Williams NI, Berga SL, Cameron JL. Synergism between psychosocial and metabolic stressors: impact on reproductive function in cynomolgus monkeys. Am J Physiol Endocrinol Metab 293: E270-E276, 2007. First published April 3, 2007; doi:10.1152/ajpendo.00108.2007.-The role of energy imbalance versus psychosocial stress in the pathogenesis of female reproductive dysfunction characterized by anovulation and amenorrhea remains controversial. In women, functional hypothalamic amenorrhea can develop in the absence of significant weight loss, excessive exercise, or profound psychosocial disruption. We posited, therefore, that commonplace, seemingly minor stressors that alone would have minimal impact upon reproductive function might interact synergistically such that combinations of stressors would cause a greater impairment of the reproductive axis than any single stressor alone. We then developed a monkey model to test this hypothesis. Adult female cynomolgus monkeys with normal menstrual cycles were randomized into three experimental groups and studied over four menstrual cycles. The groups were: low-level psychosocial stress (i.e., moving to a new housing environment; Move, n ϭ 8), moderate energy imbalance (Exercise ϩ Diet, n ϭ 9); and all stressors in combination (Move ϩ Exercise ϩ Diet, n ϭ 10). Food intake, body weight, menstrual cyclicity, and reproductive hormones were assessed for two control menstrual cycles followed by two experimental cycles during which the monkeys experienced the stressors. Abnormal cycles were considered to be abnormally long or anovulatory cycles. Few abnormal cycles occurred in the Move group (1 of 8 monkeys) and in the Exercise ϩ Diet group (1 of 9 monkeys). In contrast, 7 of 10 monkeys in the Move ϩ Exercise ϩ Diet group displayed at least one abnormal cycle ( 2 ϭ 9.61, P ϭ 0.008). These findings suggest that infertility due to hypothalamic hypogonadism can result from the combination of commonplace, seemingly minor stressors that often escape clinical attention. exercise; diet; psychosocial stress; reproduction CLINICALLY RECOGNIZED FORMS of stress-induced reproductive dysfunction include functional hypothalamic amenorrhea (FHA), anorexia nervosa, bulimia nervosa, and exercise-associated amenorrhea. The proximate cause of these forms of reproductive compromise is a functional and theoretically reversible reduction in central drive to the reproductive axis provided by the hypothalamic neuroendocrine hormone gonadotropin-releasing hormone (GnRH). The presence of clinical forms of stress-induced reproductive dysfunction heightens the risk for other diseases, including cardiovascular disease, osteoporosis, depression, and other psychiatric conditions as well as infertility (1,15,20,28). Stress exposure during pregnancy can also have a negative impact on fetal development. Potential fetal consequences include preterm labor, poor neurodevelopment, and compromised psychosocial development (26, 31, 35).Although it was previously believed that different forms of stress-induced reproductive dy...