Age-related eye disease and gender

G Model MAT-6494; No. of Pages 8

ARTICLE IN PRESS Maturitas xxx (2015) xxx–xxx

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Review article

Age-related eye disease and gender Madeleine Zetterberg a,b,∗ a Department of Clinical Neuroscience and Rehabilitation/Ophthalmology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden b Department of Ophthalmology at Sahlgrenska University Hospital, Mölndal, Sweden

a r t i c l e

i n f o

Article history: Received 1 October 2015 Accepted 5 October 2015 Available online xxx Keywords: Age-related macular degeneration Aging Blindness Cataract Diabetic retinopathy Estrogen Eye disease Gender Glaucoma Visual impairment

a b s t r a c t Worldwide, the prevalence of moderate to severe visual impairment and blindness is 285 millions, with 65% of visually impaired and 82% of all blind people being 50 years and older. Meta-analyses have shown that two out of three blind people are women, a gender discrepancy that holds true for both developed and developing countries. Cataract accounts for more than half of all blindness globally and gender inequity in access to cataract surgery is the major cause of the higher prevalence of blindness in women. In addition to gender differences in cataract surgical coverage, population-based studies on the prevalence of lens opacities indicate that women have a higher risk of developing cataract. Laboratory as well as epidemiologic studies suggest that estrogen may confer antioxidative protection against cataractogenesis, but the withdrawal effect of estrogen in menopause leads to increased risk of cataract in women. For the other major age-related eye diseases; glaucoma, age-related macular degeneration (AMD) and diabetic retinopathy, data are inconclusive. Due to anatomic factors, angle closure glaucoma is more common in women, whereas the dominating glaucoma type; primary open-angle glaucoma (POAG), is more prevalent in men. Diabetic retinopathy also has a male predominance and vascular/circulatory factors have been implied both in diabetic retinopathy and in POAG. For AMD, data on gender differences are conflicting although some studies indicate increased prevalence of drusen and neovascular AMD in women. To conclude, both biologic and socioeconomic factors must be considered when investigating causes of gender differences in the prevalence of age-related eye disease. © 2015 Elsevier Ireland Ltd. All rights reserved.

Contents 1. 2. 3. 4.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 Gender-based differences in visual impairment and blindness . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 Gender differences in specific age-related eye diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 4.1. Lens opacities and cataract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 4.2. Age-related macular degeneration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 4.3. Glaucoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 4.4. Diabetic retinopathy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 5. Gender differences in access to health care . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 6. Conclusion and future perspectives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 Conflicts of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 Contributor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

∗ Corresponding author at: Department of Clinical Neuroscience and Rehabilitation/Ophthalmology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden. E-mail address: [email protected] http://dx.doi.org/10.1016/j.maturitas.2015.10.005 0378-5122/© 2015 Elsevier Ireland Ltd. All rights reserved.

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Age-related

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(2015),

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1. Introduction In the aging population, age-related cataract, age-related macular degeneration (AMD), glaucoma, and diabetic retinopathy (DR) are prevalent in high numbers, with about 37%, 10%, 3%, and 2% of people 70–74 years old suffering from these conditions [1]. Even though the female to male ratio varies among these eye diseases, women are in majority among the blind and the visually impaired; about two of three blind people are women [2]. This gender difference may in part be explained by the longevity of women. Other causes however, such as differences in requirement for good vision in daily life activities, in the propensity to seek health care or gender inequity in access to health care, may also contribute to this discrepancy. In addition, life-style related factors, such as smoking and sun exposure, may differ between genders and thus influence the risk of eye diseases and its distribution between sexes. Lastly, there are sex-dependent biologic differences, which may affect the disease-causing pathogenic mechanisms. In all parts of the world and at all time periods for which data exist, the longevity pattern is the same; women live longer than men. In average, life expectancy for women is 5 years longer than for men [3]. Even though this difference is smaller in countries with high pediatric mortality and more pronounced in countries with a high overall longevity, women outlive men everywhere regardless of educational, economic, political and health critera [3]. Men have higher mortality rates than women for all the common death causes, including accidents, cardio- and cerebrovascular disorders, cancers, infections and chronic pulmonary disease [4]. Possible biologic explanations for gender-related differences in mortality and morbidity basically fall into two categories; genetical or hormonal. Genetic factors that favor female longevity are 1. the heterogametic sex hypothesis; 2. telomere attrition; and 3. mitochondrial inheritance. The importance of sexual hormones in aging is central in the reproductive theory of aging, according to which a dysfunctional hypothalmic-pituitary-gonodal (HPG) axis is associated with increased mortality in both sexes [5]. The longer life-span in women, which is even more pronounced in those entering menopause at higher age, and the fact that castrated men have the same life expectancy as women suggest that estrogens are beneficial in the aging process [6]. It is known that the risk of cardiovascular disease increases with high androgen levels and low estrogen levels both in men and in postmenopausal women [7]. Compared to premenopausal women, men have a higher prevalence of hypertension and a higher risk of cardiovascular disease. However, after menopause there is no gender difference in risk of cardiovascular disease and women even have a higher prevalence

Table 1 Biologic factors that may promote female longevity and health. A. Genetic factors 1. The heterogametic sex hypothesis 2. Telomere attrition 3. Mitochondrial inheritance B. Estrogen-mediated protection 1. Favorable distribution of body fat and beneficial lipid metabolization 2. Neuroprotective effects 3. Activation of immune system 4. Improved stress response 5. Anti-oxidative properties - ROS scavenging - Generation of NO which can neutralize ROS - Activation of the thioredoxin pathway - Upregulation/activation of Mn-SOD and GPx

of hypertension than men of the same age [8]. A summary of genetical and hormonal effects that may promote female longevity and health is shown in Table 1. For details on the listed mechanisms, see reviews by Austad and Zetterberg [4,9]. This review will focus on the four most common eye diseases in elderly people; age-related cataract, age-related macular degeneration, glaucoma and diabetic retinopathy. Gender-specific prevalences and possible mechanisms for any gender differences, as well as the effect of endogenous and/or exogenous estrogen, will be presented. Knowledge on sex-related effects on pathogenic mechanisms is important to understand the basis of disease and thus provide means for new therapies. Also, finding socioeconomic explanations to gender differences in disease prevalence, such as gender inequity in access to cataract surgery, is crucial for equal allocation of health care resources (Table 2). 2. Methods Data was identified through search in PubMed (http://www. ncbi.nlm.nih.gov/pubmed) using the terms “age-related macular degeneration”, “aging”, “blindness”, “cataract”, “diabetic retinopathy”, “estrogen”, “eye disease”, “gender”, “glaucoma” and “visual impairment”. Bibliographies from identified articles were used to further augment the search. By design, both summaries of previous reviews, older original articles and newer studies were included. Only articles written in English were included. There was no time limit for inclusion of the studies. 3. Gender-based differences in visual impairment and blindness The estimated number of people suffering from blindness globally is 32.4 millions [2]. For people with moderate and severe visual impairment (MSVI; decimal visual acuity of <0.3 but ≥0.05) the number is 191 millions [2]. The major cause of blindness globally is cataract, accounting for 51% of all blind people, whereas uncorrected refractive errors is the major cause of MSVI (43%) followed by cataract (33%) [10]. There are huge inequalities in the proportion of blind and visually impaired people between different regions of the world; for people older than 50 years, the prevalence of blindness and MSVI in African and Asian regions is in the range of 4–6% and 16–24% respectively with corresponding numbers in high-income regions of ≤0.4% and <5% [2]. In all regions of the world, the prevalence of blindness and MSVI after adjusting for age is higher for women than for men [2]. Globally, in 2010 women accounted for 60% of all blindness and 57% of all MSVI [2]. A bit surprisingly, two independent studies report a higher gender inequality in industrialized countries than in Africa [2,11]. In the Sub-Saharan African region, the ratio of blindness in women as compared to men was lowest; 1.11 to 1.13, as compared to high-income countries where the difference was more than 1.5 in favor of men [2]. One possible explanation is that the longer life-expectancy in women will result in a larger discrepancy in blindness and visual impairment between genders in high-income countries, where the difference in lifespan between men and women is bigger. 4. Gender differences in specific age-related eye diseases 4.1. Lens opacities and cataract When reporting the prevalence of cataract, a variety of definitions and study designs are used; either population-based studies

GPx: Glutathione peroxidase; Mn-SOD: Manganese superoxide dismutase; NO: nitric oxide; ROS: radical oxygen species.

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Table 2 Age-related eye diseases in men and women; prevalences, pathogenesis and effects of estrogen. Eye disease/cause of visual impairment

Prevalence/Incidence RR or OR Women vs Men

Effect of endogenous and/or exogenous estrogen

Proposed pathogenesis

A.Higher prevalence in women Age-related cataract

65–74 yrs, M: 14–20%, F: 24–27% [13,16]

Early menarche/late menopause beneficial [24–27] No association with reproductive span [99,100] Protection from contraceptive pills/HRT [24–27] No effect/increased risk by HRT [99,101]

Genetic factors [18,19] Oxidative stress [22]

Angle closure glaucoma (ACG)

B. Equal prevalence in men and women or conflicting data Age-related macular degeneration

Pseudoexfoliation syndrome (XFS) and pseudoexfoliative glaucoma (XFG)

C. Higher prevalence in men Primary open-angle glaucoma (POAG)

Pigment dispersion glaucoma Diabetic retinopathy

OR F/M: 2.07 [51] RR F/M: 2.4 [53] ratio F/M: 5:1 [54] incidence ratio F/M: 10.6:5.5 per 100,000 [55]

anatomic factors [56,102–104]

Equal prevalence, [37,38,105]: 65–74 yrs, M: 6.8%, F: 9.2% ≥85 yrs, M: 29%, F: 27% Increased risk in women: Intermediate drusen: OR 1.20, 95% CI 1.01–1.43 [36]; OR 1.13, 95% CI 1.01–1.26 [106]; Large drusen: M: 8.1%, F: 19.6% [37] Neovascular AMD: OR 1.2, 95% Crl 1.0–1.5 [41] Increased incidence in women: 12-yrs-incidence: F:9.2%, M:6.6% [60] MVRR M/F: 0.32 95%CI:0.23-0.46 [62] Equal prevalence XFS (70–79 yrs): M: 2.91%, F: 1.73% [112] M: 31.3%, F: 40.5% [61]

Early menarche/late menopause beneficial [40,42,107] No association with reproductive span [108] Protection from OCs/HRT [42,109,110] No effect/increased risk by HRT [43,108]

OR M/F: 1.37 [49] OR M/F: 1.36 [47]

Increased risk by early menopause [115] Protection by early menarche [67] Protection by late menopause [68] Protection by HRT [68,73] Increased risk by OCs [74]

RR M/F:1.63[65] DM type 1, advanced DRP; RR M/F: 1.17 [81] DM type 2, presence of DRP; RR M/F: 1.1 [86] RR M/F: 2.1 [118]

Oxidative stress, chronic inflammation, angiogenesis [34,44,111]

Genetic factors [63] Vascular factors [113] Solar exposure [64,114]

Decreased risk of diabetes by HRT [88] Worsening during pregnancy [90]

Genetic factors [116] Neurodegeneration [46] Impaired ocular blood flow/ocular perfusion pressure [58,117]

Anatomic factors [50] Auto-immune (type 1)/inflammation [119] Vascular (type 1/2) [119] Oxidative stress [120] Neuropathy (type 1/2) [85]

CI: confidence interval; F: female; HRT: hormone replacement therapy; M: male; MVRR: multivariate risk ratio; OCs: oral contraceptives; OR: odds ratio; RR: risk ratio.

on the presence of lens opacities with or without the requirement of visual impairment or studies on previous or current cataract extraction rates. Regardless of the criteria used, most studies report a higher prevalence of cataract in women than in men [12–15]. Grading and classification of cataract is often done using photography-based grading scales, most commonly the Lens Opacification Classification System (LOCSII or LOCSIII). Utilizing such scales, several large epidemiologic studies have reported prevalences of lens opacities of 24–27% for women and 14–20% for men aged 65–74 years [13,16]. Consistent for all these population-based studies is the higher prevalence of lens opacities in women as compared to men, with typical risk ratios between 1.14 and 1.33 [13,16,17]. In many parts of the world, especially in developed countries, the gender-difference in prevalence of lens opacities is also reflected in a higher incidence of cataract surgery in women than in men [14,15,17]. When trying to elucidate reasons for the difference in prevalence of cataract between genders, one must consider the already known risk factors for the disease. As shown by twin-studies, genetic factors explain 35% to 53% of the variation in onset or severity of disease, whereas age accounts for 16–38% and individ-

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ual environment, i.e. life style-related risk factors, contribute with 14–26% [18,19]. Regarding life style-related risks for cataract, there is considerable evidence from epidemiologic studies that smoking and UVB exposure are cataractogenic, implying oxidative stress as a causal or contributing factor [20–22]. UVB exposure is particularly associated with one of the three common forms of cataract; cortical cataract, which is also the subtype overrepresented in women [13,16,23]. Data on gender differences in UVB exposure are conflicting, but it has been suggested that the less prominent eye brows and forehead in women may confer less protection against sun light [9]. The difference in risk of cataract between genders has lead the attention to the role of estrogen in cataractogenesis. Several epidemiologic studies indicate a protective effect of hormone replacement therapy (HRT) with estrogen in postmenopausal women [24–27]. In addition, early menarche and/or late menopause, thus a long reproductive life span, has been associated with decreased risk of cataract [24–27]. Estrogen thus seems to have protective properties against lens opacification and it has been proposed that it is the dramatic reduction in estrogen concentration at menopause, i.e. a withdrawal effect, that causes the

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increased risk of cataract in women as compared to men of the same age [9]. This theory is supported by data showing that premenopausal women and age-matched men have the same risk of cataract [13,16]. The levels of estrogen in men, as produced through aromatization of testosterone, do not show the same age-related changes as in women and older men actually have higher levels of 17␤-estradiol than postmenopausal women [28]. As mentioned above, estrogens have been ascribed antioxidative properties, something that would explain their protective effects against cataract for which oxidative stress is considered the major pathogenic pathway [22]. The anti-oxidative effect of estrogen is probably conferred through several mechanisms, see Table 1. Indeed, studies on cultured lens epithelial cells have demonstrated protection against oxidative stress by 17␤-estradiol [29,30]. 4.2. Age-related macular degeneration The proportion of all blindness caused by AMD is estimated to 5% [31]. However, in high-income countries of Asia Pacific, Australia, Western Europe and high-income North America, AMD has become the most common cause of blindness [32]. In white persons in the United States, AMD accounts for as much as 54.4% of blind cases [33]. It has been speculated that with the growing proportion of elderly people along with increased access to cataract surgery and raised standard of living in developing countries, posterior segment diseases such as AMD, glaucoma and diabetic retinopathy are likely to become relatively more common as causes of visual impairment and blindness globally [10]. AMD is usually described as either dry, accounting for 80% of all AMD cases, or wet, accounting for the remainder. The dry form is characterized by atrophy of the retinal pigment epithelium underlying the sensory retina, leading to deterioration of the photoreceptors, whereas the wet form is caused by the growth of pathologic blood vessels from the choroid into the subretinal space, resulting in edema, hemorrhages and at the final stages discoid fibrosis in the central part of the macula [34]. Although dry AMD is by far the most prevalent form, the wet type is responsible for most of severe visual impairment or blindness in AMD. In recent years, antibodies against vascular endothelial growth factor (anti-VEGF) has emerged as a new therapeutic tool in wet AMD, improving the prognosis of patients who can now maintain and even recover some of their vision [35]. Apart from aging, reported risk factors for AMD are heredity, ethnicity with a higher risk of developing AMD in white people, smoking, obesity, hypertension, hyperopia and the presence of lens opacities [36]. Gender is usually not significantly associated with risk of AMD [37,38], although some studies indicate a small overrepresentation of women as compared to men [36,39]. Data from three major population-based studies; the Beaver Dam Eye Study, the Blue Mountain Eye Study and the Rotterdam Study of the Elderly yielded a pooled OR of 1.15 (95% CI 1.10–1.21) with increased risk for AMD in women [40]. However, while some studies indicate an elevated risk of extensive small and/or intermediate to large drusen in women [36,37], a meta-analysis of populations with European ancestry suggested an association of neovascular (wet) AMD with female gender (OR 1.2, 95% credible interval [Crl] 1.0–1.5) [41]. Endogenous or exogenous estrogen exposure also show conflicting results; early menarche and/or late menopause, i.e. a long reproductive period, as well as longer duration of lactation was associated with lower risk of AMD in some studies [40,42] and protective effects of HRT have been demonstrated [42], yet other reports have failed to show such effects [43]. Oxidative stress has been implied in the pathogenesis of AMD [44,45] so the same mechanism behind the slightly higher risk of AMD in women can be applied as in cataract formation, i.e. the anti-oxidative property of estrogen and the withdrawal Please cite this article in press as: M. http://dx.doi.org/10.1016/j.maturitas.2015.10.005

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effect at menopause. Indeed, several studies have shown a significant comorbidity between these diseases, suggesting common pathogenic pathways [37,39]. In contrast to cataract however, AMD is also characterized by chronic low-grade inflammation [45]. The anti-inflammatory properties of estrogen as well as its ability to regulate several signalling pathways are additional mechanisms that have been implied in AMD pathogenesis [45]. 4.3. Glaucoma Glaucoma is a neurodegenerative disease affecting the retinal ganglion cells, leading to thinning of the retinal nerve fibre layer and changes to the optic disc [46]. As a consequence, the patient will experience a progressive visual field loss that may eventually result in blindness. The intraocular pressure (IOP) is commonly elevated in glaucoma but high IOP is not required for diagnosis. There is no curative therapy for glaucoma but progression can be prevented or delayed by lowering the IOP, something that can be achieved pharmacologically, surgically or by laser treatment. Globally, glaucoma is the second most common cause of blindness and the third most common cause of visual impairment [31]. The global prevalence of glaucoma in people aged 40–80 years is 3.54%, with an estimated number of 64.3 million affected people, a number that is expected to increase to 111.8 million in 2040 [47]. Women are overrepresentated among glaucoma patients, with 59.1% of all cases being female [48]. However, this number is affected by differences in life-expectancy, since aging is a strong risk factor for glaucoma [49]. Also, the male:female ratio differs between various subtypes of glaucoma [50]. The two main types of glaucoma are defined by the anatomy of the anterior chamber and the chamber angle. Angle closure glaucoma (ACG), accounting for 26.0% of all glaucoma worldwide, is more prevalent in women and in Asian populations [48]. The prevalence of ACG in Chinese and Indian populations over 40 years of age has been reported to 1.26–1.5% [48,51,52]. In Singapore, the prevalence of ACG for people aged ≥50 years, was reported as high as 19.3% and the relative risk of ACG for women was 2.4 [53]. In the Greenland Eskimo population the female-to-male ratio was 5:1 [54]. Although the prevalence of ACG is lower in caucasian and black populations; 0.26–0.60% for people 40–80 years of age in 2013 [47], the increased risk of ACG in women compared to men is of similar magnitude as in Asian populations [55,56]. The most probable cause of the increased risk of ACG in women is anatomical, with women having shorter eyes and a more shallow anterior chamber leading to limited space in the chamber angle and impaired outflow of aqueous humour [50]. The predominant type of glaucoma globally, open angle glaucoma (OAG), accounts for 74.0% of the disease [48]. The majority of patients with OAG are denoted as primary open angle glaucoma (POAG), without known underlying causes, but secondary forms exist. Previous studies have shown conflicting data on the gender distribution in POAG. However, two large meta-analyses have recently demonstrated a male predominance in POAG, with very similar ORs of 1.37 and 1.36 respectively [47,49]. The reason for this gender difference is unknown, although it can be speculated that the male predominance in cardiovascular disease in general may explain part of this discrepancy. Some studies have suggested shared risk factors between POAG and vascular disease like diabetes and systemic hypertension and association of POAG with vascular dementia has been demonstrated [57]. In addition, impaired ocular blood flow and decreased perfusion pressure have been implied in the pathogenesis of POAG [58]. One type of secondary OAG with a high prevalence in the Scandinavian countries is exfoliation glaucoma (XFG) [59]. Pseudoexfoliations are protein material that is deposited as fine granular or flaky material in the anterior part of the eye. Pseudoexfoliative material deposited in the chamber angle is believed to cause Age-related

eye

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gender,

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(2015),

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obstruction of aqueous humour leading to increased IOP. Both exfoliation syndrome (XFS), i.e. the presence of pseudoexfoliations without manifest glaucoma, and XFG are more common in women; the 12-year incidence of XFS in the Icelandic population was 9.2% and 6.6% for women and men respectively [60]. Although the higher incidence of XFS and XFG in women has been confirmed in other populations, yet other studies could not find a significant prevalence difference between genders [61,62]. Regarding the pathogenesis of XFS, the discovery of the sequence variants in the lysyl oxidase 1-gene (LOXL-1) by Thorleifsson et al. in 2007, clearly demonstrated the strong genetic determinant in the disease [63]. However, associations with vascular disease and outdoor exposure has also been implied [64]. An additional form of secondary OAG is pigment dispersion glaucoma (PG), which affects about 25% of patients with pigment dispersion syndrome (PDS) [65], a condition in which pigment from the iris detaches and becomes dispersed throughout the anterior chamber, resulting in impaired outflow of aqueous humour and increased IOP. The risk of developing PG in patients with PDS is higher for men than for women; RR 1.63 for men versus women [65,66]. Also, the onset of glaucoma in PDS is earlier and the progress rate more aggressive in men than in women [66]. Since men in general have a deeper anterior chamber than women, the male predominance in PG may be an effect of the closer contact between the iris and the lens resulting in increased shedding of pigment from the heavily pigmented posterior side of the iris [50]. Regarding the role of hormones in glaucoma, several studies have suggested a protective role of endogenous estrogen in glaucoma. Early menarche and/or late menopause, i.e. a longer reproductive period, was associated with decreased risk of OAG in several studies [67,68]. The mechanism by which estrogen protects against glaucoma is not known, although it has been demonstrated that IOP decreases during pregnancy and increases after menopause, indicating a role for estrogen in IOP-regulation [69,70]. However, data on the effect of postmenopausal HRT on IOP is conflicting although one study reported lower prevalence of retinal nerve fiber defects in women with HRT [71,72]. Also, the use of exogenous estrogen in the form of HRT has shown protective effects against glaucoma in some studies [73]. but no such association was found in other studies and the use of contraceptive pills for ≥5 years was associated with increased risk of glaucoma [74]. In addition to IOP-regulating effects, estrogen is known to confer neuroprotection [75], something that could be of importance in preventing apoptosis of retinal ganglion cells. 4.4. Diabetic retinopathy Globally, diabetic retinopathy accounts for 1% of all visual impairment and 1% of total blindness [31]. In high-income countries and in Eastern and Central Europe it is the fifth most common cause of blindness as well as of moderate and severe visual impairment [32]. More importantly, diabetic retinopathy is the leading cause of preventable blindness in people of working age, with huge economic impact on society [76]. About a third of all diabetes patients, regardless of type, develop diabetic retinopathy [76], which is the most common complication of diabetes. Diabetic retinopathy is a microvascular disorder that is usually classified as either non-proliferative or proliferative. The latter is a more severe condition where pathologic blood vessels develop, leading to leakage, vitreous hemorrhage and eventually fibrotic strands from the retina into the vitreous with subsequent risk of tractional retinal detachment. In addition to proliferative and non-proliferative retinopathy, diabetes may also result in macular edema, termed clinically significant diabetic macular edema, as defined by the Early Treatment Diabetic Retinopathy Study research group [77]. Although laser photocoagulation still is Please cite this article in press as: M. http://dx.doi.org/10.1016/j.maturitas.2015.10.005

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the golden standard therapy in proliferative diabetic retinopathy, intravitreal anti-VEGF has become the first choice of treatment in clinically significant diabetic macular edema [78]. The gender specific prevalence of diabetic retinopathy is naturally dependent on, but not directly proportional to, the gender distribution of the entire diabetic population. Type I diabetes is more common in men than in women after the age of puberty [79], subsequently leading to a higher prevalence of diabetic retinopathy in men. In addition, male gender seems to be a risk factor for more advanced retinopathy [80,81]. However, most studies have not been able to detect a significant difference between men and women for risk of any/mild retinopathy or for clinically significant macular edema [82,83]. Although the prevalence of type 2 diabetes is higher in children and adolescents of female gender, most studies report a male predominance after the age of 20 or no gender difference at all [84,85]. Regarding the risk of diabetic retinopathy in type 2 diabetes, a majority of studies shows no gender differences but some studies indicate male gender as an independent risk factor, especially at the time of diagnosis [86,87]. The heterogenity in findings and small discrepancies regarding gender distribution in diabetic retinopathy indicate that other risk factors than gender are more important in its pathogenesis [85]. Some support for a role of estrogen in diabetes comes from studies showing decreased risk of developing diabetes in menopausal women taking exogenous estrogen, HRT [88,89]. In addition, the worsening of retinopathy during pregnancy, especially in diabetes type 1, is well established [90]. The basis for possible gender-based effects, estrogen-related or not, in pathogenesis are unknown. 5. Gender differences in access to health care Several studies have demonstrated lower diagnostic and therapeutic efforts in women [91,92]. Rius et al. demonstrated a higher disparity between diagnosis of cataract and rates of surgery among women than men, indicating that more women were waiting for cataract extraction, thus a lower therapeutic effort [93]. Since cataract is the leading cause of blindness worldwide, gender inequity in access to cataract surgery is a major cause of the higher prevalence of visual impairment and blindness in women [94,95]. A meta-analysis of population-based surveys from low- and middle income countries demonstrated higher cataract surgical coverage for men than women in 21 of 23 surveys [96]. In the same study, men were 1.71 times (Peto odds ratio, 95%CI 1.48 to 1.97) more likely to have cataract surgery than women and it was estimated that if gender inequity in access to cataract surgery was eliminated, blindness and severe visual impairment due to cataract could be reduced by 11% [96]. Possible explanations for the gender difference in cataract surgery in large parts of the world are the low female literacy, especially among the elderly, preventing women from information on the possibility of cataract surgery. They also have less access to family financial resources to pay for eye care or transportation to reach a hospital [97]. However, even in developed countries such as Sweden, where the majority of cataract surgeries are performed in women, female patients generally have poorer vision preoperatively and longer waiting times for surgery the men [98]. In addition to gender differences in prevalence of and surgery for cataract, in parts of the world where trachoma is prevalent, a preponderance of women with trichiasis and associated vision loss have been demonstrated [10]. The same reasoning on lack of information on the possibility of surgery for trichiasis and limited resources for eye care survices for women can be applied here. 6. Conclusion and future perspectives Women account for a majority of all blindness and this can be attributed to two main causes; 1. the relative longevity of Age-related

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women making a substantial number of them suffer from agerelated eye diseases, and 2. the relative lack of information and financial resources for women compared to men. The latter is valid for treatable conditions like cataract, where gender inequity in access to surgery prevails in large parts of the world. Apart from age and socioeconomic factors, biologic factors may explain gender differences in the prevalence of eye diseases. Genetic variation, oxidative stress, inflammation, neurodegeneration, vascular factors and anatomic differences have been suggested in the pathogenesis of cataract, glaucoma, age-related macular degeneration and diabetic retinopathy and some of these factors are under the influence of hormones. Studies on endogenous and exogenous estrogen exposure give some support for the importance of hormonal status on risk of age-related eye disease. More knowledge on pathogenic mechanisms in ophthalmic disorders and the involvement of genetic and/or hormonal factors may provide the basis for new therapeutic strategies. Until then, efforts must be made to diminish and eradicate gender differences in access to eye health care services. Conflicts of interest The author declare no conflict of interest. Contributor M.Z is the sole author and contributor for this article. Acknowledgements This work was supported by grants from the Sahlgrenska University Hospital (“Agreement concerning research and education of doctors”; ALFGBG-441721), Göteborg Medical Society, Marianne and Marcus Wallenberg Foundation, Dr Reinhard Marcuses Foundation, Konung Gustaf V:s och Drottning Victorias Frimurarestiftelse, Hjalmar Svensson Foundation, Greta Andersson Foundation, Herman Svensson Foundation, Ögonfonden, De Blindas Vänner and Kronprinsessan Margaretas Arbetsnämnd för Synskadade. References [1] R. Klein, B.E. Klein, The prevalence of age-related eye diseases and visual impairment in aging: current estimates, Invest. Ophthalmol. Vis. Sci. 54 (14) (2013) ORSF5–ORSF13. [2] G.A. Stevens, R.A. White, S.R. Flaxman, H. Price, J.B. Jonas, J. Keeffe, J. Leasher, K. Naidoo, K. Pesudovs, S. Resnikoff, H. Taylor, R.R. Bourne, Vision Loss Expert G. Global prevalence of vision impairment and blindness: magnitude and temporal trends, 1990–2010, Ophthalmology 120 (12) (2013) 2377–2384. [3] A.P. Moller, C.L. Fincher, R. Thornhill, Why men have shorter lives than women: effects of resource availability, infectious disease, and senescence, Am. J. Hum. Biol. 21 (3) (2009) 357–364. [4] S.N. Austad, Why women live longer than men: sex differences in longevity, Gend. Med. 3 (2) (2006) 79–92. [5] J.A. Yonker, V. Chang, N.S. Roetker, T.S. Hauser, R.M. Hauser, C.S. Atwood, Hypothalamic-pituitary-gonadal axis homeostasis predicts longevity, Age (Dordr.) 35 (1) (2013) 129–138. [6] J.B. Hamilton, G.E. Mestler, Mortality and survival: comparison of eunuchs with intact men and women in a mentally retarded population, J. Gerontol. 24 (4) (1969) 395–411. [7] C. Vitale, M. Fini, G. Speziale, S. Chierchia, Gender differences in the cardiovascular effects of sex hormones, Fundam. Clin. Pharmacol. 24 (6) (2010) 675–685. [8] L.L. Yanes, J.F. Reckelhoff, Postmenopausal hypertension, Am. J. Hypertens. 24 (7) (2011) 740–749. [9] M. Zetterberg, D. Celojevic, Gender and cataract—the role of estrogen, Curr. Eye Res. 40 (2) (2015) 176–190. [10] D. Pascolini, S.P. Mariotti, Global estimates of visual impairment: 2010, Br. J. Ophthalmol. 96 (5) (2012) 614–618. [11] I. Abou-Gareeb, S. Lewallen, K. Bassett, P. Courtright, Gender and blindness: a meta-analysis of population-based prevalence surveys, Ophthalmic Epidemiol. 8 (1) (2001) 39–56.

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(2015),