Mechanisms of ovarian steroid regulation of norepinephrine receptor-mediated signal transduction in the hypothalamus: Implications for female reproductive physiology

In many mammalian species, the ovarian steroid hormones estradiol (E-2) and progesterone (P) act in the hypothalamus and preoptic area to coordinate t he timing of female sexual receptivity with ovulation. We study lordosis be havior, an important component of sexual receptivity in rats, and its regul ation by E-2 and P as a model system for understanding how hormonal modulat ion of synaptic neurotransmission influences reproductive physiology and be havior. Our findings suggest that E-2 and P extensively regulate synaptic c ommunication involving the catecholamine norepinephrine (NE) in the hypotha lamus. Estrogen priming shifts the balance of postsynaptic NE receptor sign aling in the hypothalamus and preoptic area away from beta -adrenergic acti vation of cAMP synthesis toward a,adrenergic signaling pathways. Attenuatio n of beta -adrenergic signal transduction is achieved by receptor-G-protein uncoupling, apparently due to stable receptor phosphorylation. E2 modifica tion of alpha (1)-adrenergic signaling includes both increased expression o f the alpha (1B)-adrenoceptor subtype and a dramatic, P-induced reconfigura tion of the biochemical responses initiated by agonist activation of alpha (1)-adrenoceptors. Among these is the emergence of alpha (1)-adrenergic rec eptor coupling to cGMP synthesis. We also present evidence that estrogen pr omotes novel, functional interactions between insulin-like growth factor-1 (IGF-1) and alpha (1)-adrenergic receptor signaling in the hypothalamus and preoptic area. Thus, estrogen amplification of signaling mediated by alpha (1)-adrenoceptors is multifaceted, involving changes in gene expression (o f the alpha (1B)-adrenoceptor), switching of receptor linkage to previously inactive intracellular pathways, and the promotion of cross talk between I GF-1 and NE receptors. We propose that this hormone-dependent remodeling of hypothalamic responses to NE maximizes reproductive success by coordinatin g the timing of the preovulatory release of gonadotropins with the period o f behavioral receptivity in female rodents. (C) 2001 Academic Press.