Sex Hormone Imbalance in Keratoconus: Estrogen-Mediated Collagen Remodeling and Biomechanical Weakening

To investigate the role of sex hormone imbalance in keratoconus (KC) pathogenesis and its effects on corneal collagen metabolism and biomechanics.

Fifteen newly diagnosed, treatment-naïve KC patients and 12 age- and sex-matched controls were enrolled. Plasma and tear estradiol (E2), testosterone (T), and matrix metalloproteinase-2 (MMP2) concentrations were measured by ELISA. Associations between sex hormone and clinical parameters were analyzed using Pearson correlation. Human corneal stromal cells (HCSCs) were exposed to physiological or supraphysiological E2/T to evaluate cell viability, matrix metalloproteinases (MMPs), tissue inhibitors of metalloproteinases (TIMPs), type I collagen (COL1), and hydroxyproline (HYP). Estrogen receptor-β (ERβ) involvement was assessed using the ERβ selective antagonist PHTPP. A high-estrogen rat model was established to evaluate central corneal thickness (CCT), stromal collagen ultrastructure, and biomechanical properties.

KC patients exhibited significantly elevated plasma and tear E2 but unchanged T levels. Tear E2 concentrations positively correlated with mean keratometry, diopter, and MMP2 levels and negatively correlated with minimum corneal thickness and best-corrected visual acuity (BCVA). Plasma and tear E2, as well as tear MMP2, were significantly increased in male KC patients and showed significant correlations with KC-related parameters. In contrast, no significant differences or associations were observed in female KC patients in this cohort. Hormone treatments showed no cytotoxicity in HCSCs. High estrogen exposure increased MMP2 and decreased TIMP2 mRNA expression, increasing the MMP2/TIMP2 ratio, reducing COL1 protein, and enhancing collagen degradation. Estrogen receptor-β (ERβ) expression was upregulated, and pharmacologic inhibition with PHTPP partially restored MMP/TIMP balance and collagen homeostasis. In vivo, estrogen-treated rats demonstrated reduced CCT, disrupted stromal collagen organization, and decreased Young's modulus.

Elevated estrogen disrupts corneal collagen homeostasis and biomechanical integrity via an E2-ERβ-MMP2 axis, establishing a mechanistic link between sex hormone imbalance and KC pathogenesis.