Stress-induced ovarian dysfunction and associated hypoestrogenism is common in women and can have a negative impact on health. Termed functional hypothalamic chronic anovulation (FHCA), this syndrome is a reversible form of ovarian failure in which cognitive responses to life events activate central neural circuits that disrupt gonadotropin releasing hormone (GnRH) secretion. Since women with FHCA are hypercortisolemic, this anovulation may result from increased release of corticotropin releasing hormone (CRH) and arginine vasopressin (AVP) produced by a dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis. However, it is not clear how behavioral events produce this dysregulation, how the dysregulation is sustained, and how excess CRH and/or AVP inhibit gonadotropin secretion. Also, genetic factors may be important as individuals with a short variant polymorphism in the gene encoding the serotonin reuptake transporter, SERT, are more susceptible to stress. Like women with FHCA, socially subordinate female rhesus monkeys living in stable groups show HPA dysregulation and sustained periods of gonadotropin deficiency. Using this animal model, the project will determine the neuroendocrine and molecular mechanisms by which social stress inhibits GnRH.
Specific Aim 1 will test the hypothesis that estradiol potentiates stress-induced increases in CRH and AVP by decreasing glucocorticoid negative feedback and this is enhanced in females with the short variant in the SERT gene.
This aim will also test the hypothesis that hypoleptinemia, characteristic of subordinate females, acts to sustain this HPA dysregulation. Using specific CRH and AVP receptor antagonists as well as infusions of CRH and/or AVP, Aim 2 will test the hypothesis that gonadotropin secretion is diminished in subordinate females by a CRH - AVP synergistic inhibition.
Aim 3 will test the hypothesis that the estradiol-induced CRH - AVP synergistic inhibition of gonadotropin secretion in subordinate females is mediated through an opioid pathway and the inhibition of hypothalamic GnRH expression. This project will clarify the neuroendocrine mechanisms mediating socially-induced gonadotropin deficiency and will thus enhance the ability of health providers to diagnose and treat FHCA in women.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD046501-03
Application #
7231017
Study Section
Neuroendocrinology, Neuroimmunology, and Behavior Study Section (NNB)
Program Officer
Lamar, Charisee A
Project Start
2005-07-20
Project End
2010-05-31
Budget Start
2007-06-01
Budget End
2008-05-31
Support Year
3
Fiscal Year
2007
Total Cost
$322,784
Indirect Cost
Name
Emory University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322
Michopoulos, Vasiliki (2016) Stress-induced alterations in estradiol sensitivity increase risk for obesity in women. Physiol Behav 166:56-64
Toufexis, D; Rivarola, M A; Lara, H et al. (2014) Stress and the reproductive axis. J Neuroendocrinol 26:573-86
Michopoulos, V; Embree, M; Reding, K et al. (2013) CRH receptor antagonism reverses the effect of social subordination upon central GABAA receptor binding in estradiol-treated ovariectomized female rhesus monkeys. Neuroscience 250:300-8
Moore, Carla J; Lowe, Jonathan; Michopoulos, Vasiliki et al. (2013) Small changes in meal patterns lead to significant changes in total caloric intake. Effects of diet and social status on food intake in female rhesus monkeys. Appetite 62:60-9
Moore, Carla J; Michopoulos, Vasiliki; Johnson, Zachary P et al. (2013) Dietary variety is associated with larger meals in female rhesus monkeys. Physiol Behav 119:190-4
Johnson, Z P; Lowe, J; Michopoulos, V et al. (2013) Oestradiol differentially influences feeding behaviour depending on diet composition in female rhesus monkeys. J Neuroendocrinol 25:729-41
Toufexis, Donna J; Wilson, Mark E (2012) Dihydrotestosterone differentially modulates the cortisol response of the hypothalamic-pituitary-adrenal axis in male and female rhesus macaques, and restores circadian secretion of cortisol in females. Brain Res 1429:43-51
Michopoulos, Vasiliki; Reding, Katherine M; Wilson, Mark E et al. (2012) Social subordination impairs hypothalamic-pituitary-adrenal function in female rhesus monkeys. Horm Behav 62:389-99
Tung, Jenny; Barreiro, Luis B; Johnson, Zachary P et al. (2012) Social environment is associated with gene regulatory variation in the rhesus macaque immune system. Proc Natl Acad Sci U S A 109:6490-5
Park, Youngja H; Lee, Kichun; Soltow, Quinlyn A et al. (2012) High-performance metabolic profiling of plasma from seven mammalian species for simultaneous environmental chemical surveillance and bioeffect monitoring. Toxicology 295:47-55

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