Introduction: Hypothalamic-pituitary-adrenal (HPA) axis abnormalities have been reported in depressed women and in women with postpartum "blues" compared with non-depressed women.

Methods: We investigated the effect of gonadal steroids on the hormonal response to oCRH 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. oCRH (1 µg/kg) stimulation tests were performed in the baseline follicular phase, during hormone addback (leuprolide acetate plus supraphysiologic doses of estradiol and progesterone-mimicking pregnancy), and following precipitous withdrawal of hormone replacement (mimicking the puerperium).

Results: 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 (PPD+). Cortisol AUC also showed a significant phase by diagnosis effect (P < 0.05). Significant increases during the supraphysiologic phase were also seen for UFC (P < 0.05), cortisol AUC (P < 0.001), and plasma CBG (P < 0.05).

Conclusion: 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.