A diametrically opposed view of the role of glucocorticoids in central serous chorioretinopathy

• Extraocular glucocorticoids are risk factor for CSCR. • We hypothesize that CGs effect results from GC-induced HPA axis suppression and intraocular cortisol deficiency, not excess. • This hypothesis suggests novel prevention and treatment strategies. Central serous chorioretinopathy (CSCR) is traditionally linked to glucocorticoid (GC) excess. We propose the opposite: in predisposed individuals, subtle hypothalamic–pituitary–adrenal (HPA) axis suppression—triggered by systemic GC exposure or maladaptive stress responses—lowers intraocular cortisol, shifts the glucocorticoid/mineralocorticoid receptor balance, and drives mineralocorticoid receptor (MR) overactivation in the retinal pigment epithelium–choroid complex. This cascade induces choroidal neuropathy, pachychoroid phenotype, and retinal pigment epithelium (RPE) barrier breakdown. Experimental models, biomarker studies, and metabolomic data support this mechanism, reconciling why systemic but not intraocular GCs are associated with CSCR. If confirmed, this paradigm shift would favor cautious GC tapering, local ocular GC supplementation, and MR antagonism as targeted therapeutic strategies.