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Postmenopausal Estrogen Use, Type of Menopause, and Lens Opacities
The Framingham Studies
Katherine Worzala, MD, MPH;
Rita Hiller, MS;
Robert D. Sperduto, MD;
Karen Mutalik, BS;
Joanne M. Murabito, MD, MPH;
Mark Moskowitz, MD, MPH;
Ralph B. D'Agostino, PhD;
Peter W. F. Wilson, MD
Arch Intern Med. 2001;161:1448-1454.
ABSTRACT
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Background Previous studies of estrogen replacement therapy and lens opacities
have not reported consistent findings.
Objective To investigate whether postmenopausal estrogen use is associated with
the occurrence of age-related lens opacities (nuclear, cortical, and posterior
subcapsular).
Methods Surviving members of the original cohort of the Framingham Heart Study
who also participated in the Framingham Eye Study (1986-1989) were examined
for the absence or presence of lens opacities. Data from the Framingham Heart
Study, including information on menopausal status (collected biennially from
approximately 1948) and use of estrogen replacement therapy (collected biennially
from approximately 1960) were used to examine associations between lens opacities
and duration of postmenopausal estrogen use, type of menopause, and age at
menopause. Five hundred twenty-nine women, aged 66 to 93 years, were included.
Multivariable-adjusted odds ratios of specific types of lens opacities were
calculated for (1) duration of estrogen use (never and 1-2, 3-9, and  10
years), (2) surgical vs natural menopause, and (3) age at menopause.
Results Longer duration of postmenopausal estrogen therapy was inversely associated
with the presence of nuclear lens opacities in an adjusted model. Women who
had taken estrogen for 10 years or longer had a 60% reduction in risk compared
with nonusers (odds ratio, 0.4; 95% confidence interval, 0.2-1.01). Longer
duration of estrogen use was associated with fewer posterior subcapsular opacities
at a borderline level of significance. No association was noted for cortical
opacities. The risk of posterior subcapsular opacities was significantly increased
for women who had undergone surgical menopause compared with women with natural
menopause (odds ratio, 2.2; 95% confidence interval, 1.1-4.3). No association
was noted for lens opacities and age at menopause.
Conclusion Data from our study and other studies suggest that a reduction in the
risk of lens opacities may be an additional benefit of postmenopausal estrogen
use.
INTRODUCTION
AGE-RELATED cataract is a major cause of visual impairment and blindness
throughout the world. In the United States, cataract surgery is the most frequently
performed surgical procedure in the Medicare program, with about 1.35 million
cataract operations done each year.1 Nuclear
and cortical cataracts are by far the most common types of cataract in the
general population, but posterior subcapsular and nuclear cataracts are the
predominant types in surgical series.2 Histologic,
biochemical, and physiologic differences in the 3 major types of cataract
suggest that risk factors for cataract be investigated separately for the
3 types. Factors that may predispose to cataract formation include aging,
diabetes mellitus, cigarette smoking, elevated body mass index (BMI), UV light,
alcohol use, and perhaps a history of systemic hypertension.3-11
A protective role of micronutrients in the development of cataracts has attracted
much recent interest, but studies to date have been inconclusive.3-4,12
Previous studies have demonstrated that men and premenopausal women
have similar prevalences of cataract; however, in postmenopausal women the
prevalence of cataracts is increased relative to men of equivalent age.13-17
The increased prevalence of cataracts in postmenopausal women suggests a possible
role for estrogen in retarding cataract formation. Two population-based cross-sectional
studies have reported beneficial effects of estrogen replacement therapy on
specific types of cataract.18-19
A third population-based cross-sectional study reported no protective association
between hormone replacement therapy and cataract.17
We had the opportunity to study women participating in the Framingham Heart
Study, who have provided information on hormone use at each biennial examination
since about 1960 and who participated in the Framingham Eye Study from 1986
to 1989. Our primary goal was to examine the relationship between age-related
lens opacities, in particular the specific types of opacity, and the use of
estrogen replacement therapy. A second aim was to evaluate the relationship
between lens opacities and age and type (surgical vs natural) of menopause.
SUBJECTS AND METHODS
The Framingham Heart Study consists of a cohort that has been examined
approximately every 2 years since 1948.20 Eye
examinations were conducted on 2675 persons (1117 men and 1558 women) between
1973 and 1975, at approximately the time of the 12th biennial heart study
examination.13, 21 Of the 2675
Framingham subjects, 2670 were white.22 Survivors
of the Framingham Eye Study (FES I) were reexamined between 1986 and 1989.23 The dates of the second Framingham Eye Study (FES
II) correspond to the 19th to 20th heart study biennial examination. Of the
1558 women examined during FES I, 565 had died by the time of FES II and 340
were unavailable for the examination, leaving 653 women eligible for the study.
The 340 women who were not available for the FES II eye examination were similar
to the 653 women with respect to diabetes, hypertension, smoking history,
and BMI measurement at the time of FES I.
LENS OPACITY CLASSIFICATION
Participants in FES II were examined by 2 certified, experienced examiners
who evaluated lens status at the slit lamp through a dilated pupil by means
of a standardized grading system described by Taylor and West.24
For nuclear cataract, 3 standard photographs of lenses with increasing levels
of nuclear opalescence were used to grade nuclear status on a scale of 0 to
3. We considered a nuclear opacity to be present if the grade was 2 or 3.
Cortical opacities were graded by estimating the cumulative number of one-eighth
wedges of the retroilluminated lens affected by cortical opacities. A cortical
opacity was judged to be present if the opacity affected at least one eighth
the area of the lens cortex. Posterior subcapsular opacity was present when
either the vertical or horizontal width of a posterior subcapsular opacity
seen on retroillumination was at least 1 mm. A person was considered to have
a specific type of lens opacity when the opacity was present in either eye,
regardless of the presence or absence of other opacity types.
MENOPAUSAL STATUS AND POSTMENOPAUSAL ESTROGEN USE
Age and type of menopause were ascertained through 1978, ie, about the
time of Framingham Heart Study examination 14. At biennial examinations 1
through 14, women were asked if they were still menstruating. If menses had
ceased for 1 year or more, their age at the time of cessation of menses and
the cause of cessation (natural, surgical, or other) were recorded. The date
of menopause assigned for women with natural cessation was 1 year after the
last menstruation. Surgical menopause was defined as the cessation of menstrual
periods because of hysterectomy and bilateral oophorectomy. Cases of surgical
menopause were confirmed by examining the surgeons' operative notes and pathology
reports. For the purposes of this study, women who underwent hysterectomy
but not oophorectomy were classified as having natural menopause, and the
average age of menopause in the cohort was assigned.
Since 1960 (the seventh biennial examination), women were asked about
postmenopausal estrogen hormone use since their last examination. Charts were
reviewed to verify estrogen use. Estrogen use of less than 1 year was categorized
as 1 year of use, and estrogen use of 1 year or more, as 2 years of use. Lifetime
duration of postmenopausal estrogen use was determined by summing the estrogen
use from the 7th through the 20th biennial examinations. Almost all women
who used estrogen took the oral conjugated form at a dosage of 0.625 mg or
more daily.25-27
Reported use of progesterone was rare in the early cohort examinations. The
use of estrogen in combination with progesterone did not become widespread
until the early 1980s.28-29 Only
7% of women attending examinations 19 and 20 who reported estrogen use also
reported progesterone use.
OTHER FACTORS
Other potential risk factors for cataract were included in the analyses.
Examination 20 data were used except for subjects who did not attend examination
20; for them, examination 19 data were used. Women were considered to have
diabetes mellitus if they had a random blood glucose determination of greater
than 8.3 mmol/L (150 mg/dL) on at least 2 examinations, abnormal results of
a glucose tolerance test, or a history of treatment by a physician for diabetes
mellitus. The mean of 2 blood pressures taken by a physician was used to determine
the presence of hypertension. Hypertension was defined as a systolic blood
pressure of greater than 160 mm Hg or diastolic blood pressure of greater
than 95 mm Hg. Data on smoking status in the previous year were collected
at each biennial examination. Women who reported cigarette smoking at either
examination 19 or 20 were considered current smokers. Women who did not smoke
at examination 19 or 20 but had been smokers at preceding examinations were
considered past smokers, and women who did not smoke at any of the examinations
were categorized as never smokers. Body mass index was computed as weight
in kilograms divided by the square of height in meters.
STATISTICAL METHODS
Six hundred fifty-three women were examined in FES II. We excluded 114
women who had missing data on estrogen use on 3 or more Framingham Heart Study
examinations. Furthermore, we excluded 7 women for whom type of menopause
(natural or surgical) could not be determined, 2 women who had menopause from
other causes, and 1 woman for whom the presence or absence of lens opacity
or aphakia was not coded. The study population thus consisted of 529 women
for whom estrogen use, natural or surgical menopause, and presence or absence
of lens opacities could be determined. The 529 women in the study group were
on average about 2.5 years older at the time of the eye examination than the
124 excluded women (75.5 years in the study group vs 73.0 years in the excluded
group). The prevalences of lens opacities, diabetes, hypertension, and smoking
history were similar in both groups.
Multivariable logistic regression was used to assess the association
of lens opacities with duration of postmenopausal estrogen use, age at menopause,
and type of menopause (surgical or natural). Adjustments were made for potential
confounders: age at eye examination, diabetes, BMI, cigarette smoking, and
hypertension. All P values were 2-sided and were
obtained, except where noted, by likelihood ratio tests.30
RESULTS
Table 1 shows the characteristics
of the 529 study participants. Lens opacities, including aphakia, were present
in 395 women. Nuclear, cortical, and posterior subcapsular opacities, each
with or without other lens opacities, occurred in 269, 172, and 77 women,
respectively.
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Table 1. Characteristics of Postmenopausal Study Subjects
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The women's ages ranged from 66 to 93 years; mean age was 75.5 years.
Three hundred thirty-eight (64%) of the 529 participants were nonestrogen
users. Among the 191 estrogen users, 43 (23%) had used them for 10 years or
more (Table 1). Only 35 women
were current postmenopausal estrogen users; 21 of them (60%) had taken the
preparation for 10 years or more (data not shown).
Table 2, Table 3, Table 4, and Table 5 provide results of the multivariable
logistic regression. For each lens opacity type, we initially evaluated the
1 three-way and 3 two-way interactions of duration of postmenopausal estrogen
use, age at menopause, and type of menopause. None of the interactions were
significant at the P<.05 level. After adjustment
for age at menopause, type of menopause, age at the eye examination, BMI,
diabetes, hypertension, and cigarette smoking, we found that longer duration
of estrogen use was inversely associated with risk of lens opacities without
regard to type. For categories of increasing duration of estrogen use (never
and 1-2, 3-9, and 10 years), the odds ratios were 1.0, 0.8, 0.7, and 0.4,
respectively (test for trend, P = .02). In particular,
women who had taken estrogen preparations for 10 years or more were at significantly
lower risk of having lens opacities than the non–estrogen takers (odds
ratio, 0.4; P = .03). Increasing duration of postmenopausal
estrogen use was strongly associated with a decreased prevalence of nuclear
lens opacities (test for trend, P = .02), borderline
associated with decreased risk for posterior subcapsular lens opacities (test
for trend, P = .06), and not associated with cortical
lens opacities (test for trend, P = .81).
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Table 2. Adjusted Odds Ratios for Lens Opacities Without Regard to
Type (Including Aphakia)*
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Table 3. Adjusted Odds Ratios for Nuclear Lens Opacities*
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Table 4. Adjusted Odds Ratios for Cortical Lens Opacities*
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Table 5. Adjusted Odds Ratios for Posterior Subcapsular Lens Opacities*
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The risk of posterior subcapsular opacities was significantly increased
for women who had undergone surgical menopause (odds ratio, 2.2; 95% confidence
interval, 1.1-4.3) compared with women who had undergone natural menopause
(Table 5).
Age at menopause ranged from 26 to 58 years; mean age was 47 years (data
not shown). Compared with normal age at menopause (45 to 54 years), neither
early nor late age at menopause was associated with lens opacities (Table 2, Table 3, Table 4, and Table 5).
The multivariable logistic regression analysis found that posterior
subcapsular lens opacities were more common in diabetic subjects (Table 5) and that larger values of BMI
were associated with the presence of cortical opacities (Table 4).
COMMENT
Increasing duration of estrogen use was associated with a decreased
prevalence of nuclear opacities in the Framingham Eye Study cohort. Posterior
subcapsular opacities were also less common in estrogen users, but this finding
was at a borderline level of significance. No association was noted for cortical
lens opacities. Our finding that estrogen use had a protective effect for
lens opacities without regard to type is probably explained by the fact that
85% of the "any" opacity group had either nuclear or posterior subcapsular
opacities. These results again stress the need for studying specific types
of lens opacities when assessing risk factors for cataract.
Other studies have noted associations between postmenopausal estrogen
use and lens opacities. The Beaver Dam Eye Study reported a decreased risk
of more severe nuclear sclerosis in current users of postmenopausal estrogen.18 Younger age at menarche and older age at menopause
were also associated with decreased risk of lens opacities, further suggesting
hormonal influences on cataractogenesis. No association was found for cortical
opacities and no results were reported for posterior subcapsular opacities.
The Melton Eye Study found that "ever" use of oral contraceptives resulted
in reduced nuclear opalescence but had no effect on cortical opacities.31 The similarity of findings in these studies with
different definitions of opacity and different definitions of hormone use
strengthens the likelihood that the relationship between estrogen use and
nuclear opacity is real. However, 2 studies reported dissimilar findings.
The Blue Mountains Eye Study found that current estrogen users older than
65 years had fewer cortical lens opacities than women who had never used estrogen
therapy.19 In the subset of women with natural
rather than surgical menopause, current users of hormone replacement therapy
in the Blue Mountains Eye Study had an increased prevalence of posterior subcapsular
opacity. The population-based Melbourne Visual Impairment Project reported
no associations between hormone replacement therapy and cataract.17
In our fully adjusted models, surgical menopause was associated with
an increased prevalence of posterior subcapsular opacities. This seems consistent
with a hypothesis of a beneficial hormonal effect, since surgical menopause
results in a more abrupt decline in levels of endogenous estrogen than does
natural menopause. However, the Beaver Dam Eye Study noted a higher prevalence
of less severe nuclear sclerosis in women with hysterectomy than in women
with natural menopause.18 The authors suggested
that this might reflect the use of estrogen replacement therapy started soon
after surgery in women with complete hysterectomies. In our study, with adjustment
for estrogen therapy in the model, rates of posterior subcapsular opacity
were still higher with surgical menopause. The Blue Mountains Eye Study reported
no association between type of menopause and risk of any type of lens opacity.19
The mechanism by which estrogen replacement therapy might protect against
lens opacities is unclear. In an animal model of age-related cataract, estrogen
has been shown to reduce the incidence of methylnitrosourea-induced cataracts
in rats subjected to ovariectomy.32 Since reverse
transcription polymerase chain reaction has demonstrated that lens cells express
both  and ß types of estrogen receptors, it has been suggested
that the protective effect of estrogen may be a direct, receptor-mediated
one. Other investigators have suggested that estrogen may confer protection
against cataracts by affording protection against the effect of transforming
growth factor ß.33-34 Transforming
growth factor ß has been demonstrated to be present in the eye and is
capable of inducing opacities in cultured rat lenses. Lenses from rats subjected
to ovariectomy are sensitive to the damaging effects of transforming growth
factor ß, but in vivo or in vitro estrogen replacement restores resistance.
Finally, it has been suggested19 that the reported
antioxidant activity of estrogen35 may have
a beneficial effect on cataractogenesis.
Several potential risk factors for cataract were included in the multivariable
analyses. The findings for these factors were generally consistent with previous
reports. In particular, the associations between diabetes and posterior subcapsular
cataract5, 36 and between higher
BMI and cortical cataract9, 37
have been reported. Earlier reports have consistently linked smoking and increased
risk of nuclear cataract.10-11
The odds ratio for current smoking and nuclear cataract was 1.5 in our study,
but not significant, perhaps because of low statistical power to examine the
relationship in this cohort of women.
A strength of the current report is the prospective design of the Framingham
Study, which allowed for ascertainment of estrogen use and menopausal status
at each examination (up to 39 years preceding the eye examination). In addition,
surgical notes and pathology reports were used to substantiate menopausal
status. Previous studies that collected data with a single interview were
more likely to have been hampered by inaccurate recall of estrogen use and
self-report of details about menopause. For example, women may be aware of
their hysterectomy but are less likely to be certain about whether they underwent
bilateral oophorectomy. The collection of reliable data on duration of estrogen
use was also important because it allowed us to examine the effect of long-term
therapy. Other studies of the role of estrogen in disease prevention have
suggested that disease prevention is most manifest when estrogen therapy has
been used for an extended period. For example, in some38-39
but not other40 studies, mortality was reduced
in women with longer vs shorter duration of estrogen use. Also, women who
had taken estrogen for at least 7 years had significantly higher bone mineral
density than those who had taken it for shorter periods.25
Another strength of the study was the independent collection of estrogen data
in the Framingham Heart Study and eye data in the Framingham Eye Study. This
eliminated important potential sources of bias in ascertainment of exposure
and outcome status.
Our study had some limitations. The original Framingham Eye Study cohort
included only 5 nonwhites, so the results cannot necessarily be generalized
to nonwhite populations. Also, the study was not designed to investigate dose-response
relationships, as estrogen dose was not recorded uniformly during the exposure
period. In addition, the study did not address the influence of progesterone
on lens opacities. However, recent studies suggest that progesterone does
not eliminate the beneficial effects of estrogen on lipid or fibrinogen levels.41 Another limitation of the study is that lens status
was not determined before initiation of estrogen treatment, and therefore
some women may have had opacities before treatment. It is reassuring that
the associations were strongest for women with longest duration of estrogen
treatment and, particularly for this group, it is likely that the treatment
began before development of lens opacities. As with other observational studies,
the results could also have been affected by uncontrolled confounding. If
women who decided to take estrogen replacement therapy were different from
the women who did not use estrogen and these differences were related to their
risk of lens opacities, the results could have been affected. Adjustments
were made in the analyses for known confounders, but the possibility of uncontrolled
confounding remains.
Our data suggest a beneficial effect of long-term estrogen replacement
therapy on lens opacities. The strength of the association, the dose-response
nature of the association, the consistency of the finding across several epidemiologic
studies, and the biological plausibility of the association suggest that it
is real. Thus, our findings suggest a possible additional benefit of postmenopausal
estrogen use. Whether the findings should influence a woman's decision about
estrogen replacement therapy should take into account the widespread availability
of an effective treatment for cataract and the other potential risks and benefits
of such therapy.
AUTHOR INFORMATION
Accepted for publication December 4, 2000.
The Framingham Eye Study I and the Framingham Eye Study II were supported
by contracts N01-EY-2-2112 and N01-EY-6-2105, respectively, from the National
Eye Institute, National Institutes of Health, Bethesda, Md. The Framingham
Heart Study is supported by contract NO1-HC-38083.
Corresponding author and reprints: Rita Hiller, MS, Division of Epidemiology
and Clinical Research, National Eye Institute, Bldg 31, Room 6A52, 31 Center
Dr MSC 2510, Bethesda, MD 20892-2510.
From the Section of General Internal Medicine, University of Minnesota
School of Medicine, Minneapolis Veterans Affairs Medical Center, Minneapolis
(Dr Worzala); Division of Epidemiology and Clinical Research, National Eye
Institute, Bethesda, Md (Ms Hiller and Dr Sperduto); National Heart, Lung,
and Blood Institute, Framingham, Mass (Ms Mutalik and Drs Murabito and Wilson);
Sections of General Internal Medicine (Drs Murabito and Moskowitz) and Endocrinology
(Dr Wilson), Boston University School of Medicine, Boston, Mass; and Department
of Mathematics and Statistics, Boston University (Dr D'Agostino).
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