Mechanisms of Ovarian Steroid Regulation of Norepinephrine Receptor-Mediated Signal Transduction in the Hypothalamus: Implications for Female Reproductive Physiology

Abstract

In many mammalian species, the ovarian steroid hormones estradiol (E2) and progesterone (P) act in the hypothalamus and preoptic area to coordinate the timing of female sexual receptivity with ovulation. We study lordosis behavior, an important component of sexual receptivity in rats, and its regulation by E2 and P as a model system for understanding how hormonal modulation of synaptic neurotransmission influences reproductive physiology and behavior. Our findings suggest that E2 and P extensively regulate synaptic communication involving the catecholamine norepinephrine (NE) in the hypothalamus. Estrogen priming shifts the balance of postsynaptic NE receptor signaling in the hypothalamus and preoptic area away from β-adrenergic activation of cAMP synthesis toward α1-adrenergic signaling pathways. Attenuation of β-adrenergic signal transduction is achieved by receptor–G-protein uncoupling, apparently due to stable receptor phosphorylation. E2 modification of α1-adrenergic signaling includes both increased expression of the α1B-adrenoceptor subtype and a dramatic, P-induced reconfiguration of the biochemical responses initiated by agonist activation of α1-adrenoceptors. Among these is the emergence of α1-adrenergic receptor coupling to cGMP synthesis. We also present evidence that estrogen promotes novel, functional interactions between insulin-like growth factor-1 (IGF-1) and α1-adrenergic receptor signaling in the hypothalamus and preoptic area. Thus, estrogen amplification of signaling mediated by α1-adrenoceptors is multifaceted, involving changes in gene expression (of the α1B-adrenoceptor), switching of receptor linkage to previously inactive intracellular pathways, and the promotion of cross talk between IGF-1 and NE receptors. We propose that this hormone-dependent remodeling of hypothalamic responses to NE maximizes reproductive success by coordinating the timing of the preovulatory release of gonadotropins with the period of behavioral receptivity in female rodents.