Association Between Female Reproductive Factors and Risk of Exfoliation Glaucoma or Glaucoma Suspect
Key findings
- Exfoliation glaucoma (XFG), the most common type of secondary glaucoma, has a higher incidence in women, but the role of estrogen in the etiology of the disease is not known
- In a cohort of 121,098 women followed for up to 30 years, reproductive factors and hormone use history indicative of greater lifetime estrogen exposure were associated with greater risk of XFG/exfoliation glaucoma suspect (XFGS)
- Later age of first menstrual cycle, longer oral contraception use, and longer breastfeeding duration were generally associated with reduced risk of XFG/XFGS
- In a subset of women with high genetic susceptibility for XFG/XFGS, earlier menopause and surgical menopause were associated with lower risk compared to natural menopause
Exfoliation syndrome (XFS) is characterized by the accumulation of fibrillar extracellular substances in tissues throughout the body. In the eye, buildup of fibrillar materials can lead to exfoliation glaucoma (XFG), the most common type of secondary glaucoma.
Subscribe to the latest updates from Ophthalmology Advances in Motion
Estrogen has beneficial effects on intraocular pressure homeostasis, blood flow, and neuroprotection, but is also a regulator of the lysyl oxidase-like 1 (LOX1) pathway involved in the formation of exfoliation material and the cross-linking of collagen and elastin. Its role in XFG is not known.
After previous reports that women may be more susceptible to this complex condition, Jae Hee Kang, ScD, Janey Wiggs, MD, PhD, and collaborators at Brigham and Women’s Hospital investigated the role of estrogen-dependent reproductive factors in XFG and exfoliation glaucoma suspect (XFGS) in a prospective cohort study of 121,098 women followed for up to 30 years.
Methods
Eligible women from the Nurses’ Health Study (NHS) I/II were ≥40 years old, post-menopausal, and had no history of XFS or cataract extraction. Reproductive history–age of first menstruation (menarche) and menopause, oral contraceptive (OC) and menopausal hormone therapy use, number of pregnancies reaching ≥20 weeks (parity), breastfeeding history, and type of menopause–was collected from 1980–2018 (NHSI) and 1991–2019 (NHSII). XFG/XFGS cases were confirmed with medical records. Per-eye Cox proportional hazards models estimated multivariable-adjusted hazard ratios (MVHR) and 95% confidence intervals (CIs); false discovery rate (FDR) corrected for multiple comparisons.
Findings
Reproductive factors that signify greater lifetime estrogen exposure predicted greater risk of XFG/XFGS.
- Women with menarche after age 14 showed decreased XFG/XFGS risk compared to women with menarche before age 12 (MVHR = 0.59 [95% CI: 0.38, 0.92]; Ptrend = .006; FDR-corrected P = .048); each year of later menarche lowered risk by 9% (MVHR = 0.91; 95% CI: 0.85, 0.97).
- Women who used OCs for ≥11 years had a lower risk of XFG/XFGS compared to those who never used OCs (MVHR = 0.64; 95% CI: 0.37, 1.12; Ptrend = .04; FDR-corrected P = .10); each additional year of OC use was associated with a 4% lower risk (MVHR = 0.96; 95% CI: 0.93, 0.997).
- Breastfeeding for at least 12 months, compared to never breastfeeding, was associated with lower XFG/XFGS risk (MVHR = 0.68; 95% CI: 0.48, 0.97; Ptrend = .05; FDR-corrected P = .10).
- Menopause before age 45 was associated with increased risk compared to menopause between ages 50-53 (MVHR = 1.58; 95% CI: 1.12, 2.22; Ptrend = .04; FDR-corrected P = .10).
- Parity and age at first birth were not significantly associated with XFG/XFGS risk.
Secondary analyses showed that surgical menopause, which often occurs earlier, reduced risk for XFG/XFGS compared to natural menopause in a subset of women with higher genetic susceptibility.
This is one of few studies evaluating female reproductive factors in glaucoma. Further study is needed to confirm the results.