The estrogenic retina: The potential contribution to healthy aging and age-related neurodegenerative diseases of the retina

These last two decades have seen an explosion of clinical and epidemiological research, and basic research devoted to envisage the influence of gender and hormonal fluctuations in the retina/ocular diseases. Particular attention has been paid to age-related disorders because of the overlap of endocrine and neuronal dysfunction with aging. Hormonal withdrawal has been considered among risk factors for diseases such as glaucoma, diabetic retinopathy and age-related macular disease (AMD), as well as, for Alzheimer's disease, Parkinson's disease, or other neurodegenerative disorders. Sex hormones and aging have been also suggested to drive the incidence of ocular surface diseases such as dry eye and cataract. Hormone therapy has been approached in several clinical trials. The discovery that the retina is another CNS tissue synthesizing neurosteroids, among which neuroactive steroids, has favored these studies. However, the puzzling data emerged from clinical, epidemiological and experimental studies have added several dimensions of complexity; the current landscape is inherently limited to the weak information on the influence and interdependence of endocrine, paracrine and autocrine regulation in the retina, but also in the brain. Focusing on the estrogenic retina, we here review our knowledge on local 17?-oestradiol (E2) synthesis from cholesterol-based neurosteroidogenic path and testosterone aromatization, and presence of estrogen receptors (ER? and ER?). The first cholesterol-limiting step and the final aromatase-limiting step are discussed as possible check-points of retinal functional/dysfunctional E2. Possible E2 neuroprotection is commented as a group of experimental evidence on excitotoxic and oxidative retinal paradigms, and models of retinal neurodegenerative diseases, such as glaucoma, diabetic retinopathy and AMD. These findings may provide a framework to support clinical studies, although further basic research is needed.