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Neurobiology of Stress-Induced Reproductive Dysfunction in Female Macaques

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Abstract

It is now well accepted that stress can precipitate mental and physical illness. However, it is becoming clear that given the same stress, some individuals are very vulnerable and will succumb to illness while others are more resilient and cope effectively, rather than becoming ill. This difference between individuals is called stress sensitivity. Stress sensitivity of an individual appears to be influenced by genetically inherited factors, early life (even prenatal) stress, and by the presence or absence of factors that provide protection from stress. In comparison to other stress-related diseases, the concept of sensitivity versus resilience to stress-induced reproductive dysfunction has received relatively little attention. The studies presented herein were undertaken to begin to identify stable characteristics and the neural underpinnings of individuals with sensitivity to stress-induced reproductive dysfunction. Female cynomolgus macaques with normal menstrual cycles either stop ovulating (stress sensitive) or to continue to ovulate (stress resilient) upon exposure to a combined metabolic and psychosocial stress. However, even in the absence of stress, the stress-sensitive animals have lower secretion of the ovarian steroids, estrogen and progesterone, have higher heart rates, have lower serotonin function, have fewer serotonin neurons and lower expression of pivotal serotonin-related genes, have lower expression of 5HT2A and 2C genes in the hypothalamus, have higher gene expression of GAD67 and CRH in the hypothalamus, and have reduced gonadotropin-releasing hormone transport to the anterior pituitary. Altogether, the results suggest that the neurobiology of reproductive circuits in stress-sensitive individuals is compromised. We speculate that with the application of stress, the dysfunction of these neural systems becomes exacerbated and reproductive function ceases.

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Acknowledgments

The authors are indebted to the Division of Animal Resources at ONPRC for the expert care of the animals and to the Department of Pathobiology for performing the necropsies. In addition, we would like to acknowledge Mr. Sam Fox who conducted the fenfluramine, CRH, and TRH challenge experiments; Dr. Nick Lu who perfused the brains; Mr. John Streicher who sectioned the midbrains; Ms. Rachel Sanchez who performed the immunocytochemical analysis of the CRH fibers in the amygdale; and Ms. Arubala Reddy who assisted with the construction of the CRH cDNA. This research was supported by Eunice Kennedy Shriver NICHD/NIH through cooperative agreement U54 HD 18185 as part of the Specialized Cooperative Centers Program in Reproduction and Infertility Research, NIH/MH62677 to CLB and NIH/RR00163 for the operation of ONPRC.

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Authors and Affiliations

  1. Division of Reproductive Sciences, Oregon National Primate Research Center, Beaverton, OR, 97006, USA

    Cynthia L. Bethea, Maria Luisa Centeno & Judy L. Cameron

  2. Division of Neuroscience, Oregon National Primate Research Center, Beaverton, OR, 97006, USA

    Cynthia L. Bethea & Judy L. Cameron

  3. Department of Behavioral Neuroscience, Oregon Health and Science University, Portland, OR, 97201, USA

    Judy L. Cameron

  4. Department of Obstetrics & Gynecology, Oregon Health and Science University, Portland, OR, 97201, USA

    Judy L. Cameron

  5. Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, 15213, USA

    Judy L. Cameron

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  1. Cynthia L. Bethea
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  2. Maria Luisa Centeno
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  3. Judy L. Cameron
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Correspondence to Cynthia L. Bethea.

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Bethea, C.L., Centeno, M.L. & Cameron, J.L. Neurobiology of Stress-Induced Reproductive Dysfunction in Female Macaques. Mol Neurobiol 38, 199–230 (2008). https://doi.org/10.1007/s12035-008-8042-z

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