Greater Lifetime Estrogen Exposure Increases Exfoliation Glaucoma Risk

A large study involving a relatively homogenous population of female nurses in the US found an association between higher risk of exfoliation glaucoma or glaucoma suspect and various reproductive factors suggestive of greater lifetime estrogen exposure, including younger age at menarche, longer oral contraceptive use, longer breastfeeding duration and surgical menopause. Photo: Aaron Bronner, OD. Click image to enlarge. Considering that women have higher rates of exfoliative glaucoma (XFG) than men, researchers recently aimed to investigate which female reproductive factors might contribute to this increased risk. Their large prospective cohort study revealed that reproductive factors suggestive of greater lifetime estrogen exposure—particularly younger age at menarche, longer durations of oral contraceptive use and breastfeeding and surgical vs. natural menopause—were associated with higher risks of XFG and exfoliation glaucoma suspect (XFGS).The study involved 121,098 postmenopausal female participants from the Nurses’ Health Study and the Nurses’ Health Study II, spanning a follow-up period from 1980 to 2019. Eligible participants were aged 40 or older, had no prior glaucoma diagnosis and had undergone ophthalmic examinations during follow-up. Data on reproductive history and lifestyle factors were collected through biennial questionnaires, which included information on age at menarche, parity, oral contraceptive use, breastfeeding history, age at menopause and type and duration of menopausal hormone therapy use.Throughout up to 30 years of follow-up, 315 women developed incident XFG/XFGS affecting a total of 440 eyes. The researchers found that various reproductive factors appeared to influence the risk of developing XFG through mechanisms related to estrogen exposure. For example, every additional year in the age at menarche correlated with a 9% decreased risk of developing XFG/XFGS, and a trend towards lower risk was seen with longer durations of oral contraceptive use and breastfeeding.Compared to natural menopause, surgical menopause (bilateral oophorectomy), which induces earlier menopause, was also associated with lower XFG/XFGS risk, although only among women with high genetic susceptibility. In their paper on the study findings, published recently in American Journal of Ophthalmology, the authors suggested that in these women, “the putative adverse effects may outweigh any potential benefits of estrogen.” Interestingly, however, higher age at menopause and extended periods of using menopausal hormone therapy did not show significant associations with risk for exfoliative glaucoma.One finding that surprised the researchers was the higher risk of XFG/XFGS associated with menopause at age 20 to 44 years. “There may be pathologic mechanisms (e.g., inflammation, autoimmunity) that are common between XFG/XFGS and premature ovarian aging,” the researchers wrote. “Interestingly, Addison’s disease is a contributor to premature ovarian aging, and in a metabolomics study, we previously observed that relatively lower levels of cortisone, indicative of adrenal insufficiency, were related to XFG/XFGS.”This study is limited by its relatively homogeneous population of US women, primarily of European descent, with nursing degrees. Furthermore, they noted that the glaucoma confirmation method used in the study had low sensitivity; therefore, it’s likely that a significant portion of cases were missed.“As the role of estrogen in XFG/XFGS etiology has been studied little to date, and as we lacked external validation from an independent study, our results need confirmation and should be interpreted with caution,” the researchers concluded.Click here for the journal source. Kang JH, Wu Z, Yu M, et al. Female reproductive factors in relation to risk of exfoliation glaucoma or glaucoma suspect. Am J Ophthalmol. June 2025. [Epub ahead of print].