1 Department of Ophthalmology, University of Sydney, Westmead, New South Wales, Australia.
2 Westmead Millennium Institute, University of Sydney, Westmead, New South Wales, Australia.
3 Save Sight Institute, University of Sydney, Westmead, New South Wales, Australia.
4 Department of Public Health and Community Medicine, University of Sydney, Westmead, New South Wales, Australia.
![]() |
ABSTRACT |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
cataract; cataract extraction; hormone replacement therapy; incidence; women
Abbreviations: TGFß; transforming growth factor ß
![]() |
INTRODUCTION |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Postmenopausal estrogen has been shown to continue the relative cardiovascular (1517
) and bone (18
20
) protection of the reproductive years in women. Other protective functions have not been so clearly proven. The cause of the gender differences in cataract occurrence is not clear but could be related to the hormonal differences between women and men (21
23
). The Blue Mountains Eye Study is a population-based study in which a detailed reproductive history was taken at baseline. This has enabled a body of information to be collected regarding endogenous and exogenous exposure to estrogen and other hormones.
The Blue Mountains cross-sectional data (23) have shown that current users of hormone replacement therapy aged 65 years or older have lower rates of cortical cataract. Current or past use was associated with increased rates of posterior subcapsular cataract. Women with a later age at menarche had an increased prevalence of cortical and nuclear cataract. Prevalent data from the Beaver Dam Eye Study (21
) have found that current and longer duration of estrogen therapy, as well as ever use of the oral contraceptive pill, is protective for nuclear cataract. Although earlier age at menarche decreased the prevalence of nuclear cataract, older age at menopause decreased the rates of cortical cataract. Recently the Beaver Dam Eye Study (24
) has assessed possible associations between reproductive exposures and incident cataract. The only significant finding was a trend of decreasing incident posterior subcapsular cataract with increasing numbers of livebirths. This proposed protective role of estrogen is supported by laboratory findings, in which estrogen has been shown to directly protect in animal models of cataract (25
, 26
).
In view of the evidence of higher cataract rates among older women, we aimed in this report to assess the role of particular female reproductive hormonal exposures in relation to incident cataract and cataract surgery in a cohort of older Australian women. These findings could act as a stimulus for further clinical and laboratory-based studies of risk factors for age-related cataract.
![]() |
MATERIALS AND METHODS |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Cataract grading
Cataract was documented from both slit-lamp (Topcon SL-7e camera; Topcon Optical Co., Tokyo, Japan) and retroillumination (Neitz CT-R cataract camera; Neitz Instrument Co., Tokyo, Japan) lens photographs. Details of the photographic technique and grading used have been previously reported (9, 27
). The grading closely followed the Wisconsin Cataract Grading System (29
), with good agreement found for assessments of both inter- and intragrader reliability (9
). A history of past cataract surgery was taken and confirmed at both the examination and photographic grading. The presence of nuclear, cortical, and posterior subcapsular cataract was assessed for each eye (29
). The presence and severity of nuclear cataract (opacification of the central lens) were defined on a five-level scale by comparison with a set of four standard slit-lamp photographs; level four or level five was defined as positive for nuclear cataract. The percentage area involved by cortical (opacification of the outer lens) or posterior subcapsular (opacity at the back of the lens) cataract in each eye was calculated from the estimated percentage area involved in each of nine lens segments divided by a grid (29
). Cortical opacity involving
5 percent of the total lens area or the presence of any posterior subcapsular cataract was defined as positive for these two cataract types.
Two definitions were used to determine the subjects at risk of developing incident cataract. Initially analyses were run only with women who had both lenses and who did not have the outcome cataract type present in either eye at baseline; women who developed that cataract type in one or both eyes were considered "first eye" incident cases. Women who were bilaterally phakic at baseline (whether or not cataract was present) and had undergone cataract surgery in one or both eyes at follow-up were also considered "first eye" incident cases. To further assess these associations, we ran the analyses again with the addition of women who had only a single eye at risk, either because they had a cataract or because they were aphakic in one eye at baseline. This combined group of women were considered "any eye" incident cases. The difference between the two groups is that "first eye" cases had neither eye affected at baseline, and "any eye" cases had either no eyes or one eye affected at baseline, regardless of whether one or two eyes were affected at follow-up. This added 60 cases (31.1 percent of the new total) to cortical, 64 cases (24.0 percent) to nuclear, and 11 cases (20.8 percent) to posterior subcapsular cataract, as well as 12 cases (13.5 percent) to cataract surgery incidence. The results presented are for the risk of cataract in the first eye, unless otherwise stated.
Questionnaire and definitions
In the baseline questionnaire, a detailed female medical history was taken, including the age at menarche and menopause, the reason for menopause, and the history of hysterectomy and ovariectomy, pregnancy, parity, and ever use of hormone replacement therapy and the oral contraceptive pill. Participants were asked to bring with them all their current medications, including hormone replacement therapy. These were then recorded on their medication list. If there were any discrepancies between the history and the medication list, the information provided by the medication list was used. A list of any past medications taken for at least 3 months was also recorded. Women using hormone patches were included in statistical analyses, but those using creams were excluded.
Women who had stated that they had ever used hormone replacement therapy but did not know the name or preparation type were included in analyses of ever users but were excluded from analyses of current users in which estrogen and combined preparations were compared. Surgical menopause was defined as the cessation of menstrual periods after an ovariectomy. Women who stated that they had a natural menopause, plus those who had a hysterectomy without ovariectomy, were all considered to have had a natural menopause. The duration of endogenous estrogen was defined in postmenopausal women as the number of years between the ages at menopause and menarche. Analyses for the age at menopause and the duration of endogenous estrogen excluded 173 women who had no ovariectomy following premenopausal hysterectomy, as the age at hysterectomy would underestimate the age at menopause, and our data could not otherwise estimate this variable. Women with data missing for menopausal status, but who were aged 65 years or more, were considered postmenopausal.
During their interview, women were asked about smoking and current alcohol consumption, their history of oral or inhaled steroid use, and whether a doctor had diagnosed diabetes or hypertension. Systolic and diastolic blood pressure was measured while seated prior to instillation of any eye drops. Hypertension was defined either by history and/or a systolic measurement above 160 mmHg and/or a diastolic measurement above 95 mmHg. Higher educational achievement was defined as attainment of a qualification (certificate, diploma, or degree) after leaving school.
Statistical analysis
Statistical analyses were predominantly by logistic regression models to assess associations by subject. In the first Blue Mountains Eye Study that assessed possible associations among hormone replacement therapy, reproductive factors, and prevalent cataract, analyses were performed with nuclear cataract as a five-level variable and both cortical and posterior subcapsular cataract as three-level variables according to grading severity (23). When analyses were repeated with cataract type as a dichotomous variable, no differences were noted. Here we present analyses with cataract type as a dichotomous variable.
Multivariate logistic regression models accounted for the following potential confounding factors: age (categorized in 10-year intervals), smoking (ever vs. never), current alcohol consumption (drinks per week), ever use of oral or inhaled steroids, history of diabetes or hypertension, and educational achievement. These were chosen, as described by Cumming and Mitchell (23), because of their association with at least one type of cataract or uneven distribution across categories of use of hormone replacement therapy. Dark brown iris color was also included because of its recently reported association with cataract in this (30
) and other (10
, 11
) populations. The duration of use of hormone replacement therapy, the duration of exposure to endogenous estrogen, and the ages at menarche and menopause were categorized as presented in the tables. Tests for trend in duration were performed by modeling the median duration (in years) in each category as a single continuous variable.
Statistical Analysis System version 6.12 software (SAS Institute, Inc., Cary, North Carolina) was used for analyses. A p value of less than 0.05 was used to indicate statistical significance. Odds ratios and 95 percent confidence intervals are presented.
![]() |
RESULTS |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
|
There were no significant differences in age between those women who reported current hormone replacement therapy use at follow-up and women who had reported no prior use (mean age, 61.6 years), past use (mean age, 59.7 years), or current use (mean age, 60.2 years) at baseline. Differences between current users and past and never users were previously reported (23). Current users tended to be better educated, more likely to drink alcohol and to use inhaled steroids, and less likely to have hypertension.
Of the 1,343 women, 1,260 (93.8 percent) were postmenopausal and 59 (4.4 percent) were still menstruating. Data were missing for 24 (1.8 percent) women. The median age at menarche was 13 years, and the median age at menopause was 50 years. Natural menopause was reported by 997 women (79 percent) and a surgical menopause in 134 women (11 percent), with 10 percent of data missing for the type of menopause. Use of the oral contraceptive pill was reported by 484 women (36 percent). The median parity was two, and the median duration of endogenous estrogen exposure was 36 years.
Hormone replacement therapy and incident cataract
Ever users of hormone replacement therapy had decreased odds for incident cortical cataract compared with never users after adjustment for multiple potential confounders (odds ratio = 0.7, 95 percent confidence interval: 0.4, 1.1) (table 2). This association was further assessed with the inclusion of women with cortical cataract in one eye at baseline (any eye model). In this analysis, ever users of hormone replacement therapy had a statistically significant decreased risk of cortical cataract compared with never users (odds ratio = 0.7, 95 percent confidence interval: 0.4, 1.0). In a multivariate-adjusted model, past and current users had odds ratios of 0.6 and 0.8, respectively, but these were not statistically significant. Current users of a combined estrogen and progestin preparation had a reduced risk of incident cortical cataract compared with never users, and increasing duration of current usage was associated with decreased odds of cortical cataract, but neither was statistically significant. No significant associations were found between the use of hormone replacement therapy and incident nuclear or posterior subcapsular cataract in either the first eye or any eye models.
|
Reproductive factors and incident cataract
There appeared to be a protective effect in ever uses of oral contraceptives compared with never users for incident cortical cataract (odds ratio = 0.7, 95 percent confidence interval: 0.4, 1.1) in the multivariate-adjusted model (table 3). This relation was further assessed. In the any eye model, ever users of oral contraceptives had a statistically significant decreased risk of incident cortical cataract (odds ratio = 0.6, 95 percent confidence interval: 0.4, 0.9). The multivariate-adjusted any eye model indicates a significant trend for the association between increasing nuclear cataract incidence and increasing age at menarche (p = 0.04). Compared with women whose menopause occurred prior to the age of 50 years, those who developed menopause at older ages may have relative protection from nuclear cataract, with a multivariate-adjusted odds ratio = 0.7 (95 percent confidence interval: 0.5, 1.1). This finding was significant in the any eye model (odds ratio = 0.7, 95 percent confidence interval: 0.4, 1.0). No significant associations were found between incident cortical, nuclear, or posterior subcapsular cataract and type of menopause, parity, and duration of endogenous estrogen exposure.
|
|
![]() |
DISCUSSION |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
In studies of this type, it is important to identify the impact of potential confounders and bias. Limitations of our study include the possibility of multiple unknown confounding factors that were not controlled for. The answers to questions about past and current use of hormone replacement therapy, although unlikely, may have been influenced by a previous diagnosis or surgery for cataract. Also, our measures of endogenous estrogen exposure were fairly crude. The strengths of our study include its defined population base and careful documentation of a large number of potential confounders that were adjusted for in multivariate analyses. Prospective data collection to document incident cataract could not be influenced by recall bias.
The Blue Mountains Eye Study previously reported a number of significant cross-sectional associations between cataract and both use of hormone replacement therapy and other reproductive parameters (23). Current users aged 65 years or older had a lower prevalence of cortical cataract than did nonusers, while later age at menarche was associated with an increased prevalence of all three cataract types. Cross-sectional data from the Beaver Dam Eye Study (21
, 22
) demonstrated a similar protective association between nuclear cataract and either current use of postmenopausal estrogen or younger age at menarche. Older age at menopause was associated with reduced cortical cataract prevalence. This similar pattern of findings from two large population-based studies suggests that longer exposure to endogenous estrogen and/or use of estrogen replacement after menopause may delay or reduce the severity of cortical and nuclear lens opacities in women. There was no consensus, however, regarding hormonal influences on posterior subcapsular cataract. The Blue Mountains Eye Study found that current hormone replacement therapy users who gave a history of early nonsurgical menopause had an increased prevalence of posterior subcapsular cataract (23
). In contrast, the Beaver Dam Eye Study found no hormonal associations with prevalent posterior subcapsular cataract (21
, 22
), but it did report a trend suggesting a possible protective effect on incident cataract from an increasing number of livebirths (24
).
Findings from our current incidence study provide some support to our cross-sectional data that suggested a protective role for hormone replacement therapy use on cortical cataract. The finding of a significant trend for increasing age at menarche and increasing incidence of nuclear cataract is consistent with both the Beaver Dam and the Blue Mountains prevalent results. Concomitantly, increasing age at menopause was protective for cortical cataract. Older age at menarche, younger age at menopause, and a shorter duration of endogenous estrogen were significantly associated with an increasing incidence of cataract surgery. These findings support the hypothesis of estrogen's having a protective role for at least two cataract types.
A longer duration of postmenopausal estrogen therapy was associated with a decreased severity of prevalent nuclear cataract in the Beaver Dam Eye Study (22). Women who reported the use for over 20 years had a reduced risk of nuclear opacity (odds ratio = 0.65, 95 percent confidence interval: 0.48, 0.90) compared with those who reported no estrogen use. A recent paper that assessed participants in the original Framingham Eye Study (31
) supports this finding, with women who took estrogen replacement for 10 or more years having a reduced risk of nuclear cataract (odds ratio = 0.4, 95 percent confidence interval: 0.2, 1.01) compared with never users.
Our data on the use of hormone replacement therapy and incident cataract surgery suggest higher cataract surgery rates among women who reported having used hormonal therapy for longer periods. Although this could appear to counter our other findings, the data were not statistically significant in models adjusted for multiple confounders, and the data could have resulted from bias. Women who use hormone replacement therapy may be more likely to seek medical attention or to have private health insurance.
Our findings suggest a possible protective role for the use of oral contraceptives on the incidence of cortical cataract. The Beaver Dam Eye Study demonstrated a lower prevalence of nuclear cataract in ever users for women aged 4349 years (21). A similar finding was reported by the Melton Eye Study (32
), which showed a weak association between ever use of oral contraceptives and a decrease in lenticular opacities (p = 0.10). An assessment of two British cohort studies reported conflicting findings (33
). The Royal College of General Practitioners' Oral Contraception Study found a significant decreased cataract risk, and the Oxford Family Planning Association Contraceptive Study reported a significant increased cataract risk. This difference was explained as possibly being due to ascertainment bias. A number of case reports at the time of the study linking oral contraceptive use with eye disorders could have resulted in doctors' having a lower threshold for diagnosing cataract.
The trend for association between the increasing incidence of various cataract types and of cataract surgery with older age at menarche, younger age at menopause, and a decrease in the duration of reproductive years suggests that estrogen deficiency may contribute to cataract development and that estrogen may have a protective role in the human lens. Support for this mechanism has come from other human studies. Women using postmenopausal estrogen were shown to have increased lens transmittance and decreased lens autofluorescence (indicating less cataract) compared with postmenopausal women not using estrogen (34).
Support for the biologic plausibility of an estrogen-conferred protection against cataract has also come from a series of human and animal model studies of cataract and its etiology. First, -estrogen receptor messenger RNA (mRNA) has been detected in human lens epithelial cells (35
), suggesting a possible mechanism for a direct estrogen effect on the lens. Second, estrogen has been shown to protect against transforming growth factor ß (TGFß)-induced cataract in a rat model of cataractogenesis. With the use of animal models, TGFß has been shown to induce morphologic and molecular features of human subcapsular cataract and cortical cataract (25
, 36
). Exposure to estrogen inhibits TGFß-induced cataractous changes. Additional studies using this rat model suggest a correlation between the expression of the
-estrogen receptor in the lens epithelium and the ability of estrogen to protect against TGFß-induced cataract (37
). Estrogen has subsequently been shown to protect against methylnitrosourea-induced cortical cataract in another animal model (26
).
Oxidative damage to lens proteins (38) has also been implicated in the pathogenesis of certain forms of cataract. Increased levels of plasma antioxidants (vitamins C and E and carotenoids) have been associated with decreased prevalence (39
) and incidence (40
) of nuclear cataract. Women taking vitamin C supplements for 10 or more years were found to have a decreased prevalence of any lens opacity (41
) and a decreased incidence of cataract surgery (42
). Several estrogens (i.e., estriol, 17ß-estradiol, and 17
-estradiol) have also been shown to have significant antioxidant properties (43
). This mechanism could partly explain a protective role for estrogen. Postmenopausal women using hormone replacement therapy have been shown to have higher levels of reduced glutathione and glutathione peroxidase, measures of antioxidant activity, as well as lower levels of thiobarbituric acid-reactive substances, indicating lower levels of lipid peroxidation (44
). A protective effect of 17ß-estradiol on neuronal synapses by the prevention of oxidative impairment of Na+/K+-adenosine triphosphatase activity, glutamate transport, and glucose transport (45
) has been reported. Although no such reports are available for the lens, it seems possible that estrogen may have more than one mechanism of action and that a protective role for lenticular membrane transport systems would help to maintain a normally functioning and therefore clear lens.
The present data provide some epidemiologic evidence that the incidence of at least two types of age-related cataract may be related to estrogen deficiency. Although little benefit was found for the use of postmenopausal estrogen replacement, a number of significant protective trends for a longer duration of reproductive years are indicative of potential benefits of estrogen. A longer lead time may be needed for benefits to emerge from the use of estrogen replacement on cataract incidence, and the 10-year follow-up of both the Beaver Dam Eye and Blue Mountains Eye Study cohorts may provide this information. Additional epidemiologic studies assessing associations between estrogen and incident cataract, as well as further laboratory-based studies that focus on the role of estrogen in the pathogenesis of cataract, are needed. Such studies could provide evidence for interventions that could halt or slow the development of age-related cataract and its burden of visual impairment.
![]() |
ACKNOWLEDGMENTS |
---|
![]() |
NOTES |
---|
![]() |
REFERENCES |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|