Ophthalmic Epidemiology, 2014; 21(2): 92–98 ! Informa Healthcare USA, Inc. ISSN: 0928-6586 print / 1744-5086 online DOI: 10.3109/09286586.2014.884602
ORIGINAL ARTICLE
Female Reproductive Factors and Major Eye Diseases in Asian Women –The Singapore Malay Eye Study Janice S. H. Lam1,2, Wan Ting Tay1, Tin Aung1,3, Seang Mei Saw1,3,4, and Tien Yin Wong1,2,3,4 1
Singapore Eye Research Institute, Singapore National Eye Centre, Singapore, 2Department of Ophthalmology, National University Health System, Singapore, 3Department of Ophthalmology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, and 4Department of Community, Occupational and Family Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
ABSTRACT Purpose: To examine the association of reproductive factors and major eye diseases, including glaucoma, age-related macular degeneration (AMD), diabetic retinopathy and cataract, in Asian women. Methods: The Singapore Malay Eye Study is a population-based cross-sectional epidemiological study which examined 3280 persons (78.7% response) of Malay ethnicity aged 40–80 years; 1704 were female. Information on reproductive factors and use of hormone replacement therapy (HRT) was collected using an intervieweradministered questionnaire. Glaucoma was defined according to the International Society for Geographical and Epidemiological Ophthalmology criteria. Retinal photographs were graded for AMD following the Wisconsin grading system, and diabetic retinopathy according to the modified Airlie House classification system. Cataract was graded according to the Lens Opacity Classification System III. Results: A total of 1176 women reported having experienced menopause by the time of the study with 1073 (91%) having a natural menopause, 88 (7.5%) a hysterectomy and 9 (0.8%) due to other reasons; HRT was used by 70 (6%) women. Women whose age at menopause was 52 years were 3.5 times more likely to have glaucoma (95% confidence interval, CI, 1.23–9.98, p value = 0.02) than those whose age at menopause was 53 years. Age of menopause was not associated with AMD (age-adjusted odds ratio, OR, 1.22, 95% CI 0.65–2.31), diabetic retinopathy (age-adjusted OR 1.01, 95% CI 0.66–1.54) or cataract (age-adjusted OR 1.38, 95% CI 0.95–2.00). Use of HRT was not associated with any of these eye diseases. Conclusion: Women who had menopause at a younger age were more likely to have glaucoma. This association needs to be confirmed in other studies.
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Keywords: Age of menopause, age-related macular degeneration, cataract, diabetic retinopathy, glaucoma
INTRODUCTION
There have been few studies that have examined whether female reproductive factors, such as age of menopause, and use of hormone replacement therapy, are associated with major eye diseases. The Blue Mountains Eye Study (BMES) and the Rotterdam Study, in Caucasian people, reported that early menopause increased the risk of AMD.6,7 The only Asian study that has analyzed potential associations of female reproductive factors with eye diseases was
Glaucoma, diabetic retinopathy, age-related macular degeneration (AMD) and cataracts are the leading causes of blindness and visual impairment worldwide.1–4 With global life expectancy of females far extending beyond their reproductive years, the potential influence of female hormones on these major eye diseases should be explored.5
Received 22 April 2013; Revised 5 August 2013; Accepted 9 August 2013; Published online 13 February 2014 Correspondence: Tien Yin Wong, MD, PhD, Executive Director, Singapore Eye Research Institute, Singapore National Eye Centre, 11 Third Hospital Avenue, Singapore 168751. E-mail: [email protected]
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Female Reproductive Factors & Eye Diseases: SiMES performed in a rural Indian population, and reported that neither age at menopause nor duration of endogenous estrogen exposure was associated with any of the major ocular diseases studied, namely age-related cataract, open-angle glaucoma, AMD and myopia.8 In this population-based study in an urban Asian population, we describe the association of female reproductive factors and major eye diseases in Malay females aged 40–80 years in Singapore.
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visual acuity, subjective refraction, ocular biometry, Goldmann applanation tonometry, slit-lamp biomicroscopy, optic disc imaging, digital lens and retinal photography. Blood and urine samples were collected for biochemical analyses, and stored for future studies. Selected participants also had gonioscopic examination, visual fields test, and assessment of ankle and brachial blood pressure to detect presence of peripheral vascular disease.
Diagnosis MATERIALS AND METHODS Study Design The Singapore Malay Eye Study was a populationbased, cross-sectional epidemiologic study of vision and major eye diseases in 3280 Malay adults aged 40– 80 years in Singapore, conducted from August 2004 to June 2006. Of these, 1704 were female. The study population and methodology have been described in previous reports.9,10 In brief, the Singapore Ministry of Home Affairs provided a list of names of 16,069 Malay persons living in 15 residential districts across the southwestern part of Singapore. An age-stratified, random sampling procedure was used to select a list of 5600 names for the study (1400 residents from each decade of 40–49, 50–59, 60–69, and 70–79 years). A person was considered ineligible if he/she had moved from the residential address, had not lived there in the past 6 months, or was deceased or terminally ill. Of the selected names, 4168 (74.4%) individuals were eligible to participate. Among eligible individuals, 831 (19.9%) declined to participate, and 57 (1.4%) could not be contacted, leaving 3280 (78.7% of 4168) who participated in the study. Ethics approval was obtained from the Institutional Review Board of the Singapore Eye Research Institute, and the study was conducted in accordance with the World Medical Association’s Declaration of Helsinki. Informed written consent was obtained from all participants.
Interview and Measurements Selected individuals were invited to a centralized clinic at Singapore Eye Research Institute by letter, telephone call and home visit. A detailed intervieweradministered questionnaire was administered to collect relevant sociodemographic and medical information. Female participants were asked questions on women’s health, such as age at menopause and the reasons for menopause (natural or otherwise). Participants underwent assessment of blood pressure, anthropometry, presenting and best-corrected !
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Glaucoma was defined according to the International Society of Geographical and Epidemiological Ophthalmology criteria.11 Category 1 cases were defined as optic disc abnormality (vertical cup-disc ratio, VDCR, or VCDR asymmetry 97.5th percentile or neuroretinal rim width between 11 and 1 o’clock or 5 and 7 o’clock 50.1 VCDR) with a corresponding glaucomatous visual field defect. Category 2 cases were defined as having a severely damaged optic disc (VCDR or VCDR asymmetry 99.5th percentile) in the absence of adequate performance in a visual field test. In diagnosing category 1 or 2 glaucoma, it was required that there should be no other explanation for the VCDR finding (dysplastic disc or marked anisometropia) or visual field defect (retinal vascular disease, macular degeneration, or cerebrovascular diseases). Category 3 cases were defined as subjects without visual field or optic disc data who were blind (corrected visual acuity53/60) and who had previous glaucoma surgery or had intraocular pressure (IOP) 499.5th percentile. Any woman with one or both eyes satisfying any of the three criteria was considered to have glaucoma in our analysis.12 Retinal photographs were taken of both eyes, graded for AMD following the Wisconsin age-related maculopathy grading system and diabetic retinopathy according to the modified Airlie House classification system, described in detail elsewhere.13,14 Early AMD was defined as either soft indistinct drusen, reticular drusen, or soft, distinct drusen plus retinal pigment epithelium (RPE) abnormalities, following the definition used in the BMES.15 Neovascular AMD lesions were defined as the presence of RPE detachment; neurosensory detachment; subretinal or sub-RPE hemorrhages; or intraretinal, subretinal, or sub-RPE scar tissue. Geographic atrophy was defined by presence of visible choroidal vessels and a discrete atrophic area with a sharp border with an area of 175 mm in diameter or more. Late AMD was defined as having either neovascular AMD or geographic atrophy.16 Diabetic retinopathy was considered present if any characteristic lesion as defined by the Early Treatment Diabetic Retinopathy Study severity scale was present: microaneurysms, hemorrhages, cotton wool
94 J. S. H. Lam et al. spots, intraretinal microvascular abnormalities, hard exudates, venous beading and new vessels.17 For each eye, a retinopathy severity score was assigned according to a scale modified from the Airlie House classification system, from level 10 indicating no retinopathy was present, to level 80 where total vitreous hemorrhage was present, which is discussed in detail elsewhere.14 Cataract was assessed by slit-lamp examination and graded according to the Lens Opacity Classification System III (LOCS III).18 Nuclear cataract was assessed for both opalescence and color and grading was done using standard techniques with a standard slide transparency of the LOCS III scale. Nuclear cataract opalescence and color, and cortical and posterior subcapsular cataracts were graded on a decimalized scale from 0 to 6.9. In the LOCS III, significant cataract is defined as nuclear grade for color or opalescence 4 or cortical or posterior subcapsular cataract grades 2.19,20
For risk factor analysis (e.g. age at menopause and cataract), we compared frequency of the risk factor (e.g. age at menopause) in people with and without the outcome of interest (e.g. cataract) using 2 tests. When analyzing age at menopause with the prevalence of the major eye diseases identified, age at menopause of 53 years was selected arbitrarily. This corresponded to the cut-off for the fourth quartile for age at menopause in our study population. Both continuous and categorical variables for age at menopause were analyzed to reflect that the protective effect of older age at menopause was consistent. We performed multiple logistic regression to control for effects of age, sex, and other potential confounders. For continuous traits, t-tests, analysis of variance, analysis of covariance and linear regressions models were used. In addition, both person-specific and eyespecific analyses were conducted, the latter using generalized estimating equation models.
RESULTS Data Analysis Statistical analysis was performed using standard statistical software (SPSS version 13, SPSS Inc, Chicago, USA). Prevalence estimates for all outcomes (visual impairment, cataract etc) were performed for the overall sample, and then in age- and sex-stratified groups. As our study population was selected using an age-stratified sampling technique, age-adjusted prevalence was calculated using direct adjustment to the Malay population from the 2000 Singapore Census. Differences in prevalence between agegroups and sex were analyzed using 2 tests.
Of the 3280 participants in the SiMES study, 1704 (52%) were female. Table 1 shows the characteristics of female participants with and without glaucoma. The crude prevalence of glaucoma in female Malays was 4.2%, with a mean age of 63.3 years. Physical characteristics of statistical significance (p50.05) include age, diastolic blood pressure, smoking status at time of study, level of education, IOP and presence of ocular hypertension. A total of 1176 women reported menstruation had ceased by the time of the study, of whom 1073 stopped naturally, 88 had had a hysterectomy and for
TABLE 1. Characteristics of female participants in the Singapore Malay Eye Study. Glaucoma Characteristic
Yes (n = 68)
No (n = 1636)
p Valuea
Age, mean years (SD) Age at menopause, mean years (SD) All post-menopausal women Natural menopause Hormone replacement therapy, n (%) Body mass index, mean kg/m2 (SD) Diabetes, n (%) Hypertension, n (%) Systolic blood pressure, mean mmHg (SD) Diastolic blood pressure, mean mmHg (SD) Total cholesterol, mean mmol/L (SD) Blood glucose, mean mmol/L (SD) HbA1c, mean % (SD) Current smoking, n (%) Primary education or lower, n (%) Intraocular pressure (larger of both eyes), mean mmHg (SD) Ocular hypertension, n (%) Myopia (SE 5 0.5D), (%)
63.3 (11.56)
57.8 (10.63)
50.001
48.5 49.2 2 26.8 19 43 152.6 75.6 5.5 7.1 6.6 5 61 18.2 11 27
(5.75) (4.93) (3.8) (6.33) (27.9) (63.2) (26.33) (9.65) (1.05) (3.43) (1.81) (7.5) (89.7) (8.35) (16.2) (43.5)
49.3 49.8 68 27.5 414 1176 149.0 78.3 5.8 6.9 6.5 43 1297 16.2 45 543
(5.28) (4.92) (6.1) (5.43) (25.3) (71.9) (27.75) (11.25) (1.17) (3.81) (1.65) (2.6) (79.4) (3.40) (2.8) (34.0)
0.30 0.39 0.49 0.36 0.63 0.12 0.24 0.05 0.06 0.62 0.69 0.02 0.04 50.001 50.001 0.12
a
p value for the difference in characteristics based on 2or t-test. HbA1c, glycated hemoglobin; SD, standard deviation Ophthalmic Epidemiology
Female Reproductive Factors & Eye Diseases: SiMES
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TABLE 2. Glaucoma risk distribution by groups of age at menopause, Singapore Malay Eye Study. Age at menopause, years
Glaucoma risk factors Systolic blood pressure, mean mmHg (SD) Diastolic blood pressure, mean mmHg (SD) Pulse pressure, mean mmHg (SD) Intraocular pressure (larger of both eyes), mean mmHg (SD) Ocular hypertension, n (%) Total cholesterol, mean mmol/L (SD) Current smoking, n (%)
553 (n = 868)
53 (n = 265)
153.6 78.3 75.3 16.2 33 5.9 18
154.1 77.9 76.1 16.4 11 5.9 3
(24.48) (11.32) (18.39) (3.96) (3.8) (1.22) (2.1)
p Valuea
(24.14) (11.42) (17.99) (3.30) (4.2) (1.21) (1.1)
0.78 0.67 0.53 0.52 0.80 0.70 0.32
a
p value for the difference in characteristics based on chi-square or t-test. SD, standard deviation
TABLE 3. Associations between reproductive factors and glaucoma in the Singapore Malay Eye Study. Glaucoma
Age at menopause (continuous) Age at menopause All post-menopausal women 553 years 53 years Natural menopause 553 years 53 years
At risk, n
n (%)
Age-adjusted OR (95% CI)
p Value
Multivariate adjusted OR (95% CI)a
p Value
1136
50 (4.4)
0.97 (0.93, 1.02)
0.27
0.95 (0.91, 1.00)
0.06
870 266
43 (4.9) 7 (2.6)
2.25 (0.99, 5.09) 1
0.05 –
3.44 (1.21, 9.78) 1
0.02 –
783 259
41 (5.2) 7 (2.7)
2.28 (1.00, 5.17) 1
0.05 –
3.54 (1.24, 10.12) 1
0.02 –
a
Adjusted for age, body mass index, myopia, glycated hemoglobin (HbA1c), pulse pressure and use of hormone replacement therapy. CI, confidence interval; OR, odds ratio
9 women it had stopped because of other reasons. Table 2 shows the glaucoma risk distribution by group dichotomized according to age at menopause. For the glaucoma risk factors identified, there was no statistically significant difference between women who experienced menopause before age 53 years and their peers who experienced menopause later. As shown in Table 3, women who had menopause at a younger age were more likely to have glaucoma: Age at menopause 52 years was associated with 3.5 times higher odds of glaucoma (95% confidence interval, CI, 1.21–9.78, p = 0.02) compared to age at menopause of 53 years and older. As shown in Table 4, age at menopause was not associated with AMD (multivariate-adjusted odds ratio, OR, 0.98, 95% CI 0.93–1.02), diabetic retinopathy (multivariate-adjusted OR 1.03, 95% CI 0.97–1.08) or cataract (multivariate-adjusted OR 1.02, 95% CI 0.98–1.06). Hormone replacement therapy was not associated with any of the four major eye diseases.
DISCUSSION In this population-based study among ethnic Malay women aged 40–79 years, we found that women who had menopause at a younger age were more likely to have glaucoma. Age at menopause was not associated !
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with AMD, diabetic retinopathy or cataract and use of hormone replacement therapy was not associated with any of the four major eye diseases. A comparison on the influence of early menopause on major eye diseases between different population studies is shown in Table 5. The Rotterdam Study was the only other study which found that open angle glaucoma was associated with menopause at a younger age (OR 2.6),21 similar to our results which showed 3.5 times higher odds of glaucoma in women who had experienced menopause before the age of 52 years. Our results could be related to several factors. A low level of circulating estrogen in postmenopausal women, as estrogen deficiency has been reported to lead to premature aging and increased susceptibility of the optic nerve to glaucomatous damage.22 A consequence of this is raised IOP within the eye, as demonstrated by a study of postmenopausal women which found that IOP in women on hormone replacement therapy was 1.41 mmHg lower than in those not on hormone replacement therapy.23 This rise in IOP, combined with increased susceptibility of the optic nerve resulting from the absence of circulating estrogens, may contribute to the development of glaucoma in post-menopausal women. The age at which menopause occurs also appears to be a factor in the development of glaucoma.
96 J. S. H. Lam et al. TABLE 4. Associations between reproductive factors and eye diseases, Singapore Malay Eye Study. Age-related macular degeneration
Age at menopause, continuous Age at menopause 553 years 53years
Diabetic retinopathy Multivariate adjusted OR (95% CI)b
Cataract Multivariate adjusted OR (95% CI)c
n (%)
Multivariate adjusted OR (95% CI)a
p Value
60 (5.3)
0.98 (0.93, 1.02)
0.3
139 (12.3) 1.03 (0.97, 1.08)
0.33
677 (64.7) 1.02 (0.98, 1.06)
0.29
47 (5.4) 13 (4.9)
1.22 (0.65, 2.31) 1
0.54 –
107 (12.4) 0.94 (0.50, 1.76) 32 (12.2) 1
0.84 –
507 (63.5) 1.28 (0.87, 1.88) 170 (68.5) 1
0.22 –
n (%)
p Value
n (%)
p Value
a
Adjusted for age, current smoking and use of hormone replacement therapy. Adjusted for age, glycated hemoglobin (HbA1c), duration of diabetes, systolic blood pressure, total cholesterol levels and use of hormone replacement therapy. c Adjusted for age, HbA1c, hypertension, myopia and use of hormone replacement therapy CI, confidence interval; OR, odds ratio b
TABLE 5. Risk of early menopause on major eye diseases among population-based studies. Risk of early menopause on prevalence of
Study Singapore Malay Eye Study Aravind Comprehensive Eye Survey Blue Mountains Eye Study Rotterdam Study
Mean age of Female participants Post-menopausal participants, at time of study, women, n years n (%) 1704
63.3
1176 (69)
5150
51.3
2072 3531
Glaucoma
Age-related Diabetic macular Cataract retinopathy degeneration
Yes (MVRR 3.5)
No
No
No
4192 (81.4)
No
No
–
No
66.4
1953 (96.1)
No
No
–
Yes
68.1
3342 (94.6)
Yes (OR 2.6)
–
–
Yes (RR 1.9)
MVRR, multivariable rate ratio; OR, odds ratio; RR, risk ratio
With 21.8% of Singaporean females living beyond the age of 65 years, longer exposure to the absence of circulating estrogens in women who experience menopause at an earlier age may contribute to their increased risk of optic nerve damage.24 In a report by Pasquale and co-authors, women entering menopause at age 50–54 years had an increased risk of primary open angle glaucoma compared to women entering menopause before age 45 years.25 This interesting finding may be explained by women who experience premature menopause before age 45 years would more likely be on hormone replacement therapy than those who experience menopause later to prevent the unwanted effects of early menopause. Evidence that estrogen and progesterone may serve protective roles in glaucoma prevention has been reported in recent experimental studies, which showed that implantation of 17-beta-estradiol pellets into female mice brought about a reduction in retinal ganglion cell loss and neurofibers through the inhibition of ganglion cell apoptosis.26–28 In addition, 17-beta-estradiol and progesterone play important roles in the regulation of synaptic plasticity and neurodegeneration.29–31 Developmentally, the optic
nerve and retinal ganglion cells are known as an extension of the central nervous system and neurodegenerative diseases affecting the brain and spinal cord have often shown manifestations within the eye.32 Hence, the protective effects of estrogen and progesterone in the central nervous system can be extrapolated to include the optic nerve and retina in the eye. Estrogen receptors have been found in the neural retinas of human and animal eyes.33,34 These receptors, when activated, have been shown to enhance the activity of endothelial-based type-3 nitric oxide synthase with resultant local release of nitric oxide causing vasodilation.35–38 In view of the role of ocular ischemia and increased vascular resistance in the development of glaucoma,38,39 a reciprocal lack of estrogen in post-menopausal women, and hence a reduction in estrogen receptor activation, may result in reduced levels of nitric oxide and subsequent vascular resistance and ischemia. Estrogen receptors localized in human neuroblastoma cells have shown a potent protection against apoptotic stimuli.40 Based on the premise that glaucoma is a neurodegenerative disease involving Ophthalmic Epidemiology
Female Reproductive Factors & Eye Diseases: SiMES apoptosis of retinal ganglion cells,41–44 it may also be extrapolated that the presence of these estrogen receptors within the human eye may protect against glaucoma development. A variable of possible importance which was not investigated in our study may be the interval between menarche and menopause. The BMES postulated that shorter exposure to endogenous female hormones may lead to an increased frequency of open-angle glaucoma,45 while the Rotterdam Study used age at natural menopause as a surrogate for endogenous estrogen exposure.21 However, with the age at menarche being a continuous variable, duration of exposure to endogenous estrogen may be more accurate in determining its role in glaucoma development. Hence, further research into this would be of interest for therapeutic reasons. Our study showed that menopause did not appear to be associated with the presence of AMD, cataract or diabetic retinopathy. This is supported by similar findings from the Aravind Comprehensive Eye Survey (Table 5), which reported that female reproductive factors did not appear to influence age-related cataract, macular degeneration or myopia.8 As these conditions are largely dependent on age and presence of diabetes, it is not surprising that female reproductive factors do not play a significant role in their pathogenesis. Strengths of our study include a large sample size, high response rate of 79% and the use of standardized protocols. However, our study has some limitations. First, the study was based on self-reporting of the age at and cause of menopause, hence recall bias could be important. Second, we measured IOP only once in each eye, which could be less sensitive than multiple IOP measurements. Although, according to the Singapore Census, the residents included in the study were a fair representation of the Singapore population in terms of age distribution, housing type and socioeconomic status, we cannot entirely exclude the possibility of selection bias. Methodologically, only ethnic Malay females were included in this study and hence women included in this analysis may differ from those excluded (other ethnicities). Last, we did not stratify the data to differentiate the effect of early menopause on open-angle versus angle-closure glaucoma, which could introduce additional bias as the pathophysiology of each type of glaucoma is different. In conclusion, our study shows that women who had menopause at a younger age were more likely to have glaucoma, possibly explained by a lack of circulating estrogen leading to optic nerve susceptibility to increased IOP in post-menopausal women. However, this association should be confirmed in other studies. We did not find age of menopause to be associated with AMD, diabetic retinopathy or cataract and use of hormone replacement therapy was not associated with any of these four major eye diseases. !
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DECLARATION OF INTEREST The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper. This study was supported by the National Medical Research Council (0796/2003, 0863/2004 and CSI/ 002/2005) and the Biomedical Research Council (501/ 1/25–5). Additional support was provided by the Ministry of Health, Singapore. The sponsors had no role in the study design, acquisition of data, statistical analysis and interpretation, and the final presentation and publication of this study.
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ORIGINAL ARTICLE
Female Reproductive Factors and Major Eye Diseases in Asian Women –The Singapore Malay Eye Study Janice S. H. Lam1,2, Wan Ting Tay1, Tin Aung1,3, Seang Mei Saw1,3,4, and Tien Yin Wong1,2,3,4 1
Singapore Eye Research Institute, Singapore National Eye Centre, Singapore, 2Department of Ophthalmology, National University Health System, Singapore, 3Department of Ophthalmology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, and 4Department of Community, Occupational and Family Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
ABSTRACT Purpose: To examine the association of reproductive factors and major eye diseases, including glaucoma, age-related macular degeneration (AMD), diabetic retinopathy and cataract, in Asian women. Methods: The Singapore Malay Eye Study is a population-based cross-sectional epidemiological study which examined 3280 persons (78.7% response) of Malay ethnicity aged 40–80 years; 1704 were female. Information on reproductive factors and use of hormone replacement therapy (HRT) was collected using an intervieweradministered questionnaire. Glaucoma was defined according to the International Society for Geographical and Epidemiological Ophthalmology criteria. Retinal photographs were graded for AMD following the Wisconsin grading system, and diabetic retinopathy according to the modified Airlie House classification system. Cataract was graded according to the Lens Opacity Classification System III. Results: A total of 1176 women reported having experienced menopause by the time of the study with 1073 (91%) having a natural menopause, 88 (7.5%) a hysterectomy and 9 (0.8%) due to other reasons; HRT was used by 70 (6%) women. Women whose age at menopause was 52 years were 3.5 times more likely to have glaucoma (95% confidence interval, CI, 1.23–9.98, p value = 0.02) than those whose age at menopause was 53 years. Age of menopause was not associated with AMD (age-adjusted odds ratio, OR, 1.22, 95% CI 0.65–2.31), diabetic retinopathy (age-adjusted OR 1.01, 95% CI 0.66–1.54) or cataract (age-adjusted OR 1.38, 95% CI 0.95–2.00). Use of HRT was not associated with any of these eye diseases. Conclusion: Women who had menopause at a younger age were more likely to have glaucoma. This association needs to be confirmed in other studies.
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Keywords: Age of menopause, age-related macular degeneration, cataract, diabetic retinopathy, glaucoma
INTRODUCTION
There have been few studies that have examined whether female reproductive factors, such as age of menopause, and use of hormone replacement therapy, are associated with major eye diseases. The Blue Mountains Eye Study (BMES) and the Rotterdam Study, in Caucasian people, reported that early menopause increased the risk of AMD.6,7 The only Asian study that has analyzed potential associations of female reproductive factors with eye diseases was
Glaucoma, diabetic retinopathy, age-related macular degeneration (AMD) and cataracts are the leading causes of blindness and visual impairment worldwide.1–4 With global life expectancy of females far extending beyond their reproductive years, the potential influence of female hormones on these major eye diseases should be explored.5
Received 22 April 2013; Revised 5 August 2013; Accepted 9 August 2013; Published online 13 February 2014 Correspondence: Tien Yin Wong, MD, PhD, Executive Director, Singapore Eye Research Institute, Singapore National Eye Centre, 11 Third Hospital Avenue, Singapore 168751. E-mail: [email protected]
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Female Reproductive Factors & Eye Diseases: SiMES performed in a rural Indian population, and reported that neither age at menopause nor duration of endogenous estrogen exposure was associated with any of the major ocular diseases studied, namely age-related cataract, open-angle glaucoma, AMD and myopia.8 In this population-based study in an urban Asian population, we describe the association of female reproductive factors and major eye diseases in Malay females aged 40–80 years in Singapore.
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visual acuity, subjective refraction, ocular biometry, Goldmann applanation tonometry, slit-lamp biomicroscopy, optic disc imaging, digital lens and retinal photography. Blood and urine samples were collected for biochemical analyses, and stored for future studies. Selected participants also had gonioscopic examination, visual fields test, and assessment of ankle and brachial blood pressure to detect presence of peripheral vascular disease.
Diagnosis MATERIALS AND METHODS Study Design The Singapore Malay Eye Study was a populationbased, cross-sectional epidemiologic study of vision and major eye diseases in 3280 Malay adults aged 40– 80 years in Singapore, conducted from August 2004 to June 2006. Of these, 1704 were female. The study population and methodology have been described in previous reports.9,10 In brief, the Singapore Ministry of Home Affairs provided a list of names of 16,069 Malay persons living in 15 residential districts across the southwestern part of Singapore. An age-stratified, random sampling procedure was used to select a list of 5600 names for the study (1400 residents from each decade of 40–49, 50–59, 60–69, and 70–79 years). A person was considered ineligible if he/she had moved from the residential address, had not lived there in the past 6 months, or was deceased or terminally ill. Of the selected names, 4168 (74.4%) individuals were eligible to participate. Among eligible individuals, 831 (19.9%) declined to participate, and 57 (1.4%) could not be contacted, leaving 3280 (78.7% of 4168) who participated in the study. Ethics approval was obtained from the Institutional Review Board of the Singapore Eye Research Institute, and the study was conducted in accordance with the World Medical Association’s Declaration of Helsinki. Informed written consent was obtained from all participants.
Interview and Measurements Selected individuals were invited to a centralized clinic at Singapore Eye Research Institute by letter, telephone call and home visit. A detailed intervieweradministered questionnaire was administered to collect relevant sociodemographic and medical information. Female participants were asked questions on women’s health, such as age at menopause and the reasons for menopause (natural or otherwise). Participants underwent assessment of blood pressure, anthropometry, presenting and best-corrected !
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Glaucoma was defined according to the International Society of Geographical and Epidemiological Ophthalmology criteria.11 Category 1 cases were defined as optic disc abnormality (vertical cup-disc ratio, VDCR, or VCDR asymmetry 97.5th percentile or neuroretinal rim width between 11 and 1 o’clock or 5 and 7 o’clock 50.1 VCDR) with a corresponding glaucomatous visual field defect. Category 2 cases were defined as having a severely damaged optic disc (VCDR or VCDR asymmetry 99.5th percentile) in the absence of adequate performance in a visual field test. In diagnosing category 1 or 2 glaucoma, it was required that there should be no other explanation for the VCDR finding (dysplastic disc or marked anisometropia) or visual field defect (retinal vascular disease, macular degeneration, or cerebrovascular diseases). Category 3 cases were defined as subjects without visual field or optic disc data who were blind (corrected visual acuity53/60) and who had previous glaucoma surgery or had intraocular pressure (IOP) 499.5th percentile. Any woman with one or both eyes satisfying any of the three criteria was considered to have glaucoma in our analysis.12 Retinal photographs were taken of both eyes, graded for AMD following the Wisconsin age-related maculopathy grading system and diabetic retinopathy according to the modified Airlie House classification system, described in detail elsewhere.13,14 Early AMD was defined as either soft indistinct drusen, reticular drusen, or soft, distinct drusen plus retinal pigment epithelium (RPE) abnormalities, following the definition used in the BMES.15 Neovascular AMD lesions were defined as the presence of RPE detachment; neurosensory detachment; subretinal or sub-RPE hemorrhages; or intraretinal, subretinal, or sub-RPE scar tissue. Geographic atrophy was defined by presence of visible choroidal vessels and a discrete atrophic area with a sharp border with an area of 175 mm in diameter or more. Late AMD was defined as having either neovascular AMD or geographic atrophy.16 Diabetic retinopathy was considered present if any characteristic lesion as defined by the Early Treatment Diabetic Retinopathy Study severity scale was present: microaneurysms, hemorrhages, cotton wool
94 J. S. H. Lam et al. spots, intraretinal microvascular abnormalities, hard exudates, venous beading and new vessels.17 For each eye, a retinopathy severity score was assigned according to a scale modified from the Airlie House classification system, from level 10 indicating no retinopathy was present, to level 80 where total vitreous hemorrhage was present, which is discussed in detail elsewhere.14 Cataract was assessed by slit-lamp examination and graded according to the Lens Opacity Classification System III (LOCS III).18 Nuclear cataract was assessed for both opalescence and color and grading was done using standard techniques with a standard slide transparency of the LOCS III scale. Nuclear cataract opalescence and color, and cortical and posterior subcapsular cataracts were graded on a decimalized scale from 0 to 6.9. In the LOCS III, significant cataract is defined as nuclear grade for color or opalescence 4 or cortical or posterior subcapsular cataract grades 2.19,20
For risk factor analysis (e.g. age at menopause and cataract), we compared frequency of the risk factor (e.g. age at menopause) in people with and without the outcome of interest (e.g. cataract) using 2 tests. When analyzing age at menopause with the prevalence of the major eye diseases identified, age at menopause of 53 years was selected arbitrarily. This corresponded to the cut-off for the fourth quartile for age at menopause in our study population. Both continuous and categorical variables for age at menopause were analyzed to reflect that the protective effect of older age at menopause was consistent. We performed multiple logistic regression to control for effects of age, sex, and other potential confounders. For continuous traits, t-tests, analysis of variance, analysis of covariance and linear regressions models were used. In addition, both person-specific and eyespecific analyses were conducted, the latter using generalized estimating equation models.
RESULTS Data Analysis Statistical analysis was performed using standard statistical software (SPSS version 13, SPSS Inc, Chicago, USA). Prevalence estimates for all outcomes (visual impairment, cataract etc) were performed for the overall sample, and then in age- and sex-stratified groups. As our study population was selected using an age-stratified sampling technique, age-adjusted prevalence was calculated using direct adjustment to the Malay population from the 2000 Singapore Census. Differences in prevalence between agegroups and sex were analyzed using 2 tests.
Of the 3280 participants in the SiMES study, 1704 (52%) were female. Table 1 shows the characteristics of female participants with and without glaucoma. The crude prevalence of glaucoma in female Malays was 4.2%, with a mean age of 63.3 years. Physical characteristics of statistical significance (p50.05) include age, diastolic blood pressure, smoking status at time of study, level of education, IOP and presence of ocular hypertension. A total of 1176 women reported menstruation had ceased by the time of the study, of whom 1073 stopped naturally, 88 had had a hysterectomy and for
TABLE 1. Characteristics of female participants in the Singapore Malay Eye Study. Glaucoma Characteristic
Yes (n = 68)
No (n = 1636)
p Valuea
Age, mean years (SD) Age at menopause, mean years (SD) All post-menopausal women Natural menopause Hormone replacement therapy, n (%) Body mass index, mean kg/m2 (SD) Diabetes, n (%) Hypertension, n (%) Systolic blood pressure, mean mmHg (SD) Diastolic blood pressure, mean mmHg (SD) Total cholesterol, mean mmol/L (SD) Blood glucose, mean mmol/L (SD) HbA1c, mean % (SD) Current smoking, n (%) Primary education or lower, n (%) Intraocular pressure (larger of both eyes), mean mmHg (SD) Ocular hypertension, n (%) Myopia (SE 5 0.5D), (%)
63.3 (11.56)
57.8 (10.63)
50.001
48.5 49.2 2 26.8 19 43 152.6 75.6 5.5 7.1 6.6 5 61 18.2 11 27
(5.75) (4.93) (3.8) (6.33) (27.9) (63.2) (26.33) (9.65) (1.05) (3.43) (1.81) (7.5) (89.7) (8.35) (16.2) (43.5)
49.3 49.8 68 27.5 414 1176 149.0 78.3 5.8 6.9 6.5 43 1297 16.2 45 543
(5.28) (4.92) (6.1) (5.43) (25.3) (71.9) (27.75) (11.25) (1.17) (3.81) (1.65) (2.6) (79.4) (3.40) (2.8) (34.0)
0.30 0.39 0.49 0.36 0.63 0.12 0.24 0.05 0.06 0.62 0.69 0.02 0.04 50.001 50.001 0.12
a
p value for the difference in characteristics based on 2or t-test. HbA1c, glycated hemoglobin; SD, standard deviation Ophthalmic Epidemiology
Female Reproductive Factors & Eye Diseases: SiMES
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TABLE 2. Glaucoma risk distribution by groups of age at menopause, Singapore Malay Eye Study. Age at menopause, years
Glaucoma risk factors Systolic blood pressure, mean mmHg (SD) Diastolic blood pressure, mean mmHg (SD) Pulse pressure, mean mmHg (SD) Intraocular pressure (larger of both eyes), mean mmHg (SD) Ocular hypertension, n (%) Total cholesterol, mean mmol/L (SD) Current smoking, n (%)
553 (n = 868)
53 (n = 265)
153.6 78.3 75.3 16.2 33 5.9 18
154.1 77.9 76.1 16.4 11 5.9 3
(24.48) (11.32) (18.39) (3.96) (3.8) (1.22) (2.1)
p Valuea
(24.14) (11.42) (17.99) (3.30) (4.2) (1.21) (1.1)
0.78 0.67 0.53 0.52 0.80 0.70 0.32
a
p value for the difference in characteristics based on chi-square or t-test. SD, standard deviation
TABLE 3. Associations between reproductive factors and glaucoma in the Singapore Malay Eye Study. Glaucoma
Age at menopause (continuous) Age at menopause All post-menopausal women 553 years 53 years Natural menopause 553 years 53 years
At risk, n
n (%)
Age-adjusted OR (95% CI)
p Value
Multivariate adjusted OR (95% CI)a
p Value
1136
50 (4.4)
0.97 (0.93, 1.02)
0.27
0.95 (0.91, 1.00)
0.06
870 266
43 (4.9) 7 (2.6)
2.25 (0.99, 5.09) 1
0.05 –
3.44 (1.21, 9.78) 1
0.02 –
783 259
41 (5.2) 7 (2.7)
2.28 (1.00, 5.17) 1
0.05 –
3.54 (1.24, 10.12) 1
0.02 –
a
Adjusted for age, body mass index, myopia, glycated hemoglobin (HbA1c), pulse pressure and use of hormone replacement therapy. CI, confidence interval; OR, odds ratio
9 women it had stopped because of other reasons. Table 2 shows the glaucoma risk distribution by group dichotomized according to age at menopause. For the glaucoma risk factors identified, there was no statistically significant difference between women who experienced menopause before age 53 years and their peers who experienced menopause later. As shown in Table 3, women who had menopause at a younger age were more likely to have glaucoma: Age at menopause 52 years was associated with 3.5 times higher odds of glaucoma (95% confidence interval, CI, 1.21–9.78, p = 0.02) compared to age at menopause of 53 years and older. As shown in Table 4, age at menopause was not associated with AMD (multivariate-adjusted odds ratio, OR, 0.98, 95% CI 0.93–1.02), diabetic retinopathy (multivariate-adjusted OR 1.03, 95% CI 0.97–1.08) or cataract (multivariate-adjusted OR 1.02, 95% CI 0.98–1.06). Hormone replacement therapy was not associated with any of the four major eye diseases.
DISCUSSION In this population-based study among ethnic Malay women aged 40–79 years, we found that women who had menopause at a younger age were more likely to have glaucoma. Age at menopause was not associated !
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with AMD, diabetic retinopathy or cataract and use of hormone replacement therapy was not associated with any of the four major eye diseases. A comparison on the influence of early menopause on major eye diseases between different population studies is shown in Table 5. The Rotterdam Study was the only other study which found that open angle glaucoma was associated with menopause at a younger age (OR 2.6),21 similar to our results which showed 3.5 times higher odds of glaucoma in women who had experienced menopause before the age of 52 years. Our results could be related to several factors. A low level of circulating estrogen in postmenopausal women, as estrogen deficiency has been reported to lead to premature aging and increased susceptibility of the optic nerve to glaucomatous damage.22 A consequence of this is raised IOP within the eye, as demonstrated by a study of postmenopausal women which found that IOP in women on hormone replacement therapy was 1.41 mmHg lower than in those not on hormone replacement therapy.23 This rise in IOP, combined with increased susceptibility of the optic nerve resulting from the absence of circulating estrogens, may contribute to the development of glaucoma in post-menopausal women. The age at which menopause occurs also appears to be a factor in the development of glaucoma.
96 J. S. H. Lam et al. TABLE 4. Associations between reproductive factors and eye diseases, Singapore Malay Eye Study. Age-related macular degeneration
Age at menopause, continuous Age at menopause 553 years 53years
Diabetic retinopathy Multivariate adjusted OR (95% CI)b
Cataract Multivariate adjusted OR (95% CI)c
n (%)
Multivariate adjusted OR (95% CI)a
p Value
60 (5.3)
0.98 (0.93, 1.02)
0.3
139 (12.3) 1.03 (0.97, 1.08)
0.33
677 (64.7) 1.02 (0.98, 1.06)
0.29
47 (5.4) 13 (4.9)
1.22 (0.65, 2.31) 1
0.54 –
107 (12.4) 0.94 (0.50, 1.76) 32 (12.2) 1
0.84 –
507 (63.5) 1.28 (0.87, 1.88) 170 (68.5) 1
0.22 –
n (%)
p Value
n (%)
p Value
a
Adjusted for age, current smoking and use of hormone replacement therapy. Adjusted for age, glycated hemoglobin (HbA1c), duration of diabetes, systolic blood pressure, total cholesterol levels and use of hormone replacement therapy. c Adjusted for age, HbA1c, hypertension, myopia and use of hormone replacement therapy CI, confidence interval; OR, odds ratio b
TABLE 5. Risk of early menopause on major eye diseases among population-based studies. Risk of early menopause on prevalence of
Study Singapore Malay Eye Study Aravind Comprehensive Eye Survey Blue Mountains Eye Study Rotterdam Study
Mean age of Female participants Post-menopausal participants, at time of study, women, n years n (%) 1704
63.3
1176 (69)
5150
51.3
2072 3531
Glaucoma
Age-related Diabetic macular Cataract retinopathy degeneration
Yes (MVRR 3.5)
No
No
No
4192 (81.4)
No
No
–
No
66.4
1953 (96.1)
No
No
–
Yes
68.1
3342 (94.6)
Yes (OR 2.6)
–
–
Yes (RR 1.9)
MVRR, multivariable rate ratio; OR, odds ratio; RR, risk ratio
With 21.8% of Singaporean females living beyond the age of 65 years, longer exposure to the absence of circulating estrogens in women who experience menopause at an earlier age may contribute to their increased risk of optic nerve damage.24 In a report by Pasquale and co-authors, women entering menopause at age 50–54 years had an increased risk of primary open angle glaucoma compared to women entering menopause before age 45 years.25 This interesting finding may be explained by women who experience premature menopause before age 45 years would more likely be on hormone replacement therapy than those who experience menopause later to prevent the unwanted effects of early menopause. Evidence that estrogen and progesterone may serve protective roles in glaucoma prevention has been reported in recent experimental studies, which showed that implantation of 17-beta-estradiol pellets into female mice brought about a reduction in retinal ganglion cell loss and neurofibers through the inhibition of ganglion cell apoptosis.26–28 In addition, 17-beta-estradiol and progesterone play important roles in the regulation of synaptic plasticity and neurodegeneration.29–31 Developmentally, the optic
nerve and retinal ganglion cells are known as an extension of the central nervous system and neurodegenerative diseases affecting the brain and spinal cord have often shown manifestations within the eye.32 Hence, the protective effects of estrogen and progesterone in the central nervous system can be extrapolated to include the optic nerve and retina in the eye. Estrogen receptors have been found in the neural retinas of human and animal eyes.33,34 These receptors, when activated, have been shown to enhance the activity of endothelial-based type-3 nitric oxide synthase with resultant local release of nitric oxide causing vasodilation.35–38 In view of the role of ocular ischemia and increased vascular resistance in the development of glaucoma,38,39 a reciprocal lack of estrogen in post-menopausal women, and hence a reduction in estrogen receptor activation, may result in reduced levels of nitric oxide and subsequent vascular resistance and ischemia. Estrogen receptors localized in human neuroblastoma cells have shown a potent protection against apoptotic stimuli.40 Based on the premise that glaucoma is a neurodegenerative disease involving Ophthalmic Epidemiology
Female Reproductive Factors & Eye Diseases: SiMES apoptosis of retinal ganglion cells,41–44 it may also be extrapolated that the presence of these estrogen receptors within the human eye may protect against glaucoma development. A variable of possible importance which was not investigated in our study may be the interval between menarche and menopause. The BMES postulated that shorter exposure to endogenous female hormones may lead to an increased frequency of open-angle glaucoma,45 while the Rotterdam Study used age at natural menopause as a surrogate for endogenous estrogen exposure.21 However, with the age at menarche being a continuous variable, duration of exposure to endogenous estrogen may be more accurate in determining its role in glaucoma development. Hence, further research into this would be of interest for therapeutic reasons. Our study showed that menopause did not appear to be associated with the presence of AMD, cataract or diabetic retinopathy. This is supported by similar findings from the Aravind Comprehensive Eye Survey (Table 5), which reported that female reproductive factors did not appear to influence age-related cataract, macular degeneration or myopia.8 As these conditions are largely dependent on age and presence of diabetes, it is not surprising that female reproductive factors do not play a significant role in their pathogenesis. Strengths of our study include a large sample size, high response rate of 79% and the use of standardized protocols. However, our study has some limitations. First, the study was based on self-reporting of the age at and cause of menopause, hence recall bias could be important. Second, we measured IOP only once in each eye, which could be less sensitive than multiple IOP measurements. Although, according to the Singapore Census, the residents included in the study were a fair representation of the Singapore population in terms of age distribution, housing type and socioeconomic status, we cannot entirely exclude the possibility of selection bias. Methodologically, only ethnic Malay females were included in this study and hence women included in this analysis may differ from those excluded (other ethnicities). Last, we did not stratify the data to differentiate the effect of early menopause on open-angle versus angle-closure glaucoma, which could introduce additional bias as the pathophysiology of each type of glaucoma is different. In conclusion, our study shows that women who had menopause at a younger age were more likely to have glaucoma, possibly explained by a lack of circulating estrogen leading to optic nerve susceptibility to increased IOP in post-menopausal women. However, this association should be confirmed in other studies. We did not find age of menopause to be associated with AMD, diabetic retinopathy or cataract and use of hormone replacement therapy was not associated with any of these four major eye diseases. !
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DECLARATION OF INTEREST The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper. This study was supported by the National Medical Research Council (0796/2003, 0863/2004 and CSI/ 002/2005) and the Biomedical Research Council (501/ 1/25–5). Additional support was provided by the Ministry of Health, Singapore. The sponsors had no role in the study design, acquisition of data, statistical analysis and interpretation, and the final presentation and publication of this study.
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Ophthalmic Epidemiology
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