Sensitivity to Stress-Induced Reproductive Dysfunction Linked to Activity of the Serotonin System

Abstract

Many forms of stress, including psychosocial stress, may be associated with reproductive dysfunction. Women seeking treatment for infertility often have been subjected to multiple stressors. The authors have developed an experimental primate model of hypothalamic amenorrhea. Combining mild psychosocial stress with a mild diet and moderate exercise suppresses reproductive function in this model. Because serotonergic activity is decreased in persons who are inordinately sensitive to stress, a study was planned to determine whether differences in endogenous function of the central serotonergic system can be found in stress-sensitive and stress-resistant female cynomolgus macaques. Sedated monkeys previously categorized as highly stress-resistant (HSR, normal menstrual cyclicity through 2 stress cycles), medium stress-resistant (MSR, ovulatory in only the first cycle), or stress-sensitive (SS, anovulatory when first exposed to stress) were challenged with an intravenous dose of 5 mg/kg of the serotonin-releasing drug fenfluramine. The hypothesis was that SS animals would have lower levels of central serotonergic activity. Thyrotropin-releasing hormone (TRH) was administered to control for differences in pituitary stores of prolactin or corticotropin-releasing factor (CRF) to control for low levels of ACTH. Release of prolactin in response to fenfluramine was significantly greater in the HSR animals than in the MSR and SS groups. Cortisol responses to fenfluramine were higher in the SS group than in either group of stress-resistant animals. Similar responses to fenfluramine were no longer evident after stimulation with TRH combined with CRF. These studies in macaques indicate differing reproductive hormone responses to moderate stress. Stress sensitivity correlates with prolactin secretion in response to fenfluramine, which promotes the release of serotonin. Highly stress-resistant animals have higher endogenous serotonin levels than do stress-sensitive animals in the absence of stress. Whether this reflects secretion of ovarian steroids, social status, or genetic predisposition remains to be determined.