**Background:** Central serous chorioretinopathy (CSCR) is a chorioretinal disease characterized by serous detachments of the neuroretina, often associated with pachychoroid. Exogenous glucocorticoid intake is a known risk factor, but the role of endogenous ocular corticoids is unclear. The ocular steroidome (the complete profile of corticosteroids) has not been fully characterized in human eyes, nor in CSCR. This study aimed to profile the ocular steroidome in aqueous humor, compare it to systemic levels, and investigate potential dysregulation in complex CSCR.
**Methods:** Aqueous humor samples were collected from 50 control patients undergoing cataract surgery (25 men, 25 women; mean age 73±14.7 years). Simultaneous serum samples were obtained from 27 of these controls. Additionally, aqueous and vitreous humor were collected from 9 patients undergoing combined cataract and membrane peeling surgery. Fifteen aqueous humor samples were obtained from 14 patients with long-lasting complex CSCR (mean disease duration 23±14 years; 12 men, 2 women; mean subfoveal choroidal thickness 475±100 µm). None had active subretinal fluid at the time of sampling. Steroid concentrations (aldosterone, corticosterone [B], 11-dehydrocorticosterone [A], 11-deoxycorticosterone, progesterone, 17-hydroxyprogesterone, 11-deoxycortisol, cortisol [F], cortisone [E], DHEAS, androstenedione, testosterone, DHEA) were measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS). The 11β-HSD2 activity was estimated by the E/F ratio. Statistical analyses used Spearman correlations, Mann-Whitney U-tests, and Student t-tests.
**Key Results:** In control aqueous humor, only F, E, B, A, 17-hydroxyprogesterone, and androstenedione were quantifiable. Mean cortisol (F) was 5.05±1.34 ng/ml, cortisone (E) 0.987±0.438 ng/ml, corticosterone (B) 0.18±0.09 ng/ml, and 11-dehydrocorticosterone (A) 0.10±0.07 ng/ml. There was no correlation between serum and aqueous humor cortisol levels (Spearman r=0.138, p=0.49), but serum and aqueous cortisone correlated positively (r=0.577, p=0.0016). Aqueous humor cortisol did not vary with time of day (r=0.04, p=0.9), but cortisone increased in the evening (r=0.313, p=0.03), leading to a higher E/F ratio later in the day (r=0.38, p=0.009). No influence of age or sex on F, E, B, or A levels was found. In CSCR eyes, cortisol was significantly lower than in controls (2.9±1.2 vs. 5.0±1.3 ng/ml, p=0.0001), corticosterone was lower (0.11±0.07 vs. 0.18±0.09 ng/ml, p=0.03), and the F/E ratio was lower (3.5±2.3 vs. 6.1±3.2, p=0.023). The B/A ratio was higher in CSCR (3.36±5.1 vs. 0.99±1.56, p=0.018). These differences persisted after time-of-day and age matching. No correlation was found between intraocular corticoids and subfoveal choroidal thickness in CSCR. Two case reports illustrated that topical dexamethasone, combined with eplerenone, led to resolution of subretinal fluid in patients with chronic CSCR.
**Clinical Implications:** This study demonstrates that the ocular steroidome is locally regulated and independent of systemic levels, with no circadian variation in cortisol but a diurnal increase in cortisone. In complex CSCR, there is a significant imbalance toward lower active glucocorticoids and higher mineralocorticoid activity, suggesting local dysmetabolism. This imbalance may favor mineralocorticoid receptor (MR) overactivation, which has been linked to pachychoroid and inflammation. The findings support the rationale for using topical glucocorticoids to restore the glucocorticoid/MR balance, potentially in combination with MR antagonists. Larger studies are needed to confirm these results and to evaluate long-term treatment strategies.