Estrogen biphasically modifies hypothalamic GABAergic function concomitantly with negative and positive control of luteinizing hormone release

The principal role of estrogen is its control of the female ovulatory cycle via negative and positive feedback on gonadotropin secretion. However, a d etailed, cohesive picture of how the steroid specifically regulates the exc itability of hypothalamic neurons involved in the central control of gonado tropin secretion is still emerging. Here, we used an ovariectomized female guinea pig model to test the hypothesis that estrogen acts on GABAergic neu rons in the preoptic area (POA) to elicit a biphasic profile of luteinizing hormone (LH) secretion. Intracellular electrophysiological recordings reve aled that estradiol benzoate (EB; 25 mug, s.c.) decreased the hyperpolarizi ng response of GABAergic neurons to the GABAB receptor agonist baclofen 24 hr after treatment. This effect of GABAB receptor stimulation in unidentifi ed POA neurons was still depressed 42 hr after EB administration. By the us e of a ribonuclease protection assay, however, EB reduced glutamic acid dec arboxylase mRNA expression 42 hr but not 24 hr after its administration. Th us, estrogen attenuated the autoinhibition of GABAergic POA neurons during the initial LH suppressive (i.e., negative feedback) phase and subsequently reduced GABAergic function during the LH surge (i.e., positive feedback). These studies demonstrate that the effects of estrogen on hypothalamic GABA ergic neurons coincide with the inhibitory and stimulatory actions, respect ively, of the steroid on LH secretion. Furthermore, the data provide novel insights into the mechanism by which estrogen regulates hypothalamic GABAer gic neurons, which are critical for the biphasic modulation of LH release o bserved over the course of the female ovulatory cycle.