Evidence for Menopause as a Sex-Specific Risk Factor for Glaucoma

Abstract

Glaucoma is a leading cause of irreversible blindness worldwide and is characterized by progressive loss of visual function and retinal ganglion cells (RGC). Current epidemiological, clinical, and basic science evidence suggest that estrogen plays a role in the aging of the optic nerve. Menopause, a major biological life event affecting all women, coincides with a decrease in circulating sex hormones, such as estrogen. While 59% of the glaucomatous population are females, sex is not considered a risk factor for developing glaucoma. In this review, we explore whether menopause is a sex-specific risk factor for glaucoma. First, we investigate how menopause is defined as a sex-specific risk factor for other pathologies, including cardiovascular disease, osteoarthritis, and bone health. Next, we discuss clinical evidence that highlights the potential role of menopause in glaucoma. We also highlight preclinical studies that demonstrate larger vision and RGC loss following surgical menopause and how estrogen is protective in models of RGC injury. Lastly, we explore how surgical menopause and estrogen signaling are related to risk factors associated with developing glaucoma (e.g., intraocular pressure, aqueous outflow resistance, and ocular biomechanics). We hypothesize that menopause potentially sets the stage to develop glaucoma and therefore is a sex-specific risk factor for this disease.

Keywords: Biomechanics; Estrogen; Glaucoma; Intraocular pressure; Menopause; Outflow resistance; Ovariectomy; Retinal ganglion cells; Sex specific; Visual function.

Fig. 1

Prevalence of any type of glaucoma by age between males and females by decade. Data were adapted from the NEI database. Overall, females have a higher prevalence of glaucoma compared to males. The relative prevalence of glaucoma in females appears to change throughout life, with a higher prevalence of glaucoma in females occurring in both the early decades (40–59) and later stages of life (80+) compared to males. In comparison, the prevalence of glaucoma in males tends to consistently increase with age

Fig. 2

Highlights the vastness of research on menopause or estrogen in different fields of research. These are the results of a PubMed search (performed in May 2021) using menopause or estrogen with a field of study (underlined keyword). The number of publications in each area is listed below and expected to continuously expand as menopause becomes a topic of increased focus

Fig. 3

Relative Risk of developing glaucoma as a function of IOP based on data from Sommer et al. (1991) We examine two specific points (cyan dots) where a modest increase in IOP was associated with an increased risk of developing glaucoma. First, an individual with an IOP of 16–18 mmHg has a twofold higher risk of developing glaucoma compared to an individual with an IOP of 15 mmHg or lower. Second, there is a tenfold increased risk of developing glaucoma in an individual with an IOP of 22–24 mmHg compared to an individual with an IOP of 19–21 mmHg. The minor differences in IOP associated with estrogen deficiency/menopause will likely be an important factor to consider when treating women with glaucoma. The shaded region is considered ocular hypertension

Fig. 4

Adopted from Feola et al. (2019) A The normalized spatial frequency threshold or visual acuity decreased after ocular hypertension (OHT; ***p < 0.001) in ovariectomized (OVX) and Sham-operated controls (Sham) compared to baseline measurements. Spatial frequency was significantly lower after 4 and 8 weeks in ovariectomized animals after OHT (*p < 0.05; ***p < 0.001) compared to Sham OHT. Data plotted are mean ± S.E.M. B Displays the young (age 3–4 months) and C) displays the middle-aged (age 9–10 months) cohorts

Fig. 5

Mice with inherited ocular hypertension (DBA/2J) were divided into non-ovariectomized controls (non-OVX), ovariectomized (OVX), and ovariectomized treated with systemic 17β-estradiol (OVX + E2). Here, C57BL/6J served as a control group. At 6 months, IOP was higher in DBA/2J mice in both non-OVX and OVX animals compared to C57BL/6J mice, with OVX animals having a significantly higher IOP compared to non-OVX animals (p < 0.05). Treatment with systemic 17β-estradiol significantly lowered IOP compared to OVX animals (p < 0.05). Data were adapted from Zhou et al. (2007) and represented as mean ± SD

Fig. 6

Figures from multiple studies illustrating the neuroprotective effect of 17β-estradiol (E2) in various models of retinal ganglion cell (RGC) injury. These data are all adopted from Prokai-Tatrai et al. (2013), Zhou et al. (2007), Russo et al. (2008), and Nakazawa et al. (2006). All data are presented as mean ± SD. All bars denote significant differences (p < 0.05) noted in the literature

Fig. 7

Recent data demonstrating that surgical menopause (ovariectomy; OVX) increases outflow resistance (Left; p < 0.05) and decreases ocular stiffness (right; p < 0.05). Data are adopted from Feola et al. (2020) and presented as mean ± SD. This highlights that ovariectomy alone is related to factors associated with glaucoma

Fig. 8

Summary of the pathologies highlighted in this review, proportion of females in the affected population, and the current association with menopause. In cardiovascular disease (CVD), osteoporosis, and osteoarthritis (OA), menopause alone is considered a sex-specific factor and early menopause further increases the risk of developing these pathologies. To date, menopause has not been determined to be associated with developing glaucoma and it is not a consideration when monitoring glaucoma progression or when deciding on treatment. However, we highlight the similarities of glaucoma to these other pathologies and propose that menopause is potentially a novel sex-specific risk factor for developing glaucoma in females

Fig. 9

Illustration of how menopausal status and estrogens influence properties throughout the eye. Several of these are direct risk factors for developing glaucoma (e.g., increasing IOP and outflow resistance and decreasing ocular stiffness). However, the role of menopause and estrogen on inflammatory mediators and retinal ganglion cell survival likely plays a key role in long-term ocular health and vision