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Estradiol Stimulates Progesterone Synthesis in Hypothalamic Astrocyte Cultures

Department of Neurobiology, Laboratory of Neuroendocrinology of the Brain Research Institute, David Geffen School of Medicine at the University of California, Los Angeles, Los Angeles, California 90095

Address all correspondence and requests for reprints to: Paul Micevych, Ph.D., 73-078 CHS, Department of Neurobiology, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, California 90095-1763. E-mail: pmicevych{at}mednet.ucla.edu.

The brain synthesizes steroids de novo, especially progesterone. Recently estradiol has been shown to stimulate progesterone synthesis in the hypothalamus and enriched astrocyte cultures derived from neonatal cortex. Estradiol-induced hypothalamic progesterone has been implicated in the control of the LH surge. The present studies were undertaken to determine whether hypothalamic astrocytes derived from female neonatal or female postpubertal rats increased production of progesterone in response to an estradiol challenge. Estradiol induced progesterone synthesis in postpubertal astrocytes but not neonatal astrocytes. This estradiol action was blocked by the estrogen receptor antagonist ICI 182,780. Previously we had demonstrated that estradiol stimulates a rapid increase in free cytosolic Ca²⁺ ([Ca²⁺]_i) spikes in neonatal cortical astrocytes acting through a membrane estrogen receptor. We now report that estradiol also rapidly increased [Ca²⁺]_i spikes in hypothalamic astrocytes. The membrane-impermeable estradiol-BSA construct also induced [Ca²⁺]_i spikes. Both estradiol-BSA and estradiol were blocked by ICI 182,780. Depleting intracellular Ca²⁺ stores prevented the estradiol-induced increased [Ca²⁺]_i spikes, whereas removing extracellular Ca²⁺ did not prevent estradiol-induced [Ca²⁺]_i spikes. Together these results indicate that estradiol acts through a membrane-associated receptor to release intracellular stores of Ca²⁺. Thapsigargin, used to mimicked the intracellular release of Ca²⁺ by estradiol, increased progesterone synthesis, suggesting that estradiol-induced progesterone synthesis involves increases in [Ca²⁺]_i. Estradiol treatment did not change levels of steroid acute regulatory protein, P450 side chain cleavage, 3ß-hydroxysteroid dehydrogenase, and sterol carrier protein-2 mRNAs as measured by quantitative RT-PCR, suggesting that in vitro, estradiol regulation of progesterone synthesis in astrocytes does not depend on transcription of new steroidogenic proteins. The present results are consistent with our hypothesis that estrogen-positive feedback regulating the LH surge involves stimulating local progesterone synthesis by hypothalamic astrocytes.

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