Patients with primary affective disorders, such as melancholic depression and anorexia nervosa, frequently have a hyperactive hypothalamic-pituitary-adrenal (HPA) axis, characterized by hypersecretion of CRH and a blunted ACTH response to exogenous CRH. Premenstrual syndrome (PMS) is a luteal phase dysphoric disorder characterized by primarily affective and behavioral disturbances. HPA axis function was compared in PMS patients and control women, respectively, diagnosed by DSM3-R criteria or found to have no current psychiatric disorders, determined by the Schedule for Affective Disorders and Schizophrenia-Lifetime Interview. Urinary free cortisol excretion was the same in PMS and normal women, and no differences in urinary free cortisol excretion between the follicular and luteal phases occurred in either group. Two HPA axis abnormalities, however, were noted when PMS patients were compared to normal women. First, basal evening cortisol concentrations in plasma were significantly decreased, while the time-integrated response of plasma cortisol to ovine (o) CRH was significantly increased. Second, the negative correlation between time-integrated plasma ACTH and cortisol responses to oCRH and basal luteal progesterone concentrations present in normal control women was not seen in the PMS patients. These changes in basal and oCRH-stimulated plasma cortisol levels in association with normal urinary free cortisol excretion suggest that women with PMS might have transient or episodic disturbances of their HPA axis, which appear adequately corrected by this system's servomechanisms. This probably explains the maintenance of regular menstrual cycles in PMS patients, which contrasts with the irregular menses observed in patients with depression, anorexia nervosa, or women who participate in chronic strenuous exercise.