Endogenous oestrogens as neuroprotective modulators in the human retina: Evidence from transcriptomic profiling and aromatase inhibition

Steroid hormones, particularly estrogens, modulate neuronal survival in the central nervous system and the retina; however, their specific cell-type-specific roles in the human retina remain incompletely characterized. We analyzed the single-cell RNA sequencing dataset E-MTAB-7316 to profile genes from the KEGG steroid hormone biosynthesis and oestrogen signalling pathways. Functional relevance of local oestrogen synthesis was tested in mouse retinal explants treated with the aromatase inhibitor letrozole (20 μM). Over 50% of steroid hormone metabolism genes were expressed in retinal cells, with cell-type specificity. COMT, HSD17B12, and HSD11B1L were broadly distributed, while LRTOMT, HSD17B7, and SRD5A1 were enriched in rod photoreceptors. Among oestrogen signalling genes, 114/139 were detected, with HSP90AA1 as the most abundant. When oestrogen synthesis was blocked with letrozole, retinal explants showed increased cell death, particularly in the outer nuclear layer, without inducing macrogliosis but with significant microglial activation (IBA1+). Our data indicate that the human retina expresses multiple components of steroid hormone metabolism and oestrogen signalling. The results are consistent with a potential role of locally synthesized oestrogens in photoreceptor maintenance and immune regulation, which may warrant further investigation as a possible avenue for retinal protection.