Neurosteroids, trigger of the LH surge.
Recent experiments from our laboratory are consistent with the idea that hypothalamic astrocytes are critical components of the central nervous system (CNS) mediated estrogen positive feedback mechanism. The "astrocrine hypothesis" maintains that ovarian estradiol rapidly increases free cytoplasmic calcium concentrations ([Ca(2+)](i)) that facilitate progesterone synthesis in astrocytes. This hypothalamic neuroprogesterone along with the elevated estrogen from the ovaries allows for the surge release of gonadotropin-releasing hormone (GnRH) that triggers the pituitary luteinizing hormone (LH) surge. A narrow range of estradiol stimulated progesterone production supports an "off-on-off" mechanism regulating the transition from estrogen negative feedback to estrogen positive feedback, and back again. The rapidity of the [Ca(2+)](i) response and progesterone synthesis support a non-genomic, membrane-initiated signaling mechanism. In hypothalamic astrocytes, membrane-associated estrogen receptors (mERs) signal through transactivation of the metabotropic glutamate receptor type 1a (mGluR1a), implying that astrocytic function is influenced by surrounding glutamatergic nerve terminals. Although other putative mERs, such as mERβ, STX-activated mER-Gα(q), and G protein-coupled receptor 30 (GPR30), are present and participate in membrane-mediated signaling, their influence in reproduction is still obscure since female reproduction be it estrogen positive feedback or lordosis behavior requires mERα. The astrocrine hypothesis is also consistent with the well-known sexual dimorphism of estrogen positive feedback. In rodents, only post-pubertal females exhibit this positive feedback. Hypothalamic astrocytes cultured from females, but not males, responded to estradiol by increasing progesterone synthesis. Estrogen autoregulates its own signaling by regulating levels of mERα in the plasma membrane of female astrocytes. In male astrocytes, the estradiol-induced increase in mERα was attenuated, suggesting that membrane-initiated estradiol signaling (MIES) would also be blunted. Indeed, estradiol induced [Ca(2+)](i) release in male astrocytes, but not to levels required to stimulate progesterone synthesis. Investigation of this sexual differentiation was performed using hypothalamic astrocytes from post-pubertal four core genotype (FCG) mice. In this model, genetic sex is uncoupled from gonadal sex. We demonstrated that animals that developed testes (XYM and XXM) lacked estrogen positive feedback, strongly suggesting that the sexual differentiation of progesterone synthesis is driven by the sex steroid environment during early development. This article is part of a Special Issue entitled 'Neurosteroids'.
Department of Neurobiology, Laboratory of Neuroendocrinology of the Brain Research Institute, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, United States.
John
J
Kuo
Paul
P
Micevych
D000818:Animals; D001253:Astrocytes / Q000378:metabolism*; D004958:Estradiol / Q000502:physiology*; D047628:Estrogen Receptor alpha / Q000378:metabolism; D005246:Feedback; D005260:Female; D005971:Glutamates / Q000502:physiology; D007986:Luteinizing Hormone / Q000378:metabolism*; D008297:Male; D051379:Mice; D051381:Rats; D011960:Receptors, Estrogen; D043562:Receptors, G-Protein-Coupled / Q000502:physiology; D018094:Receptors, Metabotropic Glutamate / Q000378:metabolism
D047628:Estrogen Receptor alpha; C532507:GPER1 protein, mouse; D005971:Glutamates; C520305:Gper1 protein, rat; D011960:Receptors, Estrogen; D043562:Receptors, G-Protein-Coupled; D018094:Receptors, Metabotropic Glutamate; D004958:Estradiol; D007986:Luteinizing Hormone