Physiology of Hypothalamic Neurosteroidal Progesterone

Summary

Principal Investigator: Paul E Micevych
Abstract: DESCRIPTION (provided by applicant): Neurosteroids, steroids synthesized de novo 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. We have previously shown that peripheral estradiol (E2) increases hypothalamic neuroprogesterone (neuroP) synthesis, which initiates the luteinizing hormone (LH) surge. The LH surge triggers ovulation and the luteinization of the ruptured follicle - critical events in reproduction. Within the hypothalamus, astrocytes respond to E2 stimulation by increasing neuroP synthesis. Preliminary data point to E2-signaling that requires an interaction between membrane-associated estrogen receptor-1 (mER1) and a group 1 metabotropic glutamate receptor (mGluR1a). The resulting rise in free cytoplasmic calcium is sufficient to stimulate neuroP synthesis. Since GnRH neurons that control the LH surge do not have steroid receptors, other neurons are required to transmit steroid information to them. Kisspeptin neurons have been suggested as these intervening neurons: they project to GnRH neurons, potently excite them, and express ER1 and progesterone receptor (PR). Based on these results, we propose to test the hypothesis that estrogen positive feedback requires E2-induced neuroP synthesis involving a mER1 and mGluR1a interaction, and the activation of kisspeptin neurons. Three experiments are proposed to study E2 signaling in vitro and in vivo. Three subhypotheses will be tested: 1) E2-induced neuroP synthesis requires activation of the mGluR;2) E2 stimulates the synthesis of neuroP by activating StAR;and 3) estrogen positive feedback requires PR-mediated activation of periventricular kisspeptin neurons. These studies will use astrocyte cultures to work out cell signaling pathways, and whole animal experiments to verify the in vitro results and tie them to regulation of the LH surge. The proposed studies will test a novel mechanism regulating the transduction of E2 information into neural signals that stimulate the release of GnRH resulting in the LH surge. PUBLIC HEALTH RELEVANCE The proposed studies at the basic level seek to provide an integrated model of estrogen positive feedback to understand the mechanisms that control hypothalamic regulation of the luteinizing hormone (LH) surge and ovulation which are important for both regulating fertility as well as treating infertility. Approximately 12% of women (7.3 million) in the United States aged 15-44 had fertility difficulties (National Center for Health Statistics of the Centers for Disease Control and Prevention) because of ovulatory dysfunction that is controlled by the LH surge. This type of infertility exhibits excess estrogen production without ovulation that can lead to polycystic ovary syndrome, irregular vaginal bleeding, metabolic abnormalities as well as endometrial polyps, hyperplasia, and even cancer.
Funding Period: 2003-04-01 - 2014-05-31
more information: NIH RePORT

Top Publications

  1. ncbi Estradiol stimulates progesterone synthesis in hypothalamic astrocyte cultures
    Paul E Micevych
    Department of Neurobiology, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, California 90095 1763, USA
    Endocrinology 148:782-9. 2007
  2. pmc Estradiol signaling in the regulation of reproduction and energy balance
    Kevin Sinchak
    Department of Biological Sciences, California State University, Long Beach, 1250 Bellflower Blvd, Long Beach, CA 90840 9502, United States
    Front Neuroendocrinol 33:342-63. 2012
  3. pmc Membrane-initiated estradiol actions mediate structural plasticity and reproduction
    Paul Micevych
    Department of Neurobiology, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095 1763, United States
    Front Neuroendocrinol 33:331-41. 2012
  4. pmc Membrane estrogen receptor regulation of hypothalamic function
    Paul E Micevych
    Department of Neurobiology, Brain Research Institute, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095 1763, USA
    Neuroendocrinology 96:103-10. 2012
  5. pmc Neurosteroids, trigger of the LH surge
    John Kuo
    Department of Neurobiology, Laboratory of Neuroendocrinology of the Brain Research Institute, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, United States
    J Steroid Biochem Mol Biol 131:57-65. 2012
  6. pmc Membrane estrogen receptors stimulate intracellular calcium release and progesterone synthesis in hypothalamic astrocytes
    John Kuo
    Department of Neurobiology, Laboratory of Neuroendocrinology of the Brain Research Institute, Department of Obstetrics and Gynecology, David Geffen School of Medicine at UCLA, Los Angeles, California 90095, USA
    J Neurosci 30:12950-7. 2010
  7. pmc Estrogen actions on neuroendocrine glia
    Paul Micevych
    Department of Neurobiology, Laboratory of Neuroendocrinology, UCLA Brain Research Institute, David Geffen School of Medicine at UCLA, 10833 LeConte Avenue, Los Angeles, CA 90095 1763, USA pmicevych mednet ucla edu
    Neuroendocrinology 91:211-22. 2010
  8. pmc Estradiol-induced estrogen receptor-alpha trafficking
    Galyna Bondar
    Department of Neurobiology, Laboratory of Neuroendocrinology and Brian Research Institute, David Geffen School of Medicine, University of California, Los Angeles, California 90095, USA
    J Neurosci 29:15323-30. 2009
  9. pmc An interaction of oxytocin receptors with metabotropic glutamate receptors in hypothalamic astrocytes
    J Kuo
    Department of Neurobiology, Laboratory of Neuroendocrinology and Brain Research Institute, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095 1763, USA
    J Neuroendocrinol 21:1001-6. 2009
  10. pmc Membrane estradiol signaling in the brain
    Paul Micevych
    Department of Neurobiology and the Laboratory of Neuroendocrinology David Geffen School of Medicine at UCLA, Los Angeles, CA 90095 1763, USA
    Front Neuroendocrinol 30:315-27. 2009

Detail Information

Publications18

  1. ncbi Estradiol stimulates progesterone synthesis in hypothalamic astrocyte cultures
    Paul E Micevych
    Department of Neurobiology, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, California 90095 1763, USA
    Endocrinology 148:782-9. 2007
    ..The present results are consistent with our hypothesis that estrogen-positive feedback regulating the LH surge involves stimulating local progesterone synthesis by hypothalamic astrocytes...
  2. pmc Estradiol signaling in the regulation of reproduction and energy balance
    Kevin Sinchak
    Department of Biological Sciences, California State University, Long Beach, 1250 Bellflower Blvd, Long Beach, CA 90840 9502, United States
    Front Neuroendocrinol 33:342-63. 2012
    ....
  3. pmc Membrane-initiated estradiol actions mediate structural plasticity and reproduction
    Paul Micevych
    Department of Neurobiology, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095 1763, United States
    Front Neuroendocrinol 33:331-41. 2012
    ....
  4. pmc Membrane estrogen receptor regulation of hypothalamic function
    Paul E Micevych
    Department of Neurobiology, Brain Research Institute, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095 1763, USA
    Neuroendocrinology 96:103-10. 2012
    ..This mini-review attempts to synthesize our understanding of 17β-estradiol membrane signaling within hypothalamic circuits involved in homeostatic functions, focusing on reproduction and energy balance...
  5. pmc Neurosteroids, trigger of the LH surge
    John Kuo
    Department of Neurobiology, Laboratory of Neuroendocrinology of the Brain Research Institute, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, United States
    J Steroid Biochem Mol Biol 131:57-65. 2012
    ..This article is part of a Special Issue entitled 'Neurosteroids'...
  6. pmc Membrane estrogen receptors stimulate intracellular calcium release and progesterone synthesis in hypothalamic astrocytes
    John Kuo
    Department of Neurobiology, Laboratory of Neuroendocrinology of the Brain Research Institute, Department of Obstetrics and Gynecology, David Geffen School of Medicine at UCLA, Los Angeles, California 90095, USA
    J Neurosci 30:12950-7. 2010
    ..Together, these results indicate that mERα is mainly responsible for the rapid, membrane-initiated estradiol-signaling that leads to progesterone synthesis in hypothalamic astrocytes...
  7. pmc Estrogen actions on neuroendocrine glia
    Paul Micevych
    Department of Neurobiology, Laboratory of Neuroendocrinology, UCLA Brain Research Institute, David Geffen School of Medicine at UCLA, 10833 LeConte Avenue, Los Angeles, CA 90095 1763, USA pmicevych mednet ucla edu
    Neuroendocrinology 91:211-22. 2010
    ....
  8. pmc Estradiol-induced estrogen receptor-alpha trafficking
    Galyna Bondar
    Department of Neurobiology, Laboratory of Neuroendocrinology and Brian Research Institute, David Geffen School of Medicine, University of California, Los Angeles, California 90095, USA
    J Neurosci 29:15323-30. 2009
    ..The pattern of trafficking into and out of the membrane suggests that the changing concentration of estradiol during the estrous cycle regulates ERalpha to augment and then terminate membrane-initiated signaling...
  9. pmc An interaction of oxytocin receptors with metabotropic glutamate receptors in hypothalamic astrocytes
    J Kuo
    Department of Neurobiology, Laboratory of Neuroendocrinology and Brain Research Institute, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095 1763, USA
    J Neuroendocrinol 21:1001-6. 2009
    ..These results suggest that the OTR signals through the mGluR1a to release Ca(2+) from intracellular stores and rapid, nongenomic oestradiol stimulation does not influence OTR signalling in astrocytes...
  10. pmc Membrane estradiol signaling in the brain
    Paul Micevych
    Department of Neurobiology and the Laboratory of Neuroendocrinology David Geffen School of Medicine at UCLA, Los Angeles, CA 90095 1763, USA
    Front Neuroendocrinol 30:315-27. 2009
    ....
  11. pmc Nervous system physiology regulated by membrane estrogen receptors
    Paul G Mermelstein
    Department of Neuroscience, University of Minnesota, 6 145 Jackson Hall, 321 Church St S E, Minneapolis, MN 55455, USA
    Rev Neurosci 19:413-24. 2008
    ..This ER/mGluR hypothesis explains how estradiol can activate a wide-range of intracellular pathways and provides an underlying mechanism for the hitherto seemingly unrelated rapid membrane actions in the nervous system...
  12. pmc Physiology of membrane oestrogen receptor signalling in reproduction
    P Micevych
    Department of Neurobiology, Laboratory of Neuroendocrinology, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA
    J Neuroendocrinol 21:249-56. 2009
    ..The ERalpha-mGluR1a interaction is necessary for critical calcium flux. These two examples provide support for the hypothesis that membrane ERs are not themselves G-protein receptors; rather, they use mGluRs to signal...
  13. pmc Membrane estrogen receptor-alpha interacts with metabotropic glutamate receptor type 1a to mobilize intracellular calcium in hypothalamic astrocytes
    John Kuo
    Department of Neurobiology, David Geffen School of Medicine at University of California, Los Angeles, 10833 LeConte Avenue, 73 078 CHS, Los Angeles, California 90095 1763
    Endocrinology 150:1369-76. 2009
    ..These results indicate that mERalpha acts through mGluR1a, and mGluR1a activation facilitates the estradiol response, suggesting that neural activity can modify estradiol-induced membrane signaling in astrocytes...
  14. pmc Membrane estrogen receptors acting through metabotropic glutamate receptors: an emerging mechanism of estrogen action in brain
    Paul E Micevych
    Department of Neurobiology and Laboratory of Neuroendocrinology of the Brain Research Institute, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA
    Mol Neurobiol 38:66-77. 2008
    ....
  15. pmc Estradiol regulation of progesterone synthesis in the brain
    Paul Micevych
    Department of Neurobiology, David Geffen School of Medicine at ULCA, Los Angeles, CA 90095, USA
    Mol Cell Endocrinol 290:44-50. 2008
    ..Thus, it is a cooperative action of astrocytes and neurons that is needed for estrogen positive feedback and stimulation of the LH surge...
  16. pmc Synthesis and function of hypothalamic neuroprogesterone in reproduction
    Paul Micevych
    Department of Neurobiology, David Geffen School of Medicine, Brain Research Institute at University of California Los Angeles, Los Angeles, California 90095 1763, USA
    Endocrinology 149:2739-42. 2008
    ..The newly synthesized neuroprogesterone acts on estradiol-induced progesterone receptors in nearby neurons to initiate the LH surge...
  17. pmc Neuroprogesterone: key to estrogen positive feedback?
    Paul Micevych
    Department of Neurobiology, David Geffen School of Medicine, Laboratory of Neuroendocrinology, Brain Research Institute at UCLA, Los Angeles, CA 90095 1763, USA
    Brain Res Rev 57:470-80. 2008
    ..This neuroprogesterone also facilitated proceptive behavior. Blocking either progesterone synthesis or progesterone receptor in estrogen-primed ovx/adx prevented proceptive but not receptive behaviors...
  18. pmc Temporal and concentration-dependent effects of oestradiol on neural pathways mediating sexual receptivity
    P Micevych
    Department of Neurobiology, David Geffen School of Medicine at UCLA, Laboratory of Neuroendocrinology, Brain Research Institute, University of California, Los Angeles, CA, USA
    J Neuroendocrinol 25:1012-23. 2013
    ..These include the GRP30 and the STX activated Gq-mER. Finally, we report on the importance of GABA acting at GABAB receptors for oestradiol membrane signalling that regulates lordosis circuit activation and sexual receptivity. ..

Research Grants30

  1. Cellular/Molecular Pathophysiology of Intellectual and Developmental Disabilities
    Stuart A Lipton; Fiscal Year: 2013
    ..The CORE supports administration, statistics, tissue culture, and crystallography/modeling of NMDAR subunits and functional sites, all critical to the proposed Projects. ..
  2. Estrogen Modulation of Bursting Activity in GnRH Neurons
    Oline K Ronnekleiv; Fiscal Year: 2013
    ..It is envisioned that the results from the proposed experiments will help mold a cellular model of burst firing of GnRH neurons, pulsatile neurosecretion, and ultimately ovulation in the female. ..
  3. PROGESTERONE RECEPTOR AND ACTION IN THE PRIMATE OVARY
    Richard L Stouffer; Fiscal Year: 2013
    ....
  4. MITOCHONDRIAL ENCEPHALOMYOPATHIES AND MENTAL RETARDATION
    Salvatore DiMauro; Fiscal Year: 2013
    ....
  5. Center for Reproductive Science and Medicine
    Pamela L Mellon; Fiscal Year: 2013
    ..The SCCPIR Human Ovary Tissue Bank provides tissue to NIH-funded investigators nation-wide. ..
  6. LIPID AND LIPOPROTEIN METABOLISM IN ATHEROSCLEROSIS
    Alan M Fogelman; Fiscal Year: 2013
    ..These six Projects will be supported by four cores and together will form a highly interactive and synergistic Program Project that is focused on lipid and lipoprotein metabolism in atherosclerosis. ..
  7. Hamster: a unique model for studying implantation
    BIBHASH CHANDRA PARIA; Fiscal Year: 2013
    ..abstract_text> ..
  8. A Gene therapeutic approach to stable suppression of HIV-1 replication
    MICHAEL R FARZAN; Fiscal Year: 2013
    ..These studies will establish principles and protocols directly applicable to subsequent human clinical trials. ..
  9. The Aging Pituitary-Gonadal Axis
    George R Bousfield; Fiscal Year: 2013
    ..While currently available preparations work well in young women, they become increasingly ineffective in older women, requiring higher doses and prolonged administration yet producing fewer oocytes. ..
  10. Role of gonadal hormones in HPA responses to alcohol administration in the rat
    Daniel Selvage; Fiscal Year: 2013
    ....
  11. Harvard Reproductive Endocrine Sciences Center
    William Francis Crowley; Fiscal Year: 2013
    ..abstract_text> ..