Female sex hormones, particularly estradiol, accelerated retinal neurodegeneration in a mouse model of retinitis pigmentosa, according to a study using functional, structural, and genetic assessments to evaluate sex-based differences in disease severity.
Researchers used RHO P23H mice, a model for autosomal dominant retinitis pigmentosa (RP), and found that female mice experienced significantly faster vision loss than males beginning at 2 months of age. Electroretinography (ERG) revealed reduced b-wave amplitudes in females under scotopic 0.01 cd·s/m² testing, with values consistently lower across 7 months. Structural analysis confirmed that outer nuclear layer (ONL) thickness was reduced in female retinas at all 38 measurement points compared with males at 7 months.
To assess hormonal effects, the researchers performed bilateral ovariectomy (OVX) and orchiectomy (OCX) at 6 weeks of age. In hormone-depleted RP females, visual function improved significantly. OVX females had higher ERG b-wave amplitudes at 0.01 cd·s/m² and 1.0 cd·s/m² compared with intact females. At 7 months, b-wave amplitudes in OVX females measured approximately 59 µV, while intact females measured 36 µV.
Photopic ERG testing at 3.0 cd·s/m² and 10.0 cd·s/m² showed cone-specific improvements in OVX females. Photopic b-wave amplitudes in OVX females at 7 months reached approximately 50 µV, while intact females recorded 35 µV. ONL thickness was also greater in OVX females at 7 and 10 months, comparable to that of male mice.
Estradiol reintroduction reversed this protective effect. At 4 months of age, OVX RP females received a 90-day slow-release pellet containing 1.5 mg of 17β-estradiol. At 6 months, ERG analysis showed a reduction in visual function compared with placebo-treated OVX females. The 0.01 cd·s/m² b-wave amplitude in estradiol-treated OVX females dropped to 28 µV, compared with 55 µV in placebo-treated OVX females. No visual changes were observed in OCX males implanted with estradiol.
Mass spectrometry confirmed that estradiol levels increased in serum and retinal tissue following a single 5-µg estradiol injection. This elevation occurred without changes in progesterone or testosterone concentrations.
These hormonal effects were only observed in diseased RP mice. Wild-type males and females receiving estradiol or undergoing gonadectomy showed no differences in retinal structure or visual function through 7 months.
Transcriptomic analysis revealed elevated expression of Casp4 and Aif1 in RP females compared with RP males. These genes are associated with pyroptosis, inflammation, and endoplasmic reticulum stress–induced apoptosis. TUNEL staining showed greater photoreceptor cell death in RP females, though the difference was not statistically significant due to inter-animal variability.
“Our data highlight an important systemic hormone-dependent interaction of the female sex hormones with the pathology and progression of an inherited retinal dystrophy that was previously thought to be unaffected by biological sex,” said Ashley A. Rowe from the Department of Ophthalmology, UT Southwestern Medical Center, Dallas, Texas.
The findings suggest that estradiol worsens RP-related degeneration by modulating stress and inflammatory pathways. These effects were specific to diseased photoreceptors and not observed in healthy tissue.
The authors noted that understanding sex-specific pathways may help guide treatment strategies and hormone therapy use in patients with retinal or neurodegenerative conditions.
No conflicts of interest were reported in the study.
Source: Science Advances