Estrogen Actions on Neuroendocrine Glia

Astrocytes are the most abundant cells in the central nervous system (CNS). It appears that astrocytes are as diverse as neurons, having different phenotypes in various regions throughout the brain and participating in intercellular communication that involves signaling to neurons. It is not surprising then that astrocytes in the hypothalamus have an active role in the CNS regulation of reproduction. In addition to the traditional mechanism involving ensheathment of neurons and processes, astrocytes may have a critical role in regulating estrogen-positive feedback. Work in our laboratory has focused on the relationship between circulating estradiol and progesterone synthesized de novo in the brain. We have demonstrated that circulating estradiol stimulates the synthesis of progesterone in adult hypothalamic astrocytes, and this neuroprogesterone is critical for initiating the LH surge. Estradiol cell signaling is initiated at the cell membrane and involves the transactivation of metabotropic glutamate receptor type 1a (mGluR1a) leading to the release of intracellular stores of calcium. We used surface biotinylation to demonstrate that estrogen receptor-alpha (ERalpha) is present in the cell membrane and has an extracellular portion. Like other membrane receptors, ERalpha is inserted into the membrane and removed via internalization after agonist stimulation. This trafficking is directly regulated by estradiol, which rapidly and transiently increases the levels of membrane ERalpha, and upon activation, increases internalization that finally leads to ERalpha degradation. This autoregulation temporally limits membrane-initiated estradiol cell signaling. Thus, neuroprogesterone, the necessary signal for the LH surge, is released when circulating levels of estradiol peak on proestrus and activate progesterone receptors whose expression has been induced by the gradual rise of estradiol during follicular development.