Prolonged HPA axis dysregulation in postpartum depression associated with adverse early life experiences: a cross-species translational study

Childhood and adolescent stress increase the risk of postpartum depression (PPD), often providing an increased probability of treatment refractoriness. Nevertheless, the mechanisms linking childhood and adolescent stress to PPD remain unclear. Here we investigated the longitudinal effects of adolescent stress on the hypothalamic–pituitary–adrenal axis and postpartum behaviors in mice and humans. Adolescent social isolation prolonged glucocorticoid elevation, leading to long-lasting postpartum behavioral changes in female mice. These changes were unresponsive to current PPD treatments but improved with post-delivery glucocorticoid receptor antagonist treatment. Childhood and adolescent stress significantly impacted hypothalamic–pituitary–adrenal axis dysregulation and PPD in human females. Repurposing glucocorticoid receptor antagonists for some cases of treatment-resistant PPD may be considered. In this cross-species translational study, the authors look at the longitudinal consequences of stress during adolescent development on HPA function and postpartum behaviors in mice and in humans and suggest that glucocorticoid receptor antagonists may serve as a potential treatment for postpartum depression.