The interaction between progesterone and glucocorticoid signaling on pregnancy-related mood symptoms

Postpartum depression (PPD) is a heterogeneous disorder whose biological basis remains incompletely understood. Although the rapid postpartum decline in progesterone and its neuroactive metabolite allopregnanolone has been implicated in PPD, this hormonal transition occurs in all pregnant individuals, whereas only a subset develop depression. This review proposes a two-hit framework in which early-life adversity establishes persistent, maladaptive stress-system vulnerability and pregnancy-related progesterone exposure subsequently interacts with that altered system to increase depression risk. Adverse childhood experiences may dysregulate the hypothalamic–pituitary–adrenal (HPA) axis through genetic and epigenetic mechanisms involving stress response genes. Progesterone and glucocorticoid signaling may converge because their receptors, which are structurally similar, recognize related hormone-response elements and regulate overlapping gene networks. In other words, progesterone may contribute to psychiatric symptoms by activating stress response genes. Associations between progesterone exposure and depression, prospective evidence linking progesterone levels with subsequent PPD and the efficacy of the gamma-aminobutyric acid. A receptor modulator allopregnanolone further support investigation of progesterone-related mechanisms. However, current evidence does not yet establish progesterone as a causal second hit. Longitudinal and mechanistic studies integrating early adversity, steroid trajectories, neuroactive-steroid metabolism, HPA-axis function and stress response gene regulation are needed to test this model.