The role of the hypothalamic-pituitary-adrenal axis in depression across the female reproductive lifecycle: current knowledge and future directions

This narrative review examines the role of the hypothalamic-pituitary-adrenal (HPA) axis in the pathophysiology of depression across three key reproductive stages: the menstrual cycle (including PMDD), the perinatal period (pregnancy and postpartum), and perimenopause. The HPA axis, a primary neuroendocrine system for stress response, is hypothesized to be a key etiological factor in depression during these windows of significant hormonal reorganization. The authors synthesize current evidence on how ovarian hormones interact with the HPA axis and how a history of trauma influences these relationships.

• Menstrual Cycle: Meta-analyses suggest higher basal cortisol in the follicular phase compared to the luteal phase. Women with Premenstrual Dysphoric Disorder (PMDD) often exhibit blunted HPA axis function, including lower baseline cortisol and attenuated responses to stress, potentially linked to dysregulated neuroactive steroid control.
• Perinatal Period: Pregnancy involves massive physiological increases in glucocorticoids. Depression in this period is associated with elevated cortisol, a blunted cortisol awakening response (CAR), and a flatter diurnal cortisol slope. These alterations often persist into the postpartum period.
• Perimenopause: Despite the significant hormonal fluctuations characterizing this transition, the evidence linking perimenopausal depression to HPA axis dysregulation is weak and controversial. Many studies find no significant differences in HPA axis markers between depressed and non-depressed perimenopausal women.

Across all reproductive stages, a history of adverse childhood experiences (ACEs) and trauma is a consistent risk factor for depression. Trauma is frequently associated with long-term HPA axis changes, such as lower mean cortisol levels and reduced reactivity to stress. The authors emphasize that trauma history is a critical, yet often under-accounted for, moderator in studies of female depression.