Maturitas 83 (2016) 19–26

Contents lists available at ScienceDirect

Maturitas
journal homepage: www.elsevier.com/locate/maturitas

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 a b s t r a c t

Article history: Worldwide, the prevalence of moderate to severe visual impairment and blindness is 285 millions, with
Received 1 October 2015 65% of visually impaired and 82% of all blind people being 50 years and older. Meta-analyses have shown
Accepted 5 October 2015 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
Keywords: in access to cataract surgery is the major cause of the higher prevalence of blindness in women. In addi-
Age-related macular degeneration
tion to gender differences in cataract surgical coverage, population-based studies on the prevalence of
Aging
lens opacities indicate that women have a higher risk of developing cataract. Laboratory as well as epi-
Blindness
Cataract
demiologic studies suggest that estrogen may confer antioxidative protection against cataractogenesis,
Diabetic retinopathy but the withdrawal effect of estrogen in menopause leads to increased risk of cataract in women. For the
Estrogen other major age-related eye diseases; glaucoma, age-related macular degeneration (AMD) and diabetic
Eye disease retinopathy, data are inconclusive. Due to anatomic factors, angle closure glaucoma is more common in
Gender women, whereas the dominating glaucoma type; primary open-angle glaucoma (POAG), is more preva-
Glaucoma lent in men. Diabetic retinopathy also has a male predominance and vascular/circulatory factors have
Visual impairment been implied both in diabetic retinopathy and in POAG. For AMD, data on gender differences are con-
flicting 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. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
2. Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
3. Gender-based differences in visual impairment and blindness . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
4. Gender differences in specific age-related eye diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
4.1. Lens opacities and cataract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
4.2. Age-related macular degeneration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22
4.3. Glaucoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22
4.4. Diabetic retinopathy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23
5. Gender differences in access to health care . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23
6. Conclusion and future perspectives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23
Conflicts of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24
Contributor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24
Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24

∗ 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: madeleine.zetterberg@gu.se

http://dx.doi.org/10.1016/j.maturitas.2015.10.005
0378-5122/© 2015 Elsevier Ireland Ltd. All rights reserved.
20 M. Zetterberg / Maturitas 83 (2016) 19–26
1. Introduction
In the aging population, age-related cataract, age-related mac-
ular 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 differ-
ence 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 gen-
der 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 com-
mon 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; genet-
ical 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 enter-
ing 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 car-
diovascular 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 preva-
lence 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
GPx: Glutathione peroxidase; Mn-SOD: Manganese superoxide dismutase; NO:
nitric oxide; ROS: radical oxygen species.
of hypertension than men of the same age [8]. A summary of genet-
ical 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 dis-
eases 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 retinopa-
thy”, “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 glob-
ally 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 uncor-
rected 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 stud-
ies 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 defini-
tions and study designs are used; either population-based studies
 M. Zetterberg / Maturitas 83 (2016) 19–26 21

Table 2
Age-related eye diseases in men and women; prevalences, pathogenesis and effects of estrogen.

Eye disease/cause of visual Prevalence/Incidence Effect of endogenous and/or Proposed pathogenesis

impairment RR or OR Women vs Men exogenous estrogen

A.Higher prevalence in
women
Age-related cataract
Angle closure glaucoma (ACG)
65–74 yrs, M: 14–20%, F: 24–27% [13,16] Early menarche/late menopause Genetic factors [18,19]
beneficial [24–27] Oxidative stress [22]
No association with reproductive
span [99,100]
Protection from contraceptive
pills/HRT [24–27]
No effect/increased risk by HRT
[99,101]
OR F/M: 2.07 [51] anatomic factors [56,102–104]
RR F/M: 2.4 [53]
ratio F/M: 5:1 [54]
incidence ratio F/M: 10.6:5.5 per 100,000 [55]

B. Equal prevalence in men

and women or conflicting
data
Age-related macular degeneration
Pseudoexfoliation syndrome (XFS)
and pseudoexfoliative glaucoma
(XFG)
Equal prevalence, [37,38,105]: Early menarche/late menopause Oxidative stress, chronic
65–74 yrs, M: 6.8%, F: 9.2% beneficial [40,42,107] inflammation, angiogenesis
≥85 yrs, M: 29%, F: 27% No association with reproductive [34,44,111]
Increased risk in women: span [108]
Intermediate drusen: OR 1.20, 95% CI 1.01–1.43 Protection from OCs/HRT
[36]; OR 1.13, 95% CI 1.01–1.26 [106]; [42,109,110]
Large drusen: M: 8.1%, F: 19.6% [37] No effect/increased risk by HRT
Neovascular AMD: OR 1.2, 95% Crl 1.0–1.5 [41] [43,108]
Increased incidence in women: Genetic factors [63]
12-yrs-incidence: F:9.2%, M:6.6% [60] Vascular factors [113]
MVRR M/F: 0.32 95%CI:0.23-0.46 [62] Solar exposure [64,114]
Equal prevalence XFS (70–79 yrs):
M: 2.91%, F: 1.73% [112]
M: 31.3%, F: 40.5% [61]

C. Higher prevalence in
men
Primary open-angle glaucoma
(POAG)
Pigment dispersion glaucoma
Diabetic retinopathy
OR M/F: 1.37 [49] Increased risk by early menopause
OR M/F: 1.36 [47] [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; Decreased risk of diabetes by HRT
RR M/F: 1.17 [81] [88]
DM type 2, presence of DRP; Worsening during pregnancy [90]
RR M/F: 1.1 [86]
RR M/F: 2.1 [118]
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 require-
ment of visual impairment or studies on previous or current
cataract extraction rates. Regardless of the criteria used, most stud-
ies 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 Opaci-
fication Classification System (LOCSII or LOCSIII). Utilizing such
scales, several large epidemiologic studies have reported preva-
lences 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 preva-
lence 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-
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; corti-
cal cataract, which is also the subtype overrepresented in women
[13,16,23]. Data on gender differences in UVB exposure are conflict-
ing, 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 cataractogene-
sis. Several epidemiologic studies indicate a protective effect
of hormone replacement therapy (HRT) with estrogen in post-
menopausal women [24–27]. In addition, early menarche and/or
late menopause, thus a long reproductive life span, has been asso-
ciated 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 con-
centration at menopause, i.e. a withdrawal effect, that causes the
22 M. Zetterberg / Maturitas 83 (2016) 19–26
increased risk of cataract in women as compared to men of the
same age [9]. This theory is supported by data showing that pre-
menopausal 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 anti-
oxidative 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 estro-
gen 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 epithe-
lium 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 over-
representation 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 reproduc-
tive 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
effect at menopause. Indeed, several studies have shown a sig-
nificant 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 phar-
macologically, 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 pop-
ulations [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 glau-
coma (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 gen-
der 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]. Pseu-
doexfoliations are protein material that is deposited as fine granular
or flaky material in the anterior part of the eye. Pseudoexfolia-
tive material deposited in the chamber angle is believed to cause
 M. Zetterberg / Maturitas 83 (2016) 19–26
obstruction of aqueous humour leading to increased IOP. Both
exfoliation syndrome (XFS), i.e. the presence of pseudoexfolia-
tions 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 signifi-
cant 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 stud-
ies 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 demon-
strated 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 con-
flicting 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 neuropro-
tection [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 coun-
tries and in Eastern and Central Europe it is the fifth most common
cause of blindness as well as of moderate and severe visual impair-
ment [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 complica-
tion of diabetes. Diabetic retinopathy is a microvascular disorder
that is usually classified as either non-proliferative or prolifer-
ative. 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 mac-
ular edema, as defined by the Early Treatment Diabetic Retinopathy
Study research group [77]. Although laser photocoagulation still is
23
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 nat-
urally 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 retinopa-
thy 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 differ-
ence 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 stud-
ies 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 ther-
apeutic 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 wait-
ing 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 differ-
ence 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
24 M. Zetterberg / Maturitas 83 (2016) 19–26
women making a substantial number of them suffer from age-
related 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 vari-
ation, oxidative stress, inflammation, neurodegeneration, vascular
factors and anatomic differences have been suggested in the patho-
genesis 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 hor-
monal status on risk of age-related eye disease. More knowledge on
pathogenic mechanisms in ophthalmic disorders and the involve-
ment 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 edu-
cation of doctors”; ALFGBG-441721), Göteborg Medical Society,
Marianne and Marcus Wallenberg Foundation, Dr Reinhard Mar-
cuses Foundation, Konung Gustaf V:s och Drottning Victorias
Frimurarestiftelse, Hjalmar Svensson Foundation, Greta Anders-
son 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.
[12] H.A. Kahn, H.M. Leibowitz, J.P. Ganley, M.M. Kini, T. Colton, R.S. Nickerson,
T.R. Dawber, The Framingham Eye Study. I. Outline and major prevalence
findings, Am. J. Epidemiol. 106 (1) (1977) 17–32.
[13] B.E. Klein, R. Klein, K.L. Linton, Prevalence of age-related lens opacities in a
population. The Beaver Dam Eye Study, Ophthalmology 99 (4) (1992)
546–552.
[14] M. Lundstrom, U. Stenevi, W. Thorburn, Gender and cataract surgery in
Sweden 1992–1997. A retrospective observational study based on the
Swedish National Cataract Register, Acta Ophthalmol. Scand. 77 (2) (1999)
204–208.
[15] M. Lundstrom, U. Stenevi, W. Thorburn, The Swedish National Cataract
Register: a 9-year review, Acta Ophthalmol. Scand. 80 (3) (2002) 248–257.
[16] P. Mitchell, R.G. Cumming, K. Attebo, J. Panchapakesan, Prevalence of
cataract in Australia: the Blue Mountains Eye Study, Ophthalmology 104 (4)
(1997) 581–588.
[17] J.S. Zhang, L. Xu, Y.X. Wang, Q.S. You, J.D. Wang, J.B. Jonas, Five-year
incidence of age-related cataract and cataract surgery in the adult
population of greater Beijing: the Beijing Eye Study, Ophthalmology 118 (4)
(2011) 711–718.
[18] C.J. Hammond, D.D. Duncan, H. Snieder, M. de Lange, S.K. West, T.D. Spector,
C.E. Gilbert, The heritability of age-related cortical cataract: the twin eye
study, Invest. Ophthalmol. Vis. Sci. 42 (3) (2001) 601–605.
[19] C.J. Hammond, H. Snieder, T.D. Spector, C.E. Gilbert, Genetic and
environmental factors in age-related nuclear cataracts in monozygotic and
dizygotic twins, N. Engl. J. Med. 342 (24) (2000) 1786–1790.
[20] B.E. Lindblad, N. Hakansson, H. Svensson, B. Philipson, A. Wolk, Intensity of
smoking and smoking cessation in relation to risk of cataract extraction: a
prospective study of women, Am. J. Epidemiol. 162 (1) (2005) 73–79.
[21] H.R. Taylor, S.K. West, F.S. Rosenthal, B. Munoz, H.S. Newland, H. Abbey, E.A.
Emmett, Effect of ultraviolet radiation on cataract formation, N. Engl. J. Med.
319 (22) (1988) 1429–1433.
[22] D.C. Beebe, N.M. Holekamp, Y.B. Shui, Oxidative damage and the prevention
of age-related cataracts, Ophthalmic. Res. 44 (3) (2010) 155–165.
[23] A. Ostberg, A. Loth, D. Gustafson, B. Lindblom, Skovde cataract study: I:
Prevalence of lens opacities in a Swedish community, Ophthalmology 113
(6) (2006) 970–975.
[24] E.E. Freeman, B. Munoz, O.D. Schein, S.K. West, Hormone replacement
therapy and lens opacities: the Salisbury Eye Evaluation project, Arch.
Ophthalmol. 119 (11) (2001) 1687–1692.
[25] B.E. Klein, Lens opacities in women in Beaver Dam, wisconsin: is there
evidence of an effect of sex hormones, Trans. Am. Ophthalmol. Soc. 91
(1993) 517–544.
[26] B.E. Klein, R. Klein, L.L. Ritter, Is there evidence of an estrogen effect on
age-related lens opacities? The Beaver Dam Eye Study, Arch. Ophthalmol.
112 (1) (1994) 85–91.
[27] C. Younan, P. Mitchell, R.G. Cumming, J. Panchapakesan, E. Rochtchina, A.M.
Hales, Hormone replacement therapy, reproductive factors, and the
incidence of cataract and cataract surgery: the Blue Mountains Eye Study,
Am. J. Epidemiol. 155 (11) (2002) 997–1006.
[28] E. Barrett-Connor, J.E. Mueller, D.G. von Muhlen, G.A. Laughlin, D.L.
Schneider, D.J. Sartoris, Low levels of estradiol are associated with vertebral
fractures in older men, but not women: the Rancho Bernardo Study, J. Clin.
Endocrinol. Metab. 85 (1) (2000) 219–223.
[29] D. Celojevic, A. Petersen, J.O. Karlsson, A. Behndig, M. Zetterberg, Effects of
17beta-estradiol on proliferation, cell viability and intracellular redox status
in native human lens epithelial cells, Mol. Vis. 17 (2011) 1987–1996.
[30] X. Wang, J.W. Simpkins, J.A. Dykens, P.R. Cammarata, Oxidative damage to
human lens epithelial cells in culture: estrogen protection of mitochondrial
potential, ATP, and cell viability, Invest. Ophthalmol. Vis. Sci. 44 (5) (2003)
2067–2075.
[31] Vision. 2020. Right to sight. Blindness and visual impairment: Global facts.
cited 2015. Available from: http://www.iapb.org/vision-2020/global-facts.
[32] R.R. Bourne, J.B. Jonas, S.R. Flaxman, J. Keeffe, J. Leasher, K. Naidoo, M.B.
Parodi, K. Pesudovs, H. Price, R.A. White, T.Y. Wong, S. Resnikoff, H.R. Taylor,
Vision Loss Expert Group of the Global Burden of Disease S. Prevalence and
causes of vision loss in high-in come countries and in eastern and central
europe: 1990–2010, Br. J. Ophthalmol. 98 (5) (2014) 629–638.
[33] N. Congdon, B. O’Colmain, C.C. Klaver, R. Klein, B. Munoz, D.S. Friedman, J.
Kempen, H.R. Taylor, P. Mitchell, Eye Diseases Prevalence Research Group,
Causes and prevalence of visual impairment among adults in the United
States, Arch. Ophthalmol. 122 (4) (2004) 477–485.
[34] J. Ambati, B.K. Ambati, S.H. Yoo, S. Ianchulev, A.P. Adamis, Age-related
macular degeneration: etiology, pathogenesis, and therapeutic strategies,
Surv. Ophthalmol. 48 (3) (2003) 257–293.
[35] U. Schmidt-Erfurth, V. Chong, A. Loewenstein, M. Larsen, E. Souied, R.
Schlingemann, B. Eldem, J. Mones, G. Richard, F. Bandello, European Society
of Retina S. Guidelines for the management of neovascular age-related
macular degeneration by the European Society of Retina Specialists
(EURETINA), Br. J. Ophthalmol. 98 (9) (2014) 1144–1167.
[36] Age-Related Eye Disease Study Research Group, Risk factors associated with
age-related macular degeneration. A case-control study in the age-related
eye disease study: age-related eye disease study report number 3,
Ophthalmology 107 (12) (2000) 2224–2232.
[37] H. Buch, N.V. Nielsen, T. Vinding, G.B. Jensen, J.U. Prause, M. la Cour, 14-year
incidence, progression, and visual morbidity of age-related maculopathy:
the Copenhagen City Eye Study, Ophthalmology 112 (5) (2005) 787–798.
 M. Zetterberg / Maturitas 83 (2016) 19–26
[38] A. Laitinen, L. Laatikainen, T. Harkanen, S. Koskinen, A. Reunanen, A. Aromaa,
Prevalence of major eye diseases and causes of visual impairment in the
adult Finnish population: a nationwide population-based survey, Acta
Ophthalmol. 88 (4) (2010) 463–471.
[39] U. Chakravarthy, T.Y. Wong, A. Fletcher, E. Piault, C. Evans, G. Zlateva, R.
Buggage, A. Pleil, P. Mitchell, Clinical risk factors for age-related macular
degeneration: a systematic review and meta-analysis, BMC Ophthalmol. 10
(2010) 31.
[40] W. Smith, P. Mitchell, J.J. Wang, Gender, oestrogen, hormone replacement
and age-related macular degeneration: results from the Blue Mountains Eye
Study, Aust. N. Z. J. Ophthalmol. 25 (Suppl. 1) (1997) 13–15.
[41] A.R. Rudnicka, Z. Jarrar, R. Wormald, D.G. Cook, A. Fletcher, C.G. Owen, Age
and gender variations in age-related macular degeneration prevalence in
populations of European ancestry: a meta-analysis, Ophthalmology 119 (3)
(2012) 571–580.
[42] K.K. Snow, J. Cote, W. Yang, N.J. Davis, J.M. Seddon, Association between
reproductive and hormonal factors and age-related maculopathy in
postmenopausal women, Am. J. Ophthalmol. 134 (6) (2002) 842–848.
[43] R. Defay, S. Pinchinat, S. Lumbroso, C. Sutan, C. Delcourt, Pola Study Group,
Sex steroids and age-related macular degeneration in older French women:
the POLA study, Ann. Epidemiol. 14 (3) (2004) 202–208.
[44] J. Blasiak, G. Petrovski, Z. Vereb, A. Facsko, K. Kaarniranta, Oxidative stress,
hypoxia, and autophagy in the neovascular processes of age-related macular
degeneration, BioMed Res. Int. 2014 (2014), 768026.
[45] K. Kaarniranta, A. Machalinska, Z. Vereb, A. Salminen, G. Petrovski, A.
Kauppinen, Estrogen signalling in the pathogenesis of age-related macular
degeneration, Curr. Eye Res. 40 (2) (2015) 226–233.
[46] D.J. Calkins, Critical pathogenic events underlying progression of
neurodegeneration in glaucoma, Prog. Retin. Eye Res. 31 (6) (2012) 702–719.
[47] Y.C. Tham, X. Li, T.Y. Wong, H.A. Quigley, T. Aung, C.Y. Cheng, Global
prevalence of glaucoma and projections of glaucoma burden through 2040:
a systematic review and meta-analysis, Ophthalmology 121 (11) (2014)
2081–2090.
[48] H.A. Quigley, A.T. Broman, The number of people with glaucoma worldwide
in 2010 and 2020, Br. J. Ophthalmol. 90 (3) (2006) 262–267.
[49] A.R. Rudnicka, S. Mt-Isa, C.G. Owen, D.G. Cook, D. Ashby, Variations in
primary open-angle glaucoma prevalence by age, gender, and race: a
Bayesian meta-analysis, Invest. Ophthalmol. Vis. Sci. 47 (10) (2006)
4254–4261.
[50] S. Tehrani, Gender difference in the pathophysiology and treatment of
glaucoma, Curr. Eye Res. 40 (2) (2015) 191–200.
[51] S. Senthil, C. Garudadri, R.C. Khanna, K. Sannapaneni, Angle closure in the
Andhra Pradesh eye disease study, Ophthalmology 117 (9) (2010)
1729–1735.
[52] W. Song, L. Shan, F. Cheng, P. Fan, L. Zhang, W. Qu, Q. Zhang, H. Yuan,
Prevalence of glaucoma in a rural northern china adult population: a
population-based survey in kailu county, inner mongolia, Ophthalmology
118 (10) (2011) 1982–1988.
[53] S.K. Seah, P.J. Foster, P.T. Chew, A. Jap, F. Oen, H.B. Fam, A.S. Lim, Incidence of
acute primary angle-closure glaucoma in Singapore. An island-wide survey,
Arch. Ophthalmol. 115 (11) (1997) 1436–1440.
[54] P.H. Alsbirk, Anatomical risk factors in primary angle-closure glaucoma. A
ten year follow up survey based on limbal and axial anterior chamber
depths in a high risk population, Int. Ophthalmol. 16 (4-5) (1992) 265–272.
[55] J.C. Erie, D.O. Hodge, D.T. Gray, The incidence of primary angle-closure
glaucoma in Olmsted County, Minnesota, Arch. Ophthalmol. 115 (2) (1997)
177–181.
[56] W.S. Ng, G.S. Ang, A. Azuara-Blanco, Primary angle closure glaucoma: a
descriptive study in Scottish Caucasians, Clin. Exp. Ophthalmol. 36 (9)
(2008) 847–851.
[57] T.D. Keenan, R. Goldacre, M.J. Goldacre, Associations between primary open
angle glaucoma, Alzheimer’s disease and vascular dementia: record linkage
study, Br. J. Ophthalmol. 99 (4) (2015) 524–527.
[58] D. Moore, A. Harris, D. Wudunn, N. Kheradiya, B. Siesky, Dysfunctional
regulation of ocular blood flow: a risk factor for glaucoma? Clin.
Ophthalmol. 2 (4) (2008) 849–861.
[59] F. Jonasson, From epidemiology to lysyl oxidase like one (LOXL1)
polymorphisms discovery: phenotyping and genotyping exfoliation
syndrome and exfoliation glaucoma in Iceland, Acta Ophthalmol. 87 (5)
(2009) 478–487.
[60] A. Arnarsson, H. Sasaki, F. Jonasson, Twelve-year incidence of exfoliation
syndrome in the Reykjavik Eye Study, Acta Ophthalmol. 91 (2) (2013)
157–162.
[61] S. Astrom, H. Stenlund, C. Linden, Incidence and prevalence of
pseudoexfoliations and open-angle glaucoma in northern Sweden: II.
Results after 21 years of follow-up, Acta Ophthalmol. Scand. 85 (8) (2007)
832–837.
[62] J.H. Kang, S. Loomis, J.L. Wiggs, J.D. Stein, L.R. Pasquale, Demographic and
geographic features of exfoliation glaucoma in 2 United States-based
prospective cohorts, Ophthalmology 119 (1) (2012) 27–35.
[63] G. Thorleifsson, K.P. Magnusson, P. Sulem, G.B. Walters, D.F. Gudbjartsson, H.
Stefansson, T. Jonsson, A. Jonasdottir, A. Jonasdottir, G. Stefansdottir, G.
Masson, G.A. Hardarson, H. Petursson, A. Arnarsson, M. Motallebipour, O.
Wallerman, C. Wadelius, J.R. Gulcher, U. Thorsteinsdottir, A. Kong, F.
Jonasson, K. Stefansson, Common sequence variants in the LOXL1 gene
25
confer susceptibility to exfoliation glaucoma, Science 317 (5843) (2007)
1397–1400.
[64] J.H. Kang, J.L. Wiggs, L.R. Pasquale, Relation between time spent outdoors
and exfoliation glaucoma or exfoliation glaucoma suspect, Am. J.
Ophthalmol. 158 (3) (2014) 605–614, e601.
[65] H.G. Scheie, J.D. Cameron, Pigment dispersion syndrome: a clinical study, Br.
J. Ophthalmol. 65 (4) (1981) 264–269.
[66] W.E. Gillies, A.M. Brooks, Clinical features at presentation of anterior
segment pigment dispersion syndrome, Clin. Exp. Ophthalmol. 29 (3) (2001)
125–127.
[67] A.J. Lee, P. Mitchell, E. Rochtchina, P.R. Healey, S. Blue Mountains Eye,
Female reproductive factors and open angle glaucoma: the Blue Mountains
Eye Study, Br. J. Ophthalmol. 87 (11) (2003) 1324–1328.
[68] L.R. Pasquale, B.A. Rosner, S.E. Hankinson, J.H. Kang, Attributes of female
reproductive aging and their relation to primary open-angle glaucoma: a
prospective study, J. Glaucoma 16 (7) (2007) 598–605.
[69] J.A. Ebeigbe, P.N. Ebeigbe, A. Ighoroje, Ocular changes in pregnant Nigerian
women, Niger. J. Clin. Pract. 15 (3) (2012) 298–301.
[70] I.A. Qureshi, Measurements of intraocular pressure throughout the
pregnancy in Pakistani women, Chin. Med. Sci. J. 12 (1) (1997) 53–56.
[71] K.S. Na, D.H. Jee, K. Han, Y.G. Park, M.S. Kim, E.C. Kim, The ocular benefits of
estrogen replacement therapy: a population-based study in
postmenopausal Korean women, PLoS One 9 (9) (2014) e106473.
[72] N.L. Tint, P. Alexander, K.M. Tint, G.T. Vasileiadis, A.M. Yeung, A.
Azuara-Blanco, Hormone therapy and intraocular pressure in
nonglaucomatous eyes, Menopause 17 (1) (2010) 157–160.
[73] P.A. Newman-Casey, N. Talwar, B. Nan, D.C. Musch, L.R. Pasquale, J.D. Stein,
The potential association between postmenopausal hormone use and
primary open-angle glaucoma, JAMA Ophthalmol. 132 (3) (2014) 298–303.
[74] L.R. Pasquale, J.H. Kang, Female reproductive factors and primary open-angle
glaucoma in the Nurses’ Health Study, Eye (Lond.) 25 (5) (2011) 633–641.
[75] M.A. Arevalo, I. Azcoitia, L.M. Garcia-Segura, The neuroprotective actions of
oestradiol and oestrogen receptors, Nat. Rev. Neurosci. 16 (1) (2015) 17–29.
[76] N. Cheung, P. Mitchell, T.Y. Wong, Diabetic retinopathy, Lancet 376 (9735)
(2010) 124–136.
[77] ETDRS, Photocoagulation for diabetic macular edema. Early Treatment
Diabetic Retinopathy Study report number 1. Early treatment diabetic
retinopathy study research group, Arch. Ophthalmol. 103 (12) (1985)
1796–1806.
[78] G. Virgili, M. Parravano, F. Menchini, J.R. Evans, Anti-vascular endothelial
growth factor for diabetic macular oedema, Cochrane Database Syst. Rev. 10
(2014), PubMed CD007419.
[79] P.E. Wandell, A.C. Carlsson, Time trends and gender differences in incidence
and prevalence of type 1 diabetes in Sweden, Curr. Diabetes Rev. 9 (4)
(2013) 342–349.
[80] H.P. Hammes, W. Kerner, S. Hofer, O. Kordonouri, K. Raile, R.W. Holl,
D.P.-W.S. Group, Diabetic retinopathy in type 1 diabetes-a contemporary
analysis of 8784 patients, Diabetologia 54 (8) (2011) 1977–1984.
[81] M.S. Roy, R. Klein, B.J. O’Colmain, B.E. Klein, S.E. Moss, J.H. Kempen, The
prevalence of diabetic retinopathy among adult type 1 diabetic persons in
the United States, Arch. Ophthalmol. 122 (4) (2004) 546–551.
[82] N. Chaturvedi, A.K. Sjoelie, M. Porta, S.J. Aldington, J.H. Fuller, M. Songini,
E.M. Kohner, Study E.P.C. markers of insulin resistance are strong risk factors
for retinopathy incidence in type 1 diabetes, Diabetes Care 24 (2) (2001)
284–289.
[83] R. Klein, M.D. Knudtson, K.E. Lee, R. Gangnon, B.E. Klein, The Wisconsin
epidemiologic study of diabetic retinopathy XXIII: the twenty-five-year
incidence of macular edema in persons with type 1 diabetes,
Ophthalmology 116 (3) (2009) 497–503.
[84] D.S. Group, Age- and sex-specific prevalences of diabetes and impaired
glucose regulation in 13 European cohorts, Diabetes Care 26 (1) (2003)
61–69.
[85] G.Y. Ozawa, M.A. Bearse Jr., A.J. Adams, Male-female differences in diabetic
retinopathy? Curr. Eye Res. 40 (2) (2015) 234–246.
[86] K. Kostev, W. Rathmann, Diabetic retinopathy at diagnosis of type 2 diabetes
in the UK: a database analysis, Diabetologia 56 (1) (2013) 109–111.
[87] H.C. Looker, S.O. Nyangoma, D. Cromie, J.A. Olson, G.P. Leese, M. Black, J. Doig,
N. Lee, R.S. Lindsay, J.A. McKnight, A.D. Morris, S. Philip, N. Sattar, S.H. Wild,
H.M. Colhoun, Scottish Diabetic Retinopathy Screening C, Scottish Diabetes
Research Network Epidemiology G. Diabetic retinopathy at diagnosis of type
2 diabetes in Scotland, Diabetologia 55 (9) (2012) 2335–2342.
[88] J.E. Manson, et al., Menopausal hormone therapy and health outcomes
during the intervention and extended poststopping phases of the women’s
health initiative randomized trials, JAMA 310 (13) (2013) 1353–1368.
[89] E.D. Szmuilowicz, C.A. Stuenkel, E.W. Seely, Influence of menopause on
diabetes and diabetes risk, Nat. Rev. Endocrinol. 5 (10) (2009) 553–
558.
[90] C. Diabetes, Complications Trial Research Group, Effect of pregnancy on
microvascular complications in the diabetes control and complications trial.
The Diabetes Control and Complications Trial Research Group, Diabetes Care
23 (8) (2000) 1084–1091.
[91] S. Arber, J. McKinlay, A. Adams, L. Marceau, C. Link, A. O’Donnell, Patient
characteristics and inequalities in doctors’ diagnostic and management
strategies relating to CHD: a video-simulation experiment, Soc. Sci. Med. 62
(1) (2006) 103–115.
26 M. Zetterberg / Maturitas 83 (2016) 19–26
[92] A.R. Ulldemolins, V.C. Lansingh, L.G. Valencia, M.J. Carter, K.A. Eckert, Social
inequalities in blindness and visual impairment: a review of social
determinants, Indian J. Ophthalmol. 60 (5) (2012) 368–375.
[93] A. Rius, L. Artazcoz, L. Guisasola, J. Benach, Visual impairment and blindness
in spanish adults: geographic inequalities are not explained by age or
education, Ophthalmology 121 (1) (2014) 408–416.
[94] S. Lewallen, P. Courtright, Gender and use of cataract surgical services in
developing countries, Bull. World Health Org. 80 (4) (2002) 300–303.
[95] P.K. Nirmalan, A. Padmavathi, R.D. Thulasiraj, Sex inequalities in cataract
blindness burden and surgical services in south India, Br. J. Ophthalmol. 87
(7) (2003) 847–849.
[96] S. Lewallen, A. Mousa, K. Bassett, P. Courtright, Cataract surgical coverage
remains lower in women, Br. J. Ophthalmol. 93 (3) (2009) 295–298.
[97] M. Khairallah, R. Kahloun, S.R. Flaxman, J.B. Jonas, J. Keeffe, J. Leasher, K.
Naidoo, K. Pesudovs, H. Price, R.A. White, T.Y. Wong, S. Resnikoff, H.R. Taylor,
R.R. Bourne, Vision Loss Expert Group, Prevalence and causes of vision loss
in North Africa and the Middle East: 1990–2010, Br. J. Ophthalmol. 98 (5)
(2014) 605–611.
[98] G. Smirthwaite, M. Lundstrom, S. Albrecht, K. Swahnberg, Indication criteria
for cataract extraction and gender differences in waiting time, Acta
Ophthalmol. 92 (5) (2014) 432–438.
[99] G.L. Kanthan, J.J. Wang, G. Burlutsky, E. Rochtchina, R.G. Cumming, P.
Mitchell, Exogenous oestrogen exposure, female reproductive factors and
the long-term incidence of cataract: the Blue Mountains Eye Study, Acta
Ophthalmol. 88 (7) (2010) 773–778.
[100] K. Worzala, R. Hiller, R.D. Sperduto, K. Mutalik, J.M. Murabito, M. Moskowitz,
R.B. D’Agostino, P.W. Wilson, Postmenopausal estrogen use, type of
menopause, and lens opacities: the Framingham studies, Arch. Intern. Med.
161 (11) (2001) 1448–1454.
[101] B.E. Lindblad, N. Hakansson, B. Philipson, A. Wolk, Hormone replacement
therapy in relation to risk of cataract extraction: a prospective study of
women, Ophthalmology 117 (3) (2010) 424–430.
[102] R.J. Casson, D. Marshall, H.S. Newland, S. McGovern, J. Muecke, E.W. Tan, D.
Selva, T. Aung, Risk factors for early angle-closure disease in a Burmese
population: the Meiktila Eye Study, Eye (Lond.) 23 (4) (2009) 933–939.
[103] G.H. Van Rens, S.M. Arkell, W. Charlton, W. Doesburg, Primary angle-closure
glaucoma among Alaskan Eskimos, Doc. Ophthalmol. 70 (2-3) (1988)
265–276.
[104] L. Xu, W.F. Cao, Y.X. Wang, C.X. Chen, J.B. Jonas, Anterior chamber depth and
chamber angle and their associations with ocular and general parameters:
the Beijing Eye Study, Am. J. Ophthalmol. 145 (5) (2008) 929–936.e1.
[105] P. Mitchell, W. Smith, K. Attebo, J.J. Wang, Prevalence of age-related
maculopathy in Australia. The Blue Mountains Eye Study, Ophthalmology
102 (10) (1995) 1450–1460.
[106] J.R. Evans, Risk factors for age-related macular degeneration, Prog. Retin. Eye
Res. 20 (2) (2001) 227–253.
[107] J.R. Vingerling, I. Dielemans, J.C. Witteman, A. Hofman, D.E. Grobbee, P.T. de
Jong, Macular degeneration and early menopause: a case-control study, BMJ
310 (6994) (1995) 1570–1571.
[108] M.G. Erke, G. Bertelsen, T. Peto, A.K. Sjolie, H. Lindekleiv, I. Njolstad,
Lactation, female hormones and age-related macular degeneration: the
Tromso Study, Br. J. Ophthalmol. 97 (8) (2013) 1036–1039.
[109] D. Feskanich, E. Cho, D.A. Schaumberg, G.A. Colditz, S.E. Hankinson,
Menopausal and reproductive factors and risk of age-related macular
degeneration, Arch. Ophthalmol. 126 (4) (2008) 519–524.
[110] S. Fraser-Bell, J. Wu, R. Klein, S.P. Azen, R. Varma, Smoking, alcohol intake,
estrogen use, and age-related macular degeneration in Latinos: the Los
Angeles Latino Eye Study, Am. J. Ophthalmol. 141 (1) (2006) 79–87.
[111] K. Kinnunen, G. Petrovski, M.C. Moe, A. Berta, K. Kaarniranta, Molecular
mechanisms of retinal pigment epithelium damage and development of
age-related macular degeneration, Acta Ophthalmol. 90 (4) (2012) 299–309.
[112] C.A. McCarty, H.R. Taylor, Pseudoexfoliation syndrome in Australian adults,
Am. J. Ophthalmol. 129 (5) (2000) 629–633.
[113] W. Wang, M. He, M. Zhou, X. Zhang, Ocular pseudoexfoliation syndrome and
vascular disease: a systematic review and meta-analysis, PLoS One 9 (3)
(2014) e92767.
[114] L.R. Pasquale, A.Z. Jiwani, T. Zehavi-Dorin, A. Majd, D.J. Rhee, T. Chen, A.
Turalba, L. Shen, S. Brauner, C. Grosskreutz, M. Gardiner, S. Chen, S.
Borboli-Gerogiannis, S.H. Greenstein, K. Chang, R. Ritch, S. Loomis, J.H. Kang,
J.L. Wiggs, H. Levkovitch-Verbin, Solar exposure and residential geographic
history in relation to exfoliation syndrome in the United States and Israel,
JAMA Ophthalmol. 132 (12) (2014) 1439–1445.
[115] C.A. Hulsman, I.C. Westendorp, R.S. Ramrattan, R.C. Wolfs, J.C. Witteman, J.R.
Vingerling, A. Hofman, P.T. de Jong, Is open-angle glaucoma associated with
early menopause? The Rotterdam Study, Am. J. Epidemiol. 154 (2) (2001)
138–144.
[116] L.P. Doucette, A. Rasnitsyn, M. Seifi, M.A. Walter, The interactions of genes,
age, and environment in glaucoma pathogenesis, Surv. Ophthalmol. 60 (4)
(2015) 310–326.
[117] J. Caprioli, A.L. Coleman, Blood flow in Glaucoma D. Blood pressure,
perfusion pressure, and glaucoma, Am. J. Ophthalmol. 149 (5) (2010)
704–712.
[118] X. Zhang, J.B. Saaddine, C.F. Chou, M.F. Cotch, Y.J. Cheng, L.S. Geiss, E.W.
Gregg, A.L. Albright, B.E. Klein, R. Klein, Prevalence of diabetic retinopathy in
the United States, 2005–2008, JAMA 304 (6) (2010) 649–656.
[119] F. Semeraro, A. Cancarini, R. dell’Omo, S. Rezzola, M.R. Romano, C.
Costagliola, Diabetic eetinopathy vascular and inflammatory disease, J.
Diabetes Res. 2015 (2015) 582060.
[120] T. Behl, I. Kaur, A. Kotwani, Implication of oxidative stress in progression of
diabetic retinopathy, Surv. Ophthalmol. (June (11)) (2015), http://dx.doi.org/
10.1016/j.survophthal.2015.06.001, pii: S0039-6257(15)00100-9 [Epub
ahead of print].