Dual Mechanisms of Chronic Stress in Recurrent Pregnancy Loss: Progesterone Deficiency and Inflammatory Amplification

Recurrent pregnancy loss (RPL), defined as the loss of two or more pregnancies, is a significant health issue in obstetrics. As a chronic stressor, RPL exerts numerous uncertain effects on pregnancy outcomes. While prior research has recognized psychological contributors, the comprehensive investigation of psychobiological mechanisms remains incomplete. During early pregnancy, the HPA axis continues to respond to chronic stress. Chronic stress leads to a prolonged elevation of glucocorticoids (GCs) by reducing the protective function of 11β‐hydroxysteroid dehydrogenase type 2 (11β‐HSD2), resulting in sustained GC exposure. Hallmarks of RPL include progesterone deficiency and inflammation, both of which exhibit intricate associations with the effects of chronic stress and GCs. In this review, we integrate the key mechanisms of progesterone deficiency caused by chronic stress and GCs, including precursor competition, reactive oxygen species (ROS) overproduction, and FK506‐binding protein 51 (FKBP51) overexpression. Specifically, we discuss the effects of chronic stress and GCs on inflammatory amplification, including glucocorticoid resistance (GCR) and M1 macrophage polarization. Mediators including transcription factor nuclear factor kappa B (NF‐κB), ROS, lactic acid (LA) and FKBP51 are central to the link between stress‐induced inflammation and RPL. We further incorporated the potential role of the endoplasmic reticulum stress‐related unfolded protein response (UPR) in progesterone deficiency and inflammatory amplification. By integrating these pathways, this review offers a more comprehensive framework for understanding how chronic stress contributes to the pathogenesis of RPL.