Glucocorticoid Receptor Signaling: Multilevel Organization, Roles in Fetal Development, and Postnatal Outcomes

The hypothalamic-pituitary-adrenal (HPA) axis coordinates metabolic, immune, and behavioral responses to a changing environment. Its molecular effectors are the nuclear receptors for glucocorticoids and mineralocorticoids (the GRs/MRs), encoded by <i>nr3c1</i>/<i>nr3c2</i>. The MR serves as the high-affinity sensor of basal hormone concentrations, whereas the GR amplifies the stress response and mediates negative feedback. Despite their shared domain architecture, the receptors have diverged functionally: isoform composition, post-translational modifications, and the complement of co-regulators together determine which genes are activated or repressed in a given tissue at a given time. The regulation of the HPA axis activity is a major determinant of embryonic development. Pregnancy adds a placental control layer that meters maternal signals: 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) in the syncytiotrophoblast inactivates cortisol, whereas 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) can regenerate it, and systemic buffering by transcortin (cortisol-binding globulin, CBG) limits the free hormone fraction. Under stress, inflammation, or hypoxia, this barrier weakens, exposing the fetus to stronger glucocorticoid pulses during windows of heightened vulnerability for brain and immune development. Such overexposure not only reshapes ongoing transcription but is also epigenetically inscribed: the methylation of alternative <i>nr3c1</i> promoters, the remodeling of histones, and the shifts in ncRNA profiles recalibrate the axis sensitivity for the long term. At the phenotypic level, this manifests as variability in stress reactivity, cognitive and affective trajectories, and an immune and metabolic risk across later ontogeny. In this review, we integrate evidence on the structure and functions of the GR, the mechanisms of its post-translational and epigenetic regulation, and the role of the placenta, to provide a coherent framework for understanding the multifaceted consequences of prenatal stress and to identify potential targets for early prevention.