The effects of stress on reproductive function are poorly understood. Yet it is commonly acknowledged that stress and the resulting activation of the hypothalamic-pituitary-adrenocortical (HPA) axis are frequently accompanied by reproductive dysfunction in many species. We hypothesize that stress, as expressed by this activation of the HPA axis, often leads to inhibition of follicular development and consequent reproductive dysfunction in women, manifested as amenorrhea. Utilizing human disease models and exogenously administered agents in women and in cynomolgus monkeys, we will determine if acutely or chronically increased corticotropin releasing factor (CRF), ACTH, and/or corticosteroids alter the secretion of reproductive hormones, including LH, FSH, prolactin, estradiol, and progesterone. Specifically, we propose to characterize both reproductive and adrenocortical hormones in amenorrheic women with documented hypercortisolism in order to determine if consistent patterns of abnormalities exist regardless of etiology. Women with psychogenic and exercise-associated amenorrhea and those with Cushing's syndrome will be included in these studies. We plan to follow cortisol excretion prospectively in these women to determine if the hypercortisolism resolves prior to the resumption of menstruation. we also will determine if characteristic psychological profiles are associated with amenorrhea in women with hypercortisolism and if these profiles change with resumption to menses. We also intend to examine the acute affects of exogenous glucocorticoids, ACTH, and CRF in normal women. To examine the effects of chronic iatrogenically induced hypercortisolism, we shall examine reproductive function in women placed on exogenous corticosteroids for medical indications. In cynomolgus monkeys we shall determine if chronic administration of CRF, ACTH or cortisol leads to reproductive dysfunction. Ethical considerations preclude such chronic studies in human subjects. If, as we suspect, the monkeys do develop abnormalities, then this model will afford us the opportunity to examine the mechanism(s) of stress-induced reproductive dysfunction. Together, these experiments should provide new insights into the interaction between the HPA and the hypothalamic-pituitary-ovarian (HPO) axes and may help explain one of the major causes of amenorrhea.
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