Hormonal Modulation of Keratoconus: A Systematic Review and Screening Strategy for At-Risk Populations

Keratoconus (KCN) is a progressive corneal ectasia with poorly understood etiology and risk factors leading to inadequate screening methods for at-risk populations. One potentially vulnerable population includes individuals experiencing fluctuations in hypothalamic-pituitary-gonadal (HPG) axis hormones. This systematic review aims to evaluate the association between HPG-axis hormonal fluctuations and the development or progression of KCN.

Elucidating the relationship between HPG-axis hormone fluctuations and KCN may enhance screening strategies, facilitate early detection, and inform preventive measures in at-risk populations. Improved awareness among clinicians could lead to targeted monitoring and timely interventions.

A comprehensive literature search was conducted in PubMed, Scopus, Web of Science, Embase, and Google Scholar databases up to July 2025, adhering to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Studies were included if they provided clinical evidence of associations between HPG-axis hormone fluctuations and KCN onset or progression. Two reviewers independently extracted relevant data on hormone changes and KCN. Methodological quality was assessed using the Joanna Briggs Institute (JBI) appraisal tools.

Twenty-six studies met inclusion criteria, comprising 16 descriptive studies and 10 case-control studies, with an aggregate of 4201 participants (∼8000 eyes). Endogenous hormonal shifts related to pregnancy and congenital hormonal abnormalities accounted for 56.2% of identified triggers (9 of 16 studies; 26 patients), while exogenous hormone exposure from hormone replacement therapy and antiandrogen treatment represented 31.2% (5 of 16 studies; 7 patients). Ten case-control studies included 3834 participants (1623 KCN patients and 2211 controls). Of these 10, 8 studies (80%) demonstrated significant alterations in sex steroid hormones (elevated dehydroepiandrosterone sulfate [DHEAS] and estradiol; decreased estrone and estriol; mixed results for testosterone) or gonadotropins (altered luteinizing hormone/follicle-stimulating hormone ratios, reduced gonadotropin-releasing hormone) in association with KCN. Methodological quality assessment indicated that 22 of the 26 studies had high reporting quality per JBI items.

This systematic review highlights consistent associations between HPG-axis hormone fluctuations and KCN development and progression, as evidenced across observational studies. Specifically, altered levels of DHEAS, estrogens, and gonadotropins emerged as key hormones linked to KCN pathology. These findings support a systemic component in the etiology of KCN, underscoring the importance of hormonal influences in clinical management and screening, particularly during periods of significant hormonal fluctuation, such as pregnancy, congenital endocrine disorders, or hormonal therapy.

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