The Role of Estrogen Signaling in Intraocular Pressure Regulation and Glaucoma Risk


Glaucoma, a group of progressive optic neuropathies, stands as the leading cause of irreversible blindness worldwide, affecting around 80 million individuals (Budenz et al., 2013; Doshi et al., 2008; Lee and Mackey, 2022; Paterson and Miller, 1963; Rudnicka et al., 2006; Tham et al., 2014; Ziai et al., 1994).

Glaucoma, a leading cause of irreversible blindness globally, affects millions of individuals, with projections indicating a substantial increase by 2040. Characterized by specific visual field decline and structural changes in the eye, glaucoma poses a significant public health challenge.

While elevated intraocular pressure (IOP) is a well-established risk factor, glaucoma comprises a diverse group of diseases, with open-angle and closed-angle glaucoma being the major forms.

Despite the prevailing focus on IOP as the primary modifiable risk factor, recent investigations suggest a potential link between menopause, estrogen signaling, and the development and progression of glaucoma.

Glaucoma is characterized by progressive loss of visual function and retinal ganglion cells (RGCs). While 59% of the glaucomatous population are females, sex is not considered a risk factor for developing glaucoma. However, recent studies have suggested a potential link between estrogen dysregulation, intraocular pressure, and the risk of glaucoma.

Structural Changes in Glaucoma: Glaucoma manifests through hallmark structural alterations, such as thinning of the retinal nerve fiber layer (RNFL) and remodeling at the optic nerve head (ONH). The loss of retinal ganglion cells (RGCs) and their axons, responsible for transmitting visual information, contributes to the visual impairment associated with glaucoma.

Heterogeneity of Glaucoma: Recognizing glaucoma as a heterogeneous group of diseases, it is classified into open-angle, closed-angle, and developmental types based on etiology. Primary open-angle glaucoma (POAG) prevails in the USA, Europe, Africa, and Australia, with elevated IOP, age, ethnicity, and family history identified as risk factors. Primary angle closure glaucoma (PACG) is predominant in Asia, with risk factors including ethnicity, age, refractive error, sex, and family history.

Biomechanical Properties and IOP Regulation: While IOP remains the primary target for glaucoma treatment, the biomechanical properties of ocular tissues, particularly the sclera, are increasingly recognized as influential in ONH deformation. The response of ONH cells to mechanical loads, combined with the mechanical properties of the posterior eye, contributes to the pathophysiology of glaucoma.

Aqueous Humor Dynamics: IOP regulation is intricately tied to the production and removal of aqueous humor. Aqueous humor, produced by the ciliary body, nourishes avascular tissues and is removed through conventional (trabecular meshwork-Schlemm’s canal) and unconventional (uveoscleral) outflow pathways. Outflow resistance, increased in POAG, is predominantly controlled through the trabecular meshwork.

Menopause as a Sex-Specific Risk Factor: In this comprehensive review, we explore the potential role of menopause as a sex-specific risk factor for glaucoma. Menopause, accompanied by changes in estrogen signaling, is proposed to influence IOP, aqueous humor outflow resistance, cell survival, response to loading conditions, and ocular biomechanical properties, all contributing to glaucoma development and progression.

The Role of Estrogen in Glaucoma
Estrogen affects many processes involved in glaucoma. Researchers have found an association between oral contraceptive (OC) use and glaucoma. Women who used OCs for more than three years had a twofold risk of developing primary open-angle glaucoma (POAG) later in life. However, this does not indicate a direct causative effect; rather, it suggests OC use as a potential risk factor for glaucoma .

Intraocular Pressure and Glaucoma
Increased pressure in the eyes is one specific characteristic associated with glaucoma. Post-menopausal women in one study had intraocular pressure between 1.5 and 3.5 mmHg higher than pre-menopausal women of the same age.

Hormone Replacement Therapy and Glaucoma
A number of studies have suggested that hormone replacement therapy (HRT) in postmenopausal women may be beneficial in reducing intraocular pressure or the incidence of glaucoma. However, most of these studies have been limited by methodological issues, particularly small sample sizes.

Primary open-angle glaucoma (POAG) constitutes three-fourths of glaucoma cases and is distinctive for its lack of a discernible cause (Liu and Allingham, 2017). While various risk factors contribute to POAG, including genetic factors, aging, positive family history, African ancestry, and elevated intraocular pressure (IOP), the precise etiology remains elusive (Liu and Allingham, 2017).

Intraocular Pressure Regulation: IOP, defined as the pressure exerted by the aqueous humor (AH) within the eye, is crucial in maintaining ocular health (Liu and Allingham, 2017; Stamer, 2012). AH, found in the anterior segment of the eye, nourishes the cornea, lens, and trabecular meshwork (TM) while facilitating waste removal (Fig. 1A) (Liu and Allingham, 2017; Stamer, 2012). IOP balance over a lifetime results from the equilibrium between AH production and outflow, primarily occurring through the conventional outflow pathway consisting of the TM, Schlemm’s canal (SC), and the episcleral vein (Stamer, 2012).

Current Therapies and Challenges: Existing therapeutic approaches predominantly target AH production or unconventional outflow pathways, yielding modest results and often accompanied by adverse effects (Stamer, 2012; Tanna and Johnson, 2018). Novel therapies focusing on the conventional outflow pathway, such as the Rho kinase inhibitor netarsudil (Rhopressa®), have shown promise in mitigating glaucoma-related TM fibrosis (Sturdivant et al., 2016). However, its third-line status underscores the need for more effective and well-tolerated treatments (Stamer, 2012).

Estrogen Signaling and Glaucoma Risk: Intriguingly, dysregulated sex hormone levels, particularly decreased estrogen levels, have emerged as potential contributors to glaucoma risk (Hulsman et al., 2001; Patel et al., 2018; Qureshi, 1995; Vajaranant and Pasquale, 2012). Epidemiological studies have consistently shown an inverse relationship between estrogen levels and IOP, with factors such as menopause, shorter fertility duration, and the use of postmenopausal hormones influencing glaucoma risk (Altintas et al., 2004; Lang et al., 2002; Patel et al., 2018; Sator et al., 1997, 1998; Sorrentino et al., 1998; Uncu et al., 2006; Wojtowiec et al., 2016).

Genetic Associations and Experimental Evidence: Genetic studies have identified single nucleotide polymorphisms (SNPs) in estrogen metabolic and signaling pathway genes linked to POAG and high-tension glaucoma, strengthening the connection between estrogen and glaucoma (Pasquale et al., 2013). Experimental evidence, including the loss of aromatase leading to elevated IOP and retinal ganglion cell (RGC) loss in female mice, underscores the biological significance of estrogen in ocular health (Chen et al., 2018).

Expression in Ocular Tissues: Estrogen receptors and metabolizing enzymes are expressed in various ocular tissues, suggesting a protective role for estrogen signaling (Deschênes et al., 2010; Lang et al., 2002; Munaut et al., 2001; Ogueta et al., 1999; Patel et al., 2018; Rocha et al., 2000; Suzuki et al., 2001). Beyond IOP regulation, estrogen’s neuroprotective effects on the retina have been extensively documented in separate reviews (Cascio et al., 2015; Douglass et al., 2023; Fotesko et al., 2022; Levi and Brimble, 2004; Nuzzi et al., 2018, 2019).

Conclusion: As research continues to unravel the multifaceted aspects of glaucoma, understanding sex-specific risk factors, particularly the influence of menopause and estrogen signaling, may pave the way for targeted interventions. The intricate interplay between hormonal changes, biomechanical properties, and ocular health underscores the need for a holistic approach to glaucoma research and management.

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