Neurobiology of Stress-Induced Reproductive Dysfunction in Female Macaques

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 GnRH 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.

Sensitivity to stress-induced reproductive dysfunction is associated with a selective but not a generalized increase in activity of the adrenal axis

“…SS monkeys have suppressed physiological release of serotonin (6), fewer serotonergic cells, and low expression of a number of genes in the serotonin pathway, including FEV1, TPH2, SERT, MAO-A, and MAO-B, in the dorsal raphe nucleus (5,7). Moreover, treatment with a selective serotonin reuptake inhibitor, citalopram, increases ovarian steroid hormone secretion in SS monkeys (14).…”

Developmental variations in environmental influences including endocrine disruptors on pubertal timing and neuroendocrine control: Revision of human observations and mechanistic insight from rodents

“…It is well established that stress factors have an inhibitory impact on the neuroendocrine regulation of reproduction in women (Warren and Fried, 2001 ) as in adult nonhuman female primates (Bethea et al, 2008). Strenuous physical exercise, emotional stress or weight loss are associated with hypothalamic amenorrhea (Warren and Fried, 2001 ;Bethea et al, 2008).…”

“…Strenuous physical exercise, emotional stress or weight loss are associated with hypothalamic amenorrhea (Warren and Fried, 2001 ;Bethea et al, 2008). The impact of stress on timing of puberty is particularly complex to study.…”

Interactions of Corticotropin-Releasing Factor, Urocortin and Citalopram in a Primate Model of Stress-Induced Amenorrhea

“…SS animals chronically have a lower release of serotonin (5-HT) in response to fenfluramine [6], and have a downregulation of the central serotonergic system, as indicated by significantly less tryptophan hydroxylase 2 (TPH2) expression [9], less serotonin reuptake transporter (SERT) gene expression, less 5-HT 1A receptor gene expression and less expression of the genes that degrade serotonin (MAO-A and MAO-B) in the raphe nucleus [7,10]. In the hypothalamus, there is an upregulation of 5-HT 2A and 5-HT 2C receptors [11], and an increase in GAD67 gene expression [11], which are inhibitory to the reproductive axis.…”

“…In the hypothalamus, there is an upregulation of 5-HT 2A and 5-HT 2C receptors [11], and an increase in GAD67 gene expression [11], which are inhibitory to the reproductive axis. We also found that SS animals have less immunoreactive gonadotropin-releasing hormone (GnRH) in the median eminence, lower pituitary luteinizing hormone and follicle-stimulating hormone secretion, and lower ovarian estradiol and progesterone secretion compared to more stress-resilient monkeys, even when they are not experiencing stress [10,12]. …”