b'haveanoverallhigherprevalenceofalltypesofmodestly higher prevalence of glaucoma compared glaucoma compared to men2.21% in females vs.to similarly aged men.1.67% in malesresearchers said the difference isOne possible explanation for the difference, they not fully explained by the usual explanation. Thatadded, is that current epidemiological, clinical and essentially is that longer life expectancies in womenbasic science evidence suggest that estrogen plays ledtotheoverallhigherprevalenceofglaucoma,a role in the aging of the optic nerve. Circulating which increases with age. sexhormones,suchasestrogen,decreasewith Studyauthorsarguedthatthedifferenceinlifemenopause.expectancy cannot fully explain the overall higherThat led to an exploration of whether menopause prevalenceofalltypesofglaucomainfemales,is a sex-specific risk factor for glaucoma. To answer asmiddle-agedwomen(ages40-59)alsohaveathatquestion,researchersinvestigatedhowmeno-pause is defined as a sex-specific risk Cellular and Molecular Neurobiology factor for other pathologies, including tissues, including ligaments, bone, cartilage, cervix, and thecardiovasculardisease,osteoarthritis vagina (Feola etal. 2013; Moalli etal. 2008; Urbankovaand bone health. Next, they reviewed clinical evidence on the potential role etal. 2018; Lin etal. 2018; Komatsuda etal. 2006; Chenofmenopauseinglaucoma.They etal. 2000), by influencing multiple pathways that modu- also analyzed preclinical studies that late cellular responses to mechanical loads (Li etal. 2014b;showedgreatervisionandretinal Richette etal. 2003) and the production of matrix metallo- ganglioncell(RGC)lossfollowing proteinases and collagen (Elliot etal. 2008; Zong etal. 2007;surgicalmenopauseandhowestro-Moalli etal. 2002). The importance of estrogen signalinggen is protective in models of RGC and its response to mechanical loading has been highlightedinjury. The study team also explored by a study examining trabecular meshwork cells subjected tohowsurgicalmenopauseandestro-stretch from non-glaucomatous patients (Youngblood etal.gen signaling are related to risk fac-2020). Trabecular meshwork cells play an important role intors associated with developing glau-coma, including intraocular pressure, outflow resistance and these cells differently expressed estro- aqueous outflow resistance and ocular gen receptor 1 after stretch (Youngblood etal. 2020). There- biomechanics. fore, it is likely that the effects of menopause and estrogen signaling on ocular biomechanical properties are mediatedSex-Specific Factorthrough similar, if not the same, pathways. Theresultwasthehypothesisthat menopause potentially sets the stage todevelopglaucomaandtherefore Summary Fig. 8 Summary of the pathologies highlighted in this review, pro- isasex-specificriskfactorforthis portion of females in the affected population, and the current associa- disease.Menopause is well known to be involved as a sex-specifiction with menopause. In cardiovascular disease (CVD), osteoporosis,Some of the same researchers sug-and osteoarthritis (OA), menopause alone is considered a sex-specificgested that estrogen deficiency inten-risk factor in the pathogenesis of multiple systemic diseases,factor and early menopause further increases the risk of developingsifiesvisualimpairment,basedon such as cardiovascular disease, osteoarthritis, and osteopo- these pathologies. To date, menopause has not been determined totheir research with rats. That report, rosis (Fig.8). Menopause and estrogen signaling are alsobe associated with developing glaucoma and it is not a considerationwhichinvolvedexperimentalmeno-known to affect the biomechanical properties of multiple tis- when monitoring glaucoma progression or when deciding on treat- pause, was published in Experimental sues, including the vagina, the cervix, ligaments, bones, andment. However, we highlight the similarities of glaucoma to theseEye Research in 2019. 2other pathologies and propose that menopause is potentially a novel cartilage (Feola etal. 2013; Moalli etal. 2008; Urbankovasex-specific risk factor for developing glaucoma in females Inthemore-recentarticle,the etal. 2018; Lin etal. 2018; Komatsuda etal. 2006; Chenresearchersemphasizedthatunder-etal. 2000). Unfortunately, the role of menopause in glau- standingtheimpactofmenopause coma and its effect on ocular biomechanical properties is notSource: Douglass A, Dattilo M, Feola AJ. Evidence for Menopause as a Sex-Specific Risk Factor for Glaucoma. Cell Molonglaucomaandretinalganglion as clearly established. Neurobiol. 2022 Jan 4. doi: 10.1007/s10571-021-01179-z. Epub ahead of print. PMID: 34981287. cellsurvivalhaspotentialclinical In this review, we have highlighted multiple clinical andContinued on Page 32 upreclinical studies showing that menopause and estrogen signaling influence IOP, RGC survival after injury, aque- 29ous humor outflow resistance, and ocular biomechanics (Fig.9). Taken together, these studies strongly suggest that menopause and estrogen signaling modulate multiple fac-tors known to be associated with the development of and progression of glaucoma, including IOP, which is a major causal risk factor for developing glaucoma (Fig.3).Understanding how menopause influences the devel- Fig. 9 Illustration of how menopausal status and estrogens influence opment and progression of glaucoma may affect clinicalproperties throughout the eye. Several of these are direct risk factors decision-making when evaluating a woman with glaucomafor developing glaucoma (e.g., increasing IOP and outflow resistance and decreasing ocular stiffness). However, the role of menopause and or who is considered a glaucoma suspect. Knowledge ofestrogen on inflammatory mediators and retinal ganglion cell survival a womans reproductive status (i.e., premenopausal, peri- likely plays a key role in long-term ocular health and visionmenopausal, or postmenopausal) may influence a clinicians decision about when to initiate IOP lowering therapies and what is an appropriate therapeutic IOP target, given theestrogen-based treatment for glaucoma has been proposed effects of menopause on IOP. In addition and potentially(Wei etal. 2012; Wu etal. 2020; Dewundara etal. 2016); more important, further knowledge of the effects of meno- however, these treatments lack preclinical and clinical evi-pause and estrogen signaling on glaucoma will likely leaddence to support their widespread use. Based on the litera-to novel targets for glaucoma treatment. The concept of anture, glaucoma treatments developed around the impact of 1 3'