Adjunct Associate Professor, Department of Obstetrics & Gynecology and Women's Health (Reproductive Endocrinology and Infertility)
Adjunct Associate Professor, Dominick P. Purpura Department of Neuroscience
One area of particular interest is the role of the neuroendocrine axis in female reproductive aging, especially the cellular events that alter the brain’s responsiveness to ovarian steroids. Reproductive senescence in female rodents and humans is heralded by reduced responsive of the hypothalamus to estrogen positive feedback, resulting in abnormal luteinizing hormone surges, ovarian failure, and infertility. There are several candidate neurotransmitter systems and neurotrophic factors that might contribute to age-related LH surge failure and subsequent ovarian exhaustion.
Our research suggests that age-related changes in the hypothalamic response to ovarian hormones and the LH surgemechanismare causally related to reduced excitatory neurotransmission mediated by the excitatory neuropeptide kisspeptin. Additional studies have suggested that decreased kisspeptin availability results in an imbalance in excitatory (glutamatergic; decreased) and inhibitory (GABAergic; increased) neurotransmission within the hypothalamus.
We have recently demonstrated that reduced brain insulin growth factor-1 (IGF-1) signaling in the aging brain impairs hypothalamic responsiveness to estrogen positive feedback conditions. We also have evidence that hypogonadism in young females trigger a response that is similar to nutrient deprivation and consistent with disruption of autophagic pathways. The hypothalamus is a primary site of convergence and integration for nutrient-related feedback. Moreover, hypothalamic IGF-1 receptor signaling regulates female reproductive function, hypothalamic kisspeptin expression and nutrient sensing through cellular mechanisms that rely upon autophagy. Future experiments in our lab are designed to determine whether reduced hypothalamic IGF-1 receptor signaling observed in reproductively aging females gives rise to altered neuronal nutrient sensing and abnormal autophagic cellular processes which then affect estrogen responsiveness in the brain.
Vitamin D receptors are located in the central nervous system, gonads and uterus. Vitamin D3 is hypothesized to be important for fertility and reproductive success. The mechanism by which vitamin D3 deficiency affects the hypothalamic-pituitary-gonadal axis is unknown. Our lab is interested in the role of vitamin D3 in female reproductive physiology and how vitamin D3 deficiency disrupts fertility. We are investigating the impact of vitamin D3 deficiency on hypothalamic-pituitary physiology and subsequent effects on ovarian physiology, embryo cleavage, fertilization and implantation rates.
Our research relies upon expertise in multiple microsurgical techniques, intracerebral microdialysis, intracerebral drug infusion, HPLC, controlled ovarian hyperstimulation, immunohistochemistry, immunoassays, serial blood sampling, in vitro fertilization, and a number of molecular biochemistry techniques.
Todd BJ, Merhi ZO, Shu J, Etgen AM, Neal-Perry GS (2010) Hypothalamic Insulin-Like Growth Factor-I Receptors Are Necessary for Hormone-Dependent Luteinizing Hormone Surges: Implications for Female Reproductive Aging. Endocrinology 151(3):1356–66.
Lederman M, Lebesgue D, Gonzalez V, Shu J, Merhi ZO, Etgen AM, and Neal-Perry G (2010) Age-related LH surge dysfunction correlates with reduced responsiveness of hypothalamic anteroventral periventricular nucleus kisspeptin neurons to estradiol positive feedback in middle-aged rats. Neuropharmacology 58(1): 314–320.
Neal-Perry GS, Lebesgue D, Zeevalk GD, Shu J, and Etgen AM (2009) The Excitatory Peptide Kisspeptin Restores the Luteinizing Hormone Surge and Modulates Amino Acid Neurotransmission in the Medial Preoptic Area. Endocrinology 150(8):3699–3708.
Neal-Perry GS, Zeevalk GD, Shu, J, and Etgen, AM. (2008) Restoration of the Luteinizing Hormone Surge in Middle-aged Rats by Altering the Balance of GABA and Glutamate Transmission in the Medial Preoptic Area. Biology of Reproduction 79(5): 878–888.
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