Stress and the reproductive cycle

Although there is general agreement that the functional hypothalamic amenorrhea syndrome is linked to psychogenic stress and the resultant suppression of the normal activity of the GnRH pulse generator, the independent association between stress and the inhibition of the GnRH pulse generator remains to be demonstrated in the human. The challenge for the researcher remains to identify relevant and reliable stress paradigms so that prospective investigations of an HPA-HPG link can be initiated. Stress affects multiple sites; behavioral, metabolic, cardiac, and endocrine responses can be activated (Fig. 1). Stress research will be complicated by the probability that different stress challenges may activate each site to varying degrees and that each site may be variously sensitized by the presence of each ovarian steroid. In regard to the neuroendocrine response to stress, we can predict from animal studies that both HPA neuropeptides, CRH and vasopressin, and the endogenous opioid peptides will play a role in the inhibition by stress of the hypothalamic-pituitary-ovarian axis. Both the ability of CRH and vasopressin to inhibit GnRH and gonadotropin secretion and their mediation of the effects of several types of stress challenges have been demonstrated. Initial studies in the nonhuman primate of the effects of a short term stress episode on the menstrual cycle are of potential interest to the clinician because they indicate that although a stress may be insufficient to produce amenorrhea, it may interfere with the normal cycle in subtle ways and thereby potentially affect normal fertility. Primate studies have also described a paradoxical gonadotropin response to a stress challenge in the presence of estradiol, such as during the mid- to late follicular phase, resulting in an acute release of LH. The factor most likely responsible for this stimulatory effect of HPA on LH release, at least in the acute situation, may be progesterone released by the adrenals in response to HPA activation (Fig. 2). Whether this represents an additional mechanism by which an acute stress stimulus, again insufficient to interrupt the reproductive cycle, may interfere with the normal progression of folliculogenesis and with fertility remains to be determined.