b'VA Researchers Look at Role of Estrogen, Menopause in Elevated RatesOf Glaucoma in WomenWomen represented less than 10% of U.S. veterans in 2017, according to the National Center for Veterans Analysis and Statistics, but the number of women veterans receiving VHA care has increased by 22.1%, from 423,642 in 2014 to 517,241 in 2018 and is predicted to burgeon even more in the future. Thats why studies such as one examining the role of estrogen and menopause in glaucoma are so important to the VA.By Brenda L. MooneyATLANTAMost, 59%, of the 41.3 mil- Cellular and Molecular Neurobiologylionpatientsworldwidewithglaucoma are women, who, even though they report10 (Minkin 2019; Monteleone etal. 2018; Nelson 2008; Taka-FemaleahigherrateofvisualimpairmentthanMale hashi and Johnson 2015).men, are 24% less likely to seek treatment(%) Age by Glaucoma of Prevalence 8 After puberty, a female has a menstrual cycle that nor-for the ophthalmologic condition. mally occurs once a month and typically occurs for the next Thatsaccordingtoastudyledbythe30years (Allshouse etal. 2018; ACOG Committee Opinion Atlanta VA Healthcare System and Emory6 No 2015). The menstrual cycle is regulated by hormones, University School of Medicine. The authorsincluding those produced by the pituitary gland (luteinizing advised that, based on the data, glaucoma4 hormone and follicle-stimulating hormone) which regu-affects women more severely than men andlate ovulation and ovarian function. The ovaries produce that the number of affected women remains2 estrogen and progesterone which stimulate the uterus and underreported.Unfortunately,inpreclini- breasts to prepare the body for fertilization (Mihm etal. cal research, female animals are frequently0 2011). Menopause, which marks the termination of ovar-omitted, with 75-82% of rodent studies only40-49 50-54 55-59 60-64 65-69 70-74 75-79 80+ Overall ian function, is defined as the absence of menstruation for usingmaleanimals. ThismakesitnearlyYears 12 contiguous months. However, a woman rarely becomes impossible to identify underlying causes ofmenopausal abruptly; it is common for a womans body to adiseaseorresponsivenesstodrugtreat- Fig. 1 Prevalence of any type of glaucoma by age between males andbegin transitioning through a period called perimenopause.ments that may differ between sexes. females by decade. Data were adapted from the NEI database. Over- Perimenopause typically begins in a womans 40s and all, females have a higher prevalence of glaucoma compared to males. TheirreportinCellularandMolecularThe relative prevalence of glaucoma in females appears to changehas several hallmark symptoms (Bacon 2017), including Neurobiologypointedout,however,thatthroughoutlife,withahigherprevalenceofglaucomainfemalespoor sleep, depression, vaginal dryness, dyspareunia, and theimportanceoffocusingonsex-basedoccurring in both the early decades (4059) and later stages of lifeseverely problematic vasomotor symptoms in 33% of women differences in glaucoma concerning disease(80+) compared to males. In comparison, the prevalence of glaucoma(hot flashes) (Santoro 2016). After perimenopause, women development,progressionandtreatmentin males tends to consistently increase with age become postmenopausal, often referred to as menopausal, hasbeenunderscoredbyrecentfundingSource: Douglass A, Dattilo M, Feola AJ. Evidence for Menopause as a Sex-Specific Risk Factor for Glaucoma. Cell Molat the average age of 51years old (Takahashi and Johnson policies, including the National InstitutesNeurobiol. 2022 Jan 4. doi: 10.1007/s10571-021-01179-z. Epub ahead of print. PMID: 34981287.with glaucoma (e.g., IOP) and that the timing of menopause2015; Santoro 2016; Gold etal. 2013). The age a woman ofHealth(NIH)andWomensVeteransaffects the risk of developing glaucoma (Vajaranant and Pas- enters menopause is complex, and there are many potential Health Research Network. 1 oftenconsidered,likelybecausesexhasnotbeen quale 2012; Fotesko etal. 2020). factors, including genetics, reproductive history, lifestyle, Thus,inglaucomatheimportanceofsexhasunequivocally identified as a risk factororlaucoma.f gIn this review, we aim to better understand if menopauseearly life, and social/environmental influences (Mishra etal. become more relevant, the authors wrote, Yet, theNotingthattheNationalEyeInstitute(NEI) and estrogen play a role in developing glaucoma. The topic2019). Women may enter premature menopause, defined as effect of sex-specific risk factors in glaucoma is notrecently reported that females in the United States of menopause, estrogen, and glaucoma has recently been dis- becoming post-menopausal before the age of 40, or early cussed (Vajaranant and Pasquale 2012; Fotesko etal. 2020;menopause which occurs between the ages of 40 and 45 Wei etal. 2012; Yin and Liu 2008); however, whether meno- (Mishra etal. 2019). Overall, data from the InterLACE 28 pause or estrogen plays a role in glaucoma development isconsortium suggest that 10% of women have premature or still debated. Therefore, instead of focusing on sex as a riskearly menopause (Mishra etal. 2019). For simplicity, in this for glaucoma we ask the important question: Is menopausereview, we will refer to early menopause as entering meno-a sex-specific risk factor for glaucoma? We believe thispause prior to the age of 45. This equals approximately 390 question remains unsettled and attempt to better understandmillion women who are expected to enter early menopause menopause as a sex-specific risk factor for developing glau- based on a global population of ~ 7.8 billion people in 2020. coma. In the following sections, we briefly outline meno- The postmenopausal phase transpires for the remainder of pause, estrogen signaling, and evidence that menopause isa womens life and on average accounts for 3040% of a considered a sex-specific risk factor for other pathologieswomans total lifespan.involving the cardiovascular and musculoskeletal systems.There are many health concerns associated with meno-Lastly, we will highlight recent literature that has shown howpause (Zhu etal. 2018; Asllanaj etal. 2019). Several studies menopause and estrogen play a role related to the develop- have shown that menopause directly impacts life expectancy ment and progression of glaucoma. and increases a womans risk for various diseases, includ-ing heart disease, strokes, osteoporosis, and diabetes (Inayat Menopause etal. 2017; Anagnostis etal. 2020; Muka etal. 2016; Scara-bin 2020; Jiang etal. 2019). Therefore, it is likely that estro-We present a short overview of menopause to provide insightgen and progesterone pathways play a key role in womens into its overall complexity and the importance of the hormo- health and are often researched as potential treatments after nal cycle throughout a womans life. This section is not anmenopause (Allen etal. 2015; Allenet al. 2016; Cutler exhaustive description of the hormonal cycle or menopause,etal. 2007; Lobo 2017; Thaung Zaw etal. 2018; Hulley and and we encourage readers to read more about the subjectGrady 2004). In this review we will focus on estrogen, which appears to be linked to risks associated with glaucoma (e.g., 1 3'