{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:47:46Z","timestamp":1787028466136,"version":"build-2736575974"},"reference-count":60,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2022,1,14]],"date-time":"2022-01-14T00:00:00Z","timestamp":1642118400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000053","name":"National Eye Institute","doi-asserted-by":"publisher","award":["EY028888"],"award-info":[{"award-number":["EY028888"]}],"id":[{"id":"10.13039\/100000053","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Keratoconus (KC) is a progressive corneal thinning disease that manifests in puberty and worsens during pregnancy. KC onset and progression are attributed to diverse factors that include: environmental, genetics, and hormonal imbalances; however, the pathobiology remains elusive. This study aims to determine the role of corneal stroma sex hormone receptors in KC and their interplay with estrone (E1) and estriol (E3) using our established 3D in vitro model. Healthy cornea stromal cells (HCFs) and KC cornea stromal cells (HKCs), both male and female, were stimulated with various concentrations of E1 and E3. Significant changes were observed between cell types, as well as between males and females in the sex hormone receptors tested; androgen receptor (AR), progesterone receptor (PR), estrogen receptor alpha (ER\u03b1), and estrogen receptor beta (ER\u03b2) using Western blot analysis. E1 and E3 stimulations in HCF females showed AR, PR, and ER\u03b2 were significantly upregulated compared to HCF males. In contrast, ER\u03b1 and ER\u03b2 had significantly higher expression in HKC\u2019s females than HKC\u2019s males. Our data suggest that the human cornea is a sex-dependent, hormone-responsive tissue that is significantly influenced by E1 and E3. Therefore, it is plausible that E1, E3, and sex hormone receptors are involved in the KC pathobiology, warranting further investigation.<\/jats:p>","DOI":"10.3390\/ijms23020916","type":"journal-article","created":{"date-parts":[[2022,1,14]],"date-time":"2022-01-14T12:34:04Z","timestamp":1642163644000},"page":"916","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":28,"title":["The Role of Estriol and Estrone in Keratoconic Stromal Sex Hormone Receptors"],"prefix":"10.3390","volume":"23","author":[{"given":"Paulina","family":"Escandon","sequence":"first","affiliation":[{"name":"North Texas Eye Research Institute, University of North Texas Health Science Center, Fort Worth, TX 76107, USA"},{"name":"Department of Pharmaceutical Sciences, University of North Texas Health Science Center, Fort Worth, TX 76107, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah E.","family":"Nicholas","sequence":"additional","affiliation":[{"name":"North Texas Eye Research Institute, University of North Texas Health Science Center, Fort Worth, TX 76107, USA"},{"name":"Department of Pharmaceutical Sciences, University of North Texas Health Science Center, Fort Worth, TX 76107, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rebecca L.","family":"Cunningham","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, University of North Texas Health Science Center, Fort Worth, TX 76107, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David A.","family":"Murphy","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Dean McGee Eye Institute, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kamran M.","family":"Riaz","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Dean McGee Eye Institute, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8761-3824","authenticated-orcid":false,"given":"Dimitrios","family":"Karamichos","sequence":"additional","affiliation":[{"name":"North Texas Eye Research Institute, University of North Texas Health Science Center, Fort Worth, TX 76107, USA"},{"name":"Department of Pharmaceutical Sciences, University of North Texas Health Science Center, Fort Worth, TX 76107, USA"},{"name":"Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, Fort Worth, TX 76107, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,1,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"459.e1","DOI":"10.1016\/j.ajo.2005.03.078","article-title":"Differences in Keratoconus as a Function of Gender","volume":"140","author":"Fink","year":"2005","journal-title":"Am. J. Ophthalmol."},{"key":"ref_2","first-page":"1","article-title":"The Genetic and Environmental Factors for Keratoconus","volume":"2015","author":"Millodot","year":"2015","journal-title":"BioMed Res. Int."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"188","DOI":"10.1136\/jmg.2003.012872","article-title":"A locus for autosomal dominant keratoconus maps to human chromosome 3p14-q13","volume":"41","author":"Brancati","year":"2004","journal-title":"J. Med Genet."},{"key":"ref_4","first-page":"1","article-title":"Clinical and epidemiological features of keratoconus genetic and external factors in the pathogenesis of the disease","volume":"178","author":"Ihalainen","year":"1986","journal-title":"Acta Ophthalmol. Suppl."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"172","DOI":"10.1097\/ICO.0b013e3181aebf7a","article-title":"Absence of Pathogenic Mutations in VSX1 and SOD1 Genes in Patients With Keratoconus","volume":"29","author":"Hawlina","year":"2010","journal-title":"Cornea"},{"key":"ref_6","first-page":"3","article-title":"Genetics and clinical characteristics of keratoconus","volume":"19","author":"Strazisar","year":"2010","journal-title":"Acta Dermatovenerol. Alpina Pannonica Adriat."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1097\/00003226-198402000-00004","article-title":"An analysis of contrast sensitivity in identical twins with keratoconus","volume":"3","author":"Zadnik","year":"1984","journal-title":"Cornea"},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Karamichos, D., Barrientez, B., Nicholas, S., Ma, S., Van, L., Bak-Nielsen, S., and Hjortdal, J. (2019). Gonadotropins in Keratoconus: The Unexpected Suspects. Cells, 8.","DOI":"10.3390\/cells8121494"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"srep42896","DOI":"10.1038\/srep42896","article-title":"Differential Effects of Hormones on Cellular Metabolism in Keratoconus In Vitro","volume":"7","author":"McKay","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"214","DOI":"10.1111\/cxo.12038","article-title":"Effects of eye rubbing on the levels of protease, protease activity and cytokines in tears: Relevance in keratoconus","volume":"96","author":"Pye","year":"2013","journal-title":"Clin. Exp. Optom."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"527","DOI":"10.1016\/S0002-9394(14)76143-4","article-title":"Keratoconus and Eye Rubbing","volume":"97","author":"Coyle","year":"1984","journal-title":"Am. J. Ophthalmol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"560","DOI":"10.1097\/01.ico.0000121711.58571.8d","article-title":"Asymmetric Keratoconus Attributed to Eye Rubbing","volume":"23","author":"Jafri","year":"2004","journal-title":"Cornea"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"539","DOI":"10.1097\/01.ico.0000137168.24883.3e","article-title":"Eye Rubbing Can Cause Keratoconus","volume":"23","author":"Krachmer","year":"2004","journal-title":"Cornea"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1775","DOI":"10.18240\/ijo.2019.11.17","article-title":"The correlation between keratoconus and eye rubbing: A review","volume":"12","author":"Najmi","year":"2019","journal-title":"Int. J. Ophthalmol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1080\/09286586.2020.1804593","article-title":"Screening for Keratoconus in a High-Risk Adolescent Population","volume":"28","author":"Armstrong","year":"2020","journal-title":"Ophthalmic Epidemiol."},{"key":"ref_16","first-page":"e291","article-title":"Topographic, tomographic and biomechanical corneal changes during pregnancy in patients with keratoconus: A cohort study","volume":"95","author":"Naderan","year":"2016","journal-title":"Acta Ophthalmol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1382","DOI":"10.1097\/ICO.0000000000002054","article-title":"Keratoconus Prevalence Among High School Students in New Zealand","volume":"38","author":"Cox","year":"2019","journal-title":"Cornea"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"991","DOI":"10.1097\/ICO.0b013e3182068adc","article-title":"Pregnancy-induced Progression of Keratoconus","volume":"30","author":"Bilgihan","year":"2011","journal-title":"Cornea"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"144","DOI":"10.3928\/1081597X-20130117-11","article-title":"Transitory Topographical Variations in Keratoconus during Pregnancy","volume":"29","author":"Hoogewoud","year":"2013","journal-title":"J. Refract. Surg."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1097\/OPX.0b013e318238c3f2","article-title":"Two Cases of Keratoconus Diagnosed after Pregnancy","volume":"89","author":"Soeters","year":"2012","journal-title":"Optom. Vis. Sci."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1097\/ICO.0b013e3181ac0518","article-title":"The Influence of Gender and Hormone Status on the Severity and Progression of Keratoconus","volume":"29","author":"Sinnott","year":"2010","journal-title":"Cornea"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"25534","DOI":"10.1038\/srep25534","article-title":"Endocrine and Metabolic Pathways Linked to Keratoconus: Implications for the Role of Hormones in the Stromal Microenvironment","volume":"6","author":"McKay","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Anton, N., Doroftei, B., Ilie, O.-D., Ciuntu, R.-E., Bogd\u0103nici, C., and Nechita-Dumitriu, I. (2021). A Narrative Review of the Complex Relationship between Pregnancy and Eye Changes. Diagn., 11.","DOI":"10.3390\/diagnostics11081329"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1136\/bjophthalmol-2017-310247","article-title":"Anterior, posterior and biomechanical parameters of cornea during pregnancy in healthy eyes: A cohort study","volume":"102","author":"Naderan","year":"2017","journal-title":"Br. J. Ophthalmol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1016\/j.ajo.2017.10.001","article-title":"Pregnancy-induced Changes in Corneal Biomechanics and Topography Are Thyroid Hormone Related","volume":"184","author":"Tabibian","year":"2017","journal-title":"Am. J. Ophthalmol."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Aydin, E., Demir, H.D., Demirturk, F., Cal\u0131skan, A.C., Aytan, H., and Erkorkmaz, U. (2007). Corneal topographic changes in premenopausal and postmenopausal women. BMC Ophthalmol., 7.","DOI":"10.1186\/1471-2415-7-9"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1076\/ceyr.22.1.28.6980","article-title":"Expression of sex steroid hormone receptors in human cornea","volume":"22","author":"Suzuki","year":"2001","journal-title":"Curr. Eye Res."},{"key":"ref_28","first-page":"5089","article-title":"Altered expression of sex hormone receptors in keratoconus corneas","volume":"28","author":"Yin","year":"2017","journal-title":"Biomed Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1016\/S0378-5122(00)00156-0","article-title":"Immunohistochemical detection of estrogen and progesterone receptor in human cornea","volume":"36","author":"Kircher","year":"2000","journal-title":"Maturitas"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"146","DOI":"10.1034\/j.1600-0420.2000.078002146.x","article-title":"Identification of androgen, estrogen and progesterone receptor mRNAs in the eye","volume":"78","author":"Wickham","year":"2000","journal-title":"Acta Ophthalmol. Scand."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"274","DOI":"10.1016\/j.survophthal.2005.02.005","article-title":"Sex Hormone Receptors in the Human Eye","volume":"50","author":"Gupta","year":"2005","journal-title":"Surv. Ophthalmol."},{"key":"ref_32","first-page":"1906","article-title":"Estrogen receptor in the human eye: Influence of gender and age on gene expression","volume":"40","author":"Ogueta","year":"1999","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"877","DOI":"10.1136\/bjo.85.7.877","article-title":"Presence of oestrogen receptor type beta in human retina","volume":"85","author":"Munaut","year":"2001","journal-title":"Br. J. Ophthalmol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"737","DOI":"10.1016\/0960-0760(93)90314-M","article-title":"Influence of gender and the endocrine environment on the distribution of androgen receptors in the lacrimal gland","volume":"46","author":"Rocha","year":"1993","journal-title":"J. Steroid Biochem. Mol. Biol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"421","DOI":"10.1111\/j.1600-0420.1996.tb00594.x","article-title":"Influence of androgens and pituitary hormones on the structural profile and secretory activity of the lacrimal gland","volume":"74","author":"Sulliva","year":"2009","journal-title":"Acta Ophthalmol. Scand."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1016\/0002-9394(86)90817-2","article-title":"A 48-Year Clinical and Epidemiologic Study of Keratoconus","volume":"101","author":"Kennedy","year":"1986","journal-title":"Am. J. Ophthalmol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1547","DOI":"10.1136\/bjo.2007.124388","article-title":"Oestrogen-induced changes in biomechanics in the cornea as a possible reason for keratectasia","volume":"91","author":"Spoerl","year":"2007","journal-title":"Br. J. Ophthalmol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"2691","DOI":"10.1007\/s00417-019-04490-0","article-title":"The effect of estrogen and progesterone on porcine corneal biomechanical properties","volume":"257","author":"Walter","year":"2019","journal-title":"Graefe\u2019s Arch. Clin. Exp. Ophthalmol."},{"key":"ref_39","first-page":"51","article-title":"Androgen-dependent hereditary mouse keratoconus: Linkage to an MHC region","volume":"43","author":"Tachibana","year":"2002","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"3443","DOI":"10.1210\/en.2009-0449","article-title":"Understanding Estrogen Action during Menopause","volume":"150","author":"Iqbal","year":"2009","journal-title":"Endocrinology"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1016\/j.molmed.2012.12.007","article-title":"Estrogen synthesis and signaling pathways during aging: From periphery to brain","volume":"19","author":"Cui","year":"2013","journal-title":"Trends Mol. Med."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"110582","DOI":"10.1016\/j.mce.2019.110582","article-title":"Role of estrone on the regulation of osteoblastogenesis","volume":"498","author":"Crescitelli","year":"2019","journal-title":"Mol. Cell. Endocrinol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1081\/ERC-120022314","article-title":"The effect of low dose nylestriol-levonorgestrel replacement therapy on bone mineral density in women with postmenopausal osteoporosis","volume":"29","author":"Liao","year":"2003","journal-title":"Endocr. Res."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"978","DOI":"10.1097\/gme.0b013e3181a06c80","article-title":"Efficacy and safety of vaginal estriol and progesterone in postmenopausal women with atrophic vaginitis","volume":"16","author":"Chollet","year":"2009","journal-title":"Menopause"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1055","DOI":"10.1016\/j.jcrs.2019.04.038","article-title":"Progression of keratoconus resulting from hormone replacement therapy","volume":"45","author":"Natarajan","year":"2019","journal-title":"J. Cataract. Refract. Surg."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"100519","DOI":"10.1016\/j.ajoc.2019.100519","article-title":"Keratoconus progression associated with hormone replacement therapy","volume":"15","author":"Coco","year":"2019","journal-title":"Am. J. Ophthalmol. Case Rep."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1016\/j.steroids.2015.11.009","article-title":"Estrone sulfate and dehydroepiandrosterone sulfate: Transactivation of the estrogen and androgen receptor","volume":"105","author":"Ghisari","year":"2016","journal-title":"Steroids"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1016\/S0083-6729(08)60522-1","article-title":"Estrogens in pregnancy","volume":"35","author":"Levitz","year":"1977","journal-title":"Vitam. Horm."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"60","DOI":"10.3928\/1081597X-20151207-10","article-title":"Keratoconus Progression Induced by In Vitro Fertilization Treatment","volume":"32","author":"Yuksel","year":"2016","journal-title":"J. Refract. Surg."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1835","DOI":"10.1001\/archopht.1978.03910060347010","article-title":"Daily Assessment of Ocular and Hormonal Variables Throughout the Menstrual Cycle","volume":"96","author":"Feldman","year":"1978","journal-title":"Arch. Ophthalmol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"144","DOI":"10.1097\/01.ico.0000244873.08127.3c","article-title":"Variations in Central Corneal Thickness During the Menstrual Cycle in Women","volume":"26","author":"Fiorino","year":"2007","journal-title":"Cornea"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"30","DOI":"10.4103\/0301-4738.151463","article-title":"Evaluation of corneal thickness alterations during menstrual cycle in productive age women","volume":"63","author":"Ghahfarokhi","year":"2015","journal-title":"Indian. J. Ophthalmol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"492","DOI":"10.1016\/j.clae.2018.11.015","article-title":"Evaluation estrogen, progesteron and androgen receptor expressions in corneal epithelium in keratoconus","volume":"42","author":"Ayan","year":"2019","journal-title":"Contact Lens Anterior Eye"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"279","DOI":"10.3109\/02713689609007622","article-title":"Identification and endocrine control of sex steroid binding sites in the lacrimal gland","volume":"15","author":"Pena","year":"1996","journal-title":"Curr. Eye Res."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"353","DOI":"10.1097\/00003226-199807000-00002","article-title":"Menopause and tear function: The influence of prolactin and sex hormones on human tear production","volume":"17","author":"Mathers","year":"1998","journal-title":"Cornea"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"11209","DOI":"10.1073\/pnas.0404372101","article-title":"Subfertility and defective folliculogenesis in female mice lacking androgen receptor","volume":"101","author":"Hu","year":"2004","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_57","doi-asserted-by":"crossref","unstructured":"McKay, T.B., Priyadarsini, S., Rowsey, T., and Karamichos, D. (2021). Arginine Supplementation Promotes Extracellular Matrix and Metabolic Changes in Keratoconus. Cells, 10.","DOI":"10.3390\/cells10082076"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"341","DOI":"10.1002\/cbf.3122","article-title":"Quercetin modulates keratoconus metabolism in vitro","volume":"33","author":"McKay","year":"2015","journal-title":"Cell Biochem. Funct."},{"key":"ref_59","first-page":"577","article-title":"Keratoconus in vitro and the key players of the TGF-beta pathway","volume":"21","author":"Priyadarsini","year":"2015","journal-title":"Mol. Vis."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"4608","DOI":"10.1038\/srep04608","article-title":"In vitro model suggests oxidative stress involved in keratoconus disease","volume":"4","author":"Karamichos","year":"2015","journal-title":"Sci. Rep."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/2\/916\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,13]],"date-time":"2025-10-13T13:39:50Z","timestamp":1760362790000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/2\/916"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,1,14]]},"references-count":60,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2022,1]]}},"alternative-id":["ijms23020916"],"URL":"https:\/\/doi.org\/10.3390\/ijms23020916","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,1,14]]}}}