The Neurosteroid Progesterone Underlies Estrogen Positive Feedback of the LH Surge

Abstract

Our understanding the steroid regulation of neural function has rapidly evolved in the past decades. Not long ago the prevailing thoughts were that peripheral steroid hormones carried information to the brain which passively responded to these steroids. These steroid actions were slow, taking hours to days to be realized because they regulated gene expression. Over the past three decades, discoveries of new steroid receptors, rapid membrane-initiated signaling mechanisms, and de novo neurosteroidogenesis have shed new light on the complexity of steroids actions within the nervous system. Sexual differentiation of the brain during development occurs predominately through timed steroid-mediated expression of proteins and long term epigenetic modifications. In contrast across the estrous cycle, estradiol release from developing ovarian follicles initially increases slowly and then at proestrus increases rapidly. This pattern of estradiol release acts through both classical genomic mechanisms and rapid membrane-initiated signaling in the brain to coordinate reproductive behavior and physiology. This review focuses on recently discovered estrogen receptor-α membrane signaling mechanisms that estradiol utilizes during estrogen positive feedback to stimulate de novo progesterone synthesis within the hypothalamus to trigger the luteinizing hormone (LH) surge important for ovulation and estrous cyclicity. The activation of these signaling pathways appears to be coordinated by the rising and waning of estradiol throughout the estrous cycle and integral to the negative and positive feedback mechanisms of estradiol. This differential responsiveness is part of the timing mechanism triggering the LH surge.

Keywords: ERαΔ4; estrogen receptor; membrane estradiol signaling; receptor trafficking.

Figure 1

Blocking neuroprogesterone synthesis alters the pattern of estrous cycles in gonadally intact rats. The 4-day rat estrous cycle is diagrammatically presented. Each day of the cycle is indicated on the ordinate: D1, diestrous day 1; D2, diestrous day 2; P, proestrus; and E, estrus. Neuroprogesterone synthesis was blocked by infusion of a P450scc inhibitor, aminoglutethimide (AGT), into the third ventricle (3V) via an implanted cannula. All animals treated with DMSO (5%, vehicle n = 14; data not shown) had normal 4 day estrous cycles as determined by vaginal cytology. In contrast, 11/14 AGT treated rats (0800 hours on proestrus, indicated by the arrow) had disrupted estrous cycles with delayed onset of estrous as determined by vaginal cytology (from Micevych and Sinchak, 2008a).

Figure 2

Schematic diagram describing the role of astrocytes, which we propose mediate estrogen positive feedback of the LH surge. As follicles develop in the ovary, granulosa cells under the influence of follicle stimulating hormone (FSH) begin producing estradiol (E₂). While this level of E₂ is inhibitory to the neural network regulating the release of GnRH (negative feedback), this E₂ induces the expression of progesterone receptors in hypothalamic neurons (1) through activation of nuclear estrogen receptor-α (ERα). When circulating levels of E₂ peak on proestrus (estrogen positive feedback), E₂ now binds to ERα on the membrane of astrocytes that transactivates metabotropic glutamate receptor 1a (mGluR1a) increasing cytoplasmic calcium by releasing intracellular calcium stores (positive feedback), which stimulate the synthesis of progesterone (P₄; 2). This de novo synthesized P₄ diffuses from the astrocyte to bind E₂-induced PR in nearby neurons (3). We suspect that these neurons use kisspeptin as a transmitter and activate GnRH neurons (4) causing the surge release of GnRH (5) that stimulates LH release form pituitary gonadotropes. The LH then induces ovulation and luteinization of the follicle in which theca lutein cells synthesize P₄.