular the actions of estradiol on GnRH neurons and their synaptic afferents, the regulation of GnRH neurons by fast synaptic transmission mediated by the neurotransmitters -aminobutyric acid and glutamate, and the host of excitatory and inhibitory neuromodulators including kisspeptin, vasoactive intestinal polypeptide, catecholamines, neurokinin B, and RFamide-related peptides, that appear essential for GnRH surge regulation, and ultimately ovulation and fertility. (Endocrine Reviews 31: 544 -577, 2010) I. Introduction II. General Principles of Preovulatory and Estradiol-Induced GnRH and LH Surges III. In Vitro Studies of the Effects of In Vivo Estradiol and GnRH Surge Physiology A. Multiunit activity studies B. Direct recordings of individual GnRH neurons C. What can electrical recordings tell us about GnRH surge dynamics? IV. Circadian Regulation of the GnRH/LH Surge and Ovulation V. Potential Points of Integration of Circadian and Estradiol Feedback Signals A. Suprachiasmatic nuclei B. Anteroventral periventricular area C. GnRH neurons VI. Regulation of GnRH and LH Surges by Fast GABAergic and Glutamatergic Synaptic Transmission A. Glutamate B. GABA C. Regulation of GnRH neuron activity by GABA and glutamate VII. Neuromodulatory Regulation of GnRH and LH Surges A. Kisspeptin B. Vasoactive intestinal polypeptide C.