Physiology of Hypothalamic Neurosteroidal Progesterone

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DESCRIPTION (provided by applicant): Neurosteroids, steroids synthesized in the brain, have been implicated in functions ranging from stress, depression, anxiety, to cognition. One neurosteroid is progesterone, a classic sex hormone involved in the regulation of reproduction. Although the CNS has the capacity to synthesize progesterone, to date it has appeared that only peripheral progesterone, from the ovaries and adrenals, regulates reproduction. Our preliminary studies have demonstrated that estrogen-induced hypothalamic progesterone synthesis is sufficient to initiate reproductive events necessary for ovulation and copulation. Estrogen stimulation of ovariectomized and adrenalectomized (ovx/adx) rats increased hypothalamic progesterone levels. In such animals, estrogen induced lordosis behavior and progesterone dependent proceptive behavior. Similarly, estrogen stimulation of ovx/adx rats induced a luteinizing hormone (LH) surge. In these rats, blocking 3beta-hydroxysteroid dehydrogenase (3beta-HSD), the enzyme that converts pregnenolone to progesterone, prevented the LH surge. Estrogen stimulates astrocytes in culture to synthesize progesterone, suggesting that glial cells may mediate estrogen-positive feedback. These data indicate that, absent the peripheral steroidogenic tissues, estrogen can induce progesterone dependent events by stimulating the synthesis of neurosteroidal progesterone. We propose to test the hypothesis: estrogen stimulates synthesis of hypothalamic progesterone that activates circuits regulating the LH surge and sexual behavior. Three experiments are proposed: First, using intact and ovx/adx rat models we will directly test whether the estrogen-induced LH surge is dependent on increased hypothalamic neurosteroidal progesterone. Second, we propose to determine whether estrogen increases the expression and/or activity of steroidogenic enzymes (P450 side chain cleavage and 3beta-HSD) needed to synthesize progesterone, in vitro and in vivo. Third, using the same intact and ovx/adx rat models, we will determine whether estrogen-induced hypothalamic progesterone is sufficient to facilitate sexual behavior. These studies will demonstrate the physiology of neurosteroidal progesterone and provide important new information about the mechanism of estrogen-positive feedback in the CNS.