Hypothalamic-pituitary-adrenal axis abnormalities have been reported in depressed women and those with postpartum blues, compared with nondepressed women. We investigated the effect of gonadal steroids on the hormonal response to ovine CRH in women with (n = 5) and without (n = 7) a past history of postpartum depression (PPD) by creating an endocrine model of pregnancy and the postpartum. Ovine CRH (1 microg/kg) stimulation tests were performed in the baseline follicular phase, during hormone add-back (leuprolide acetate plus supraphysiologic doses of estradiol and progesterone-mimicking pregnancy), and after precipitous withdrawal of hormone replacement (mimicking the puerperium). Significant phase by time (P < 0.005) and phase by diagnosis (P < 0.05) interactions were observed, reflecting increased stimulated cortisol during the supraphysiologic phase, particularly in subjects with a history of PPD. Cortisol area under the curve also showed a significant phase by diagnosis effect (P < 0.05). Significant increases during the supraphysiologic phase were also seen for urinary free cortisol (P < 0.05), cortisol area under the curve (P < 0.001), and plasma corticosteroid-binding globulin (P < 0.05). Our data show that in humans, as in animals, supraphysiologic gonadal steroid levels enhance pituitary-adrenal axis activity, and, further, that women with a history of PPD have an enhanced sensitivity of the pituitary-adrenal axis to gonadal steroids.