Stress and the Reproductive Cycle

THE IDEA that by activating the hypothalamic-pituitary-adrenal (HPA) axis, stress and overt or latent psychological disturbances have the potential of inhibiting the hypothalamic-pituitary-gonadal (HPG) axis has been circulated for a long time (1). It is generally thought that, if severe enough, this condition may lead to the suppression of the normal menstrual cycle in a syndrome referred to as functional hypothalamic amenorrhea or functional hypothalamic chronic anovulation (2). When fully established, the syndrome is characterized by ovarian quiescence, amenorrhea, and infertility. Although there appears to be a relationship between the type and severity of the stress and the proportion of women who develop amenorrhea (3), in practice it is difficult if not impossible to identify a threshold at which stress will interfere with the normal cycle. The probable reason for this is that in circumstances that are not life threatening the actual stressor may be less critical in determining the outcome than the individual's response to it because psychobiological characteristics may heighten the responsiveness to the stressor (2). This particular problem may also in part reflect our ignorance of the initial steps by which stress interferes with normal cyclic events. One may assume that the degree of hypoestrogenism varies according to the severity of the stress challenge and that intermittent ovarian function may persist in less severe stress conditions. Potential differences in the individual responses to a particular stress paradigm make it difficult in clinical practice to confirm the independent association of a specific challenge with the initiation of the functional hypothalamic chronic anovulation syndrome (2). Furthermore, in many women more than one behavior may, in fact, be involved. For instance, this clinical syndrome has also been associated with other life style variables, such as weight loss or eating disorders, and certain types of excessive exercise (jogging, athletics) (4, 5, 6). Although it has been speculated that exercise-and weight-related amenorrhea is more probably caused by disturbances in the metabolic balance (7), mediators of the HPA axis may also be activated in these situations. Most investigators agree that the final neuroendocrine event responsible for the functional chronic anovulation syndrome is a decrease in the activity of the hypothalamic GnRH pulse generator. Reports in women with the established syndrome have usually demonstrated a significant slowing of LH pulse frequency, probably reflecting a decreased GnRH pulse activity (8). As proper folliculogenesis requires an optimal gonadotropin pulse regimen (9), it would be expected that …