Understanding Sexual Dimorphism in Keratoconus

Keratoconus (KC) is a progressive ocular condition characterized by corneal thinning and protrusion. Clinicians have long noted that males often experience a higher prevalence and earlier onset of the disease. Recent transcriptomic research into keratoconus hormonal mechanisms has now shed light on why these sex-based differences occur. By analyzing whole-transcriptome sequencing from human corneal tissues, scientists identified over 3,000 differentially expressed genes that drive sex-biased molecular programs.

The Impact of Testosterone and Estrogen on Stromal Remodeling

The study utilized primary human corneal stromal fibroblasts to evaluate how sex hormones modulate the cornea. Specifically, the findings reveal that testosterone down-regulates type I collagen while simultaneously up-regulating type III collagen and alpha-smooth muscle actin. This shift in collagen composition weakens the corneal matrix. However, the androgen antagonist flutamide can mitigate these harmful effects. Consequently, testosterone appears to be a major driver of the androgen-driven corneal weakening observed in male patients.

Conversely, the research highlights the protective role of estrogen in keratoconus hormonal mechanisms. Inhibiting estrogen was found to reproduce the altered stromal remodeling seen in diseased tissues. Furthermore, the administration of beta-estradiol rapidly reversed these changes. In female patients, a unique competitive endogenous RNA axis (circEPB41L2_0001-miR-942-5p-DCP1A) was identified and validated as a key regulator. These findings suggest that estrogen deficiency may contribute significantly to the progression of KC in women.

Clinical Implications for Personalized Therapy

Identifying these hormone-driven pathways provides a roadmap for more personalized medical approaches. Since the corneal tissue is highly hormone-responsive, therapeutic strategies may soon include hormonal modulation. Moreover, understanding the male-specific gonadal development programs and female-specific immune processes allows for better risk stratification. Therefore, targeted interventions that address specific keratoconus hormonal mechanisms could improve outcomes for patients across different demographics.

Frequently Asked Questions

Why do men develop keratoconus more frequently than women?

Research indicates that testosterone alters the corneal stroma by reducing type I collagen and increasing type III collagen. This androgen-driven remodeling weakens the cornea's structural integrity, leading to a higher incidence and earlier onset in males.

Can estrogen treatments help manage keratoconus?

In laboratory studies, beta-estradiol has shown the ability to reverse stromal remodeling caused by estrogen deficiency. While this suggests potential for hormonal therapy, clinicians must wait for further human trials to determine the safety and efficacy of such treatments.

What is the role of the ceRNA axis in female patients?

The circEPB41L2_0001-miR-942-5p-DCP1A axis is a female-specific molecular pathway that regulates corneal health. Its discovery helps explain the distinct transcriptomic features of keratoconus in women compared to men.

Disclaimer: This content is for informational and educational purposes only. It does not constitute medical advice or substitute for professional consultation. Refer to the latest local and national guidelines for clinical practice.

References

Sun Y et al. Sexual dimorphism in keratoconus: transcriptomic and hormonal mechanisms underlying stromal remodelling. Eye Vis (Lond). 2026 Mar 03. doi: undefined. PMID: 41772727.

Gomes JA, et al. Global consensus on keratoconus and ectatic diseases. Cornea. 2015;34(4):359-69.

Vaddavalli PK, et al. Keratoconus in India: Clinical presentation and demographic distribution based on big data analytics. Indian J Ophthalmol. 2023;71(4):1456-1463.