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The supplementation with estradiol reduces the risk in these cases and suggesting that estradiol deficiency is a mediator of the risk association. We investigated rat models of estradiol deficiency mimicking either biological ageing (22 months of age) or early menopause by ovariectomy and age of 22 months. Serum analysis of gonadal hormones in both models showed the expected reduction in estradiol levels compared to 6 months old controls but also increases in progesterone, corticosterone and dehydroepiandrosterone sulfate (DHEA-S). Comparing the two estradiol deficiency models, we found no differences except for DHEA-S that were reduced in ovariectomized rats. The hormone status was associated with degenerative changes in the retina with higher activity of mononuclear phagocytes and p16\/p21-dependent senescence. Mainly the estrogen receptor beta (ER\u03b2) expressing cells were affected by estradiol deficiency: ganglion cells, cells of the inner nuclear layer (INL) and retinal pigment epithelial cells. An exception are photoreceptors that were ER\u03b2 negative, showed stronger degeneration in ovariectomized rats compared to sham treated animals. We conclude that either biological or ovariectomy induced estradiol deficiency might not cause but rather promote mechanisms that lead to AMD. The phenotype depends on a broader spectrum of altered hormones than on estradiol alone. Photoreceptor degeneration and cellular senescence that were ER\u03b2 independent in ovariectomized rats suggest non-estradiol effects to increase AMD risk by early menopause.<\/jats:p>","DOI":"10.1371\/journal.pone.0340477","type":"journal-article","created":{"date-parts":[[2026,3,9]],"date-time":"2026-03-09T17:33:01Z","timestamp":1773077581000},"page":"e0340477","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":1,"title":["Evaluation of risk promoting effects for age-related macular degeneration by estradiol"],"prefix":"10.1371","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9314-8378","authenticated-orcid":true,"given":"Inga-Marie","family":"Pomp\u00f6s","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1269-2193","authenticated-orcid":true,"given":"Dietrich","family":"Polenz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Norbert","family":"Kociok","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silvia","family":"Winkler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6272-8596","authenticated-orcid":true,"given":"Olaf","family":"Strau\u00df","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2026,3,9]]},"reference":[{"issue":"2","key":"pone.0340477.ref001","article-title":"Causes of blindness and vision impairment in 2020 and trends over 30 years, and prevalence of avoidable blindness in relation to VISION 2020: the Right to Sight: an analysis for the Global Burden of Disease Study","volume":"9","author":"Vision Loss Expert Group of the Global Burden of Disease S.","year":"2021","journal-title":"Lancet Glob Health"},{"key":"pone.0340477.ref002","volume-title":"World report on vision","author":"World Health O","year":"2019"},{"issue":"4","key":"pone.0340477.ref003","doi-asserted-by":"crossref","first-page":"477","DOI":"10.1001\/archopht.122.4.477","article-title":"Causes and prevalence of visual impairment among adults in the United States","volume":"122","author":"N Congdon","year":"2004","journal-title":"Arch Ophthalmol"},{"key":"pone.0340477.ref004","doi-asserted-by":"crossref","first-page":"768026","DOI":"10.1155\/2014\/768026","article-title":"Oxidative stress, hypoxia, and autophagy in the neovascular processes of age-related macular degeneration","volume":"2014","author":"J Blasiak","year":"2014","journal-title":"Biomed Res Int"},{"issue":"5","key":"pone.0340477.ref005","doi-asserted-by":"crossref","first-page":"713","DOI":"10.1189\/jlb.3RI0615-239R","article-title":"Parainflammation, chronic inflammation, and age-related macular degeneration","volume":"98","author":"M Chen","year":"2015","journal-title":"J Leukoc Biol"},{"issue":"9","key":"pone.0340477.ref006","doi-asserted-by":"crossref","first-page":"1144","DOI":"10.1136\/bjophthalmol-2014-305702","article-title":"Guidelines for the management of neovascular age-related macular degeneration by the European Society of Retina Specialists (EURETINA)","volume":"98","author":"U Schmidt-Erfurth","year":"2014","journal-title":"Br J Ophthalmol"},{"issue":"4","key":"pone.0340477.ref007","doi-asserted-by":"crossref","first-page":"533","DOI":"10.1016\/j.ophtha.2004.10.047","article-title":"Risk factors for the incidence of Advanced Age-Related Macular Degeneration in the Age-Related Eye Disease Study (AREDS) AREDS report no. 19","volume":"112","author":"Age-Related Eye Disease Study Research Group","year":"2005","journal-title":"Ophthalmology"},{"issue":"12","key":"pone.0340477.ref008","first-page":"2224","article-title":"Risk factors associated with age-related macular degeneration. 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