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 lordosis, a sexual receptive behavior. Three experiments are proposed: First, 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. Second, using intact and ovx/adx rat models we will directly test whether the estrogen-induced LH surge is dependant on increased hypothalamic neurosteroidal progesterone. Third, using the same intact and ovx/adx rat models, we will determine whether estrogen induced hypothalamic progesterone is sufficient to facilitate lordosis. These studies will demonstrate the physiology of neurosteroidal progesterone and provide important new information about the mechanism of estrogen-positive feedback in the CNS

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
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Special Emphasis Panel (ZRG1)
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De Paolo, Louis V
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University of California Los Angeles
Schools of Medicine
Los Angeles
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Mittelman-Smith, Melinda A; Wong, Angela M; Micevych, Paul E (2018) Estrogen and Progesterone Integration in an in vitro Model of RP3V Kisspeptin Neurons. Neuroendocrinology 106:101-115
Micevych, Paul E; Mermelstein, Paul G; Sinchak, Kevin (2017) Estradiol Membrane-Initiated Signaling in the Brain Mediates Reproduction. Trends Neurosci 40:654-666
Mittelman-Smith, Melinda A; Rudolph, Lauren M; Mohr, Margaret A et al. (2017) Rodent Models of Non-classical Progesterone Action Regulating Ovulation. Front Endocrinol (Lausanne) 8:165
Micevych, Paul E; Meisel, Robert L (2017) Integrating Neural Circuits Controlling Female Sexual Behavior. Front Syst Neurosci 11:42
Rudolph, L M; Bentley, G E; Calandra, R S et al. (2016) Peripheral and Central Mechanisms Involved in the Hormonal Control of Male and Female Reproduction. J Neuroendocrinol 28:
Rudolph, Lauren M; Cornil, Charlotte A; Mittelman-Smith, Melinda A et al. (2016) Actions of Steroids: New Neurotransmitters. J Neurosci 36:11449-11458
Micevych, Paul E; Wong, Angela May; Mittelman-Smith, Melinda Anne (2015) Estradiol Membrane-Initiated Signaling and Female Reproduction. Compr Physiol 5:1211-22
Chen, Claire; Kuo, John; Wong, Angela et al. (2014) Estradiol modulates translocator protein (TSPO) and steroid acute regulatory protein (StAR) via protein kinase A (PKA) signaling in hypothalamic astrocytes. Endocrinology 155:2976-85
Micevych, P; Sinchak, K (2013) Temporal and concentration-dependent effects of oestradiol on neural pathways mediating sexual receptivity. J Neuroendocrinol 25:1012-23
Sinchak, Kevin; Wagner, Edward J (2012) Estradiol signaling in the regulation of reproduction and energy balance. Front Neuroendocrinol 33:342-63

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