The third trimester of human pregnancy is characterized by a hyperactive hypothalamic-pituitary-adrenal axis, possibly driven by progressively increasing circulating levels of placental CRH and gradually decreasing levels of CRH-binding protein. The postpartum period, on the other hand, is characterized by an increased vulnerability to psychiatric manifestations (postpartum "blues," depression, and psychosis), a phenomenon compatible with suppressed hypothalamic CRH secretion. To investigate the hypothesis that the postpartum period is associated with suppression of hypothalamic CRH secretion, we studied prospectively 17 healthy euthymic women (mean +/- SE age, 32.0 +/- 1.1 yr) with no prior history of depression, starting at the 20th week of gestation. Psychometric testing was performed monthly during pregnancy and postpartum on day 2 and weeks 2, 3, 6, 8, 12, 16, and 20, whereas serial ovine (o) CRH tests were performed postpartum at 3, 6, and 12 weeks. While pregnant, all 17 subjects remained euthymic; in the postpartum period, 7 women developed the "blues," and 1 developed depression. Overall, the mean plasma ACTH response to an iv bolus of 1 microgram/kg oCRH was markedly blunted at 3 and 6 weeks, but normal at 12 weeks postpartum, whereas the mean plasma cortisol response was at the upper limit of normal at all 3 times. These data are compatible with a suppressed hypothalamic CRH neuron that gradually returns to normal while hypertropic adrenal cortexes are progressively down-sizing. When the postpartum ACTH responses to oCRH were analyzed separately for the euthymic women and the women who had the "blues" or depression, the blunting of ACTH was significantly more severe and long lasting in the latter group; this was observed at all 3 times of testing. We conclude that there is central suppression of hypothalamic CRH secretion in the postpartum, which might explain the increased vulnerability to the affective disorders observed during this period. The suppressed ACTH response to oCRH might serve as a biochemical marker of the postpartum "blues" or depression.