The association of female reproductive factors with glaucoma and related traits

Author: Madjedi KM, Stuart KV, Chua SYL, Foster PJ, Strouthidis NG, Luben RN, Warwick AN, Kang JH, Wiggs JL, Pasquale LR, Khawaja AP.

Geographical coverage: USA, Turkey, Italy, South Korea, Australia, Israel, UK, Netherlands, Canada, Austria, and India

Sector: Open-angle glaucoma

Sub-sector: Gender specific risk factors

Equity focus: Not reported

Study population: Patients with glaucoma

Review type: Epidemiology (association) review

Quantitative synthesis method: Narrative synthesis

Qualitative synthesis method: Not applicable

Background

Primary open-angle glaucoma (POAG), a leading cause of irreversible blindness globally, is projected to affect 112 million individuals by 2040. Oestrogen is believed to play a neuroprotective role in POAG by influencing both mechanical and vascular mechanisms. Some studies suggest that oestrogen may modulate aqueous humour dynamics and help prevent retinal ganglion cell loss, whereas a reduction in lifetime oestrogen exposure may elevate the risk of glaucoma.

Objectives

To systematically review and analyse the associations between female reproductive factors and open-angle glaucoma (OAG), with the aim of identifying sex-specific risk factors.

Main findings

Overall, the use of postmenopausal hormone (PMH) therapy, particularly oestrogen-only treatments, may be associated with lower intraocular pressure (IOP) and a reduced risk of open-angle glaucoma (OAG).

Out of 4,516 records identified, 27 studies were included in this review. Ten of these were conducted in the USA, seven in Turkey, three each in Italy and South Korea, two each in Australia and Israel, and one each in the UK, Netherlands, Canada, Austria, and India. Sample sizes ranged from 25 (Austria) to 125,163 (USA).

There were consistent associations between PMH use and lower IOP, particularly with oestrogen-only PMH. This use may also be linked to a reduced risk of OAG, with race acting as a potential effect modifier. No clear effect was observed for combined oestrogen-and-progesterone PMH. Likewise, no strong associations were found between parity, age at menarche, or reproductive duration and OAG risk. However, younger age at menopause was associated with increased risk, and prolonged use of oral contraceptives showed adverse associations, although results were inconsistent.

Methodology

Searches were conducted in Medline, Embase, the Cochrane Database of Systematic Reviews, the Cochrane Central Register of Controlled Trials, and Google Scholar from inception to 15 September 2020. Studies included participants aged over 18 years and reported outcomes related to IOP or OAG, along with at least one of the following female reproductive factors: age at menarche, parity, gravidity, oral contraceptive (OC) use, age at menopause, reproductive duration, or PMH use. No restrictions were applied regarding language, publication date, or type.

Two reviewers independently screened titles, abstracts, and full texts according to predefined eligibility criteria. Reference lists of the included studies and relevant reviews were also examined. Additional studies were sought by consulting information specialists and clinical experts. Two reviewers independently extracted data and assessed risk of bias using the Cochrane Risk of Bias tool for randomised controlled trials and the ROBINS-I tool for observational studies. Discrepancies were resolved through discussion or referral to a third reviewer.

Due to extensive heterogeneity in study design, exposure levels, treatment doses and durations, and reference categories, a meta-analysis was not feasible. Results were therefore synthesised narratively.

Applicability / External validity

The findings are primarily derived from studies involving White populations, limiting generalisability to other ethnic groups. Significant variability in study designs, exposure definitions, and comparator groups also limits applicability. The review highlights the need for more standardised, well-controlled studies to improve generalisability.

Geographic focus

Studies included in the review were conducted in the USA, Turkey, Italy, South Korea, Australia, Israel, UK, Netherlands, Canada, Austria, and India.

Summary of quality assessment

Overall, there is medium confidence in the study’s conclusions. While the authors conducted a comprehensive review, the findings were not analysed or reported according to risk of bias status, limiting the robustness of conclusions.