{"doi":"10.1016/j.ajpath.2023.02.002","title":"Selective Modulation of the Keratoconic Stromal Microenvironment by FSH and LH","abstract":"Keratoconus (KC) affects the corneal structure, with thinning and bulging outward into a conelike shape. Irregular astigmatism and decreased visual acuity appear during puberty and progress into the mid-30s, with unpredictable disease severity. The cause of KC is recognized as multifactorial, but remains poorly understood. Hormone imbalances are a significant modulator of the onset of KC. This study sought to investigate the role of gonadotropins, follicle-stimulating hormone (FSH), and luteinizing hormone (LH) in KC, using a three-dimensional, self-assembled matrix in vitro model. Healthy corneal fibroblasts and human KC cells in the corneal stroma were isolated, cultured, and stimulated with stable vitamin C to promote extracellular matrix assembly. Cultures were further stimulated with 2.5 or 10 mIU/mL FSH and 5 or 35 mIU/mL LH. Samples were evaluated for cell proliferation and morphology via BrdU assay and imaging; protein expression was assessed via Western blot analysis. Proliferation was significantly greater in human KC cells compared to healthy corneal fibroblasts with LH stimulation, but no changes were found with FSH stimulation. Additionally, in sex hormone receptors, fibrotic markers, proteoglycans, and members of the gonadotropin signaling pathway were significantly changed, largely driven by exogenous LH. The impact of exogenous FSH/LH in the KC stromal microenvironment was demonstrated. The role of FSH/LH in KC and in human corneal homeostasis should be further examined. Keratoconus (KC) affects the corneal structure, with thinning and bulging outward into a conelike shape. Irregular astigmatism and decreased visual acuity appear during puberty and progress into the mid-30s, with unpredictable disease severity. The cause of KC is recognized as multifactorial, but remains poorly understood. Hormone imbalances are a significant modulator of the onset of KC. This study sought to investigate the role of gonadotropins, follicle-stimulating hormone (FSH), and luteinizing hormone (LH) in KC, using a three-dimensional, self-assembled matrix in vitro model. Healthy corneal fibroblasts and human KC cells in the corneal stroma were isolated, cultured, and stimulated with stable vitamin C to promote extracellular matrix assembly. Cultures were further stimulated with 2.5 or 10 mIU/mL FSH and 5 or 35 mIU/mL LH. Samples were evaluated for cell proliferation and morphology via BrdU assay and imaging; protein expression was assessed via Western blot analysis. Proliferation was significantly greater in human KC cells compared to healthy corneal fibroblasts with LH stimulation, but no changes were found with FSH stimulation. Additionally, in sex hormone receptors, fibrotic markers, proteoglycans, and members of the gonadotropin signaling pathway were significantly changed, largely driven by exogenous LH. The impact of exogenous FSH/LH in the KC stromal microenvironment was demonstrated. The role of FSH/LH in KC and in human corneal homeostasis should be further examined. Keratoconus (KC) is a progressive, ectatic corneal disease causing structural and biomechanical changes in the human cornea, leading to significant vision impairment. The disease typically emerges during the adolescent years, progresses during the young-adult years, and generally stabilizes by middle-adult years (mid–late 40s). The pathobiology of the disease is not fully understood, but it is generally considered multifactorial.1Crawford A.Z. Zhang J. Gokul A. McGhee C.N.J. Ormonde S.E. The enigma of environmental factors in keratoconus.Asia Pac J Ophthalmol (Phila). 2020; 9: 549-556Crossref PubMed Scopus (14) Google Scholar, 2Galvis V. Sherwin T. Tello A. Merayo J. Barrera R. Acera A. Keratoconus: an inflammatory disorder?.Eye (Lond). 2015; 29: 843-859Crossref PubMed Scopus (225) Google Scholar, 3Kok Y.O. Tan G.F. Loon S.C. Review: keratoconus in Asia.Cornea. 2012; 31: 581-593Crossref PubMed Scopus (85) Google Scholar, 4Moussa S. Grabner G. Ruckhofer J. Dietri","journal":"American Journal Of Pathology","year":2023,"id":359063,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":10,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9586,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":259048,"name":"Sarah E. Nicholas","orcid":"0000-0003-1738-4066","position":1,"is_corresponding":false},{"id":669338,"name":"Brenda Vasini","orcid":"0000-0002-5271-3120","position":2,"is_corresponding":false},{"id":308571,"name":"Rebecca L. Cunningham","orcid":"0000-0001-5984-5516","position":3,"is_corresponding":false},{"id":1109717,"name":"David A. Murphy","orcid":"0000-0002-6983-8894","position":4,"is_corresponding":false},{"id":259049,"name":"Kamran M. Riaz","orcid":"0000-0003-1090-5025","position":5,"is_corresponding":false},{"id":259050,"name":"Dimitrios Karamichos","orcid":"0000-0002-8761-3824","position":6,"is_corresponding":false},{"id":670100,"name":"Paulina Escandon","orcid":null,"position":0,"is_corresponding":true}],"reference_count":74,"raw_metadata":null,"created_at":"2026-07-19T01:13:52.889556Z","pmid":"36822267","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}