Girl Power in Glaucoma: The Role of Estrogen in Primary Open Angle Glaucoma

Fotesko, Kyrylo; Thomsen, Bo; Kolko, Miriam; Vohra, Rupali

doi:10.1007/s10571-020-00965-5

Cited by 10 publications

(9 citation statements)

References 150 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Altogether, these findings provide independent confirmations on the therapeutic benefits of E2 for the female retinal health [ 14 , 15 ]. In addition, they complement previous reports on the detrimental effect of estrogen deficiency on visual function in females not only through animal studies [ 16 , 17 ] but also epidemiological observations [ 18 ]. Postmenopausal women face a higher risk of developing glaucoma than prior to becoming estrogen-deficient [ 19 ].…”

Section: Introductionsupporting

confidence: 85%

Proteomics-Based Retinal Target Engagement Analysis and Retina-Targeted Delivery of 17β-Estradiol by the DHED Prodrug for Ocular Neurotherapy in Males

et al. 2021

View full text Add to dashboard Cite

We examined the impact of 17β-estradiol (E2) eye drops on the modulation of the proteome profile in the male rat retina. With discovery-driven proteomics, we have identified proteins that were regulated by our treatment. These proteins were assembled to several bioinformatics-based networks implicating E2’s beneficial effects on the male rat retina in a broad context of ocular neuroprotection including the maintenance of retinal homeostasis, facilitation of efficient disposal of damaged proteins, and mitochondrial respiratory chain biogenesis. We have also shown for the first time that the hormone’s beneficial effects on the male retina can be constrained to this target site by treatment with the bioprecursor prodrug, DHED. A large concentration of E2 was produced after DHED eye drops not only in male rat retinae but also in those of rabbits. However, DHED treatment did not increase circulating E2 levels, thereby ensuring therapeutic safety in males. Targeted proteomics focusing on selected biomarkers of E2’s target engagement further confirmed the prodrug’s metabolism to E2 in the male retina and indicated that the retinal impact of DHED treatment was identical to that of the direct E2 treatment. Altogether, our study shows the potential of topical DHED therapy for an efficacious and safe protection of the male retina without the unwanted hormonal side-effects associated with current estrogen therapies.

show abstract

Section: Introductionsupporting

confidence: 85%

Proteomics-Based Retinal Target Engagement Analysis and Retina-Targeted Delivery of 17β-Estradiol by the DHED Prodrug for Ocular Neurotherapy in Males

et al. 2021

View full text Add to dashboard Cite

show abstract

“…147 Interestingly, estrogen has been reported as having protective effects in glaucoma. 148 14 additional loci show significant effect size differences between ancestries, three of which also have significant difference in effect between males and females. Genes prioritized using TWAS that are near the lead variants for the loci these at show effect difference between the sexes have sex-biased gene expression patterns.…”

Section: Discussionmentioning

confidence: 96%

Genome-wide association meta-analysis identifies novel ancestry-specific primary open-angle glaucoma loci and shared biology with vascular mechanisms and cell proliferation

Faro

Bhattacharya

Zhou

et al. 2021

Preprint

View full text Add to dashboard Cite

Primary open-angle glaucoma (POAG) is a complex eye disease characterized by progressive loss of optic nerve function that, if untreated, ultimately leads to irreversible blindness. To date, the biological mechanisms causing POAG are still unclear. There is disparity in POAG prevalence, clinical presentations and outcomes across ancestries. Here, we aim to identify unique genetics that underlie risk to POAG and evaluate the potential connection with vascular mechanisms. We performed POAG meta-analysis across 15 biobanks that are part of the Global Biobank Meta-analysis Initiative, with two previously published multi-ancestry analyses for a total of 1,478,037 individuals from six ancestries (46,325 cases and 1,431,712 controls). A total of 109 genome-wide significantly associated loci (p<5e-8) were identified, 18 of which were novel. Three of these novel loci are ancestry-specific, two African-specific and the third specific to northern Europeans. We also identified five sex-specific novel loci, four of which are African-specific and one European-specific. To explore biological implications underlying these variant-trait associations, we performed gene enrichment analysis, gene prioritization analysis and transcriptome-wide association studies (TWAS) implicating genes related to vascular-related functions, blood vessels, angiogenesis, and cancer. A fifth of TWAS-prioritized genes with vascular-related and/or cell senescence/proliferation functional roles or have been implicated in vascular or neoplastic diseases are primary ciliary related genes. We further performed extensive statistical validation analysis of genes in the SIX6 and well-known CDKN2B-AS1 loci, previously implicated in POAG, cardiovascular diseases, and cancers across multiple ancestries. We found evidence of significant interaction between SIX6 rs33912345 and causal variants in chr9p21.3, with concomitant effect on expression of a primary cilia gene CDKN2A and CDKN2B at the CDKN2B-AS1 locus. Phenome-wide association analysis of POAG genetic risk burden across five biobanks and genetic correlation analysis also show the shared biology between POAG and vascular and neoplastic traits. In summary, our findings suggest that some POAG risk variants may be ancestry-specific, sex-specific, or both. Our findings further support the contribution of vascular and proliferation genes in POAG and suggest potential involvement of primary cilia in POAG pathogenesis.

show abstract

“…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 intraocular pressure (IOP) and aqueous outflow resistance), other ocular pathologies (e.g., AMD and dry eye) (Gibson et al 2017;Kaarniranta et al 2015;Patnaik et al 2020;Truong et al 2014) and has been suggested as a treatment for glaucoma (Vajaranant and Pasquale 2012;Fotesko et al 2020;Wei et al 2012;Yin and Liu 2008;Thaung Zaw et al 2018;Voogd et al 2008;Hutchinson et al 2014).…”

Section: Female Malementioning

confidence: 99%

“…In clinical populations, it is difficult to investigate menopause in isolation, because it is nearly impossible to separate menopause from aging. However, there is indirect evidence suggesting that menopause and estrogens modulate risk factors associated with glaucoma (e.g., IOP) and that the timing of menopause affects the risk of developing glaucoma (Vajaranant and Pasquale 2012 ; Fotesko et al 2020 ).…”

Section: Introductionmentioning

confidence: 99%

“…In this review, we aim to better understand if menopause and estrogen play a role in developing glaucoma. The topic of menopause, estrogen, and glaucoma has recently been discussed (Vajaranant and Pasquale 2012 ; Fotesko et al 2020 ; Wei et al 2012 ; Yin and Liu 2008 ); however, whether menopause or estrogen plays a role in glaucoma development is still debated. Therefore, instead of focusing on sex as a risk for glaucoma we ask the important question: “Is menopause a sex-specific risk factor for glaucoma?” We believe this question remains unsettled and attempt to better understand menopause as a sex-specific risk factor for developing glaucoma.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

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

2022

View full text Add to dashboard Cite

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. Graphical Abstract

show abstract

Girl Power in Glaucoma: The Role of Estrogen in Primary Open Angle Glaucoma

Cited by 10 publications

References 150 publications

Proteomics-Based Retinal Target Engagement Analysis and Retina-Targeted Delivery of 17β-Estradiol by the DHED Prodrug for Ocular Neurotherapy in Males

Proteomics-Based Retinal Target Engagement Analysis and Retina-Targeted Delivery of 17β-Estradiol by the DHED Prodrug for Ocular Neurotherapy in Males

Genome-wide association meta-analysis identifies novel ancestry-specific primary open-angle glaucoma loci and shared biology with vascular mechanisms and cell proliferation

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

Contact Info

Product

Resources

About