Is Open-Angle Glaucoma Associated with Early Menopause?

The Rotterdam Study

Caroline A. A. Hulsman1,2, Iris C. D. Westendorp2, Raan S. Ramrattan2,3, Roger C. W. Wolfs2,3, Jacqueline C. M. Witteman2, Johannes R. Vingerling2,3, Albert Hofman2 and Paulus T. V. M. de Jong1,2,4

1 The Netherlands Ophthalmic Research Institute, Amsterdam, the Netherlands.
2 Department of Epidemiology and Biostatistics, Erasmus University Medical School, Rotterdam, the Netherlands.
3 Department of Ophthalmology, Erasmus University Medical School, Rotterdam, the Netherlands.
4 Department of Ophthalmology, Academic Medical Center, Amsterdam, the Netherlands.


    ABSTRACT
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
The authors examined the association between age at menopause and open-angle glaucoma among women aged >=55 years in the population-based Rotterdam Study (1990–1993). Information on age and type of menopause was obtained by interview. Subjects (n = 3,078) were stratified into three categories according to age at menopause: <45 years, 45–49 years, and >=50 years, with the last group serving as the reference group. Diagnosis of open-angle glaucoma was based on the presence of a glaucomatous visual field defect and glaucomatous optic neuropathy. Open-angle glaucoma was diagnosed in 78 women with a natural menopause and 15 women with an artificial menopause. In the category of natural menopause, women who went through menopause before reaching the age of 45 years had a higher risk of open-angle glaucoma than the reference group (odds ratio = 2.6; 95% confidence interval: 1.5, 4.8), after adjustment for age and use of hormone replacement therapy. Among women who went through menopause between the ages of 45 and 49 years, the odds ratio was 1.1 (95% confidence interval: 0.7, 2.0). These findings suggest that early menopause is associated with a higher risk of open-angle glaucoma.

estrogens; glaucoma, open-angle; hormone replacement therapy; intraocular pressure; menopause; risk factors; women

Abbreviations: CI, confidence interval; OR, odds ratio.


    INTRODUCTION
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Primary open-angle glaucoma is characterized by a progressive loss of ganglion cells and their axons, resulting in glaucomatous optic neuropathy in combination with corresponding visual field defects. In the Western world, primary open-angle glaucoma is the third largest cause of irreversible visual impairment (1Go). Despite the important implications of visual field loss, little is known about the pathogenesis and etiology of primary open-angle glaucoma. Elevated intra-ocular pressure is an important risk factor (2GoGo–4Go), but in 30–50 percent of glaucoma patients intraocular pressure is within the normal range; therefore, other causative factors must be present (5Go).

Following our observation that the prevalence of primary open-angle glaucoma was twice as high in men as in women (4Go), we hypothesized that one of the possible explanations for this difference is a protective effect of female sex hormones. This hypothesis is strengthened by the finding that intraocular pressure is higher among postmenopausal women than among men of the same age (6Go, 7Go) and premenopausal women (8Go). Furthermore, hormone replacement therapy has been suggested to lower intraocular pressure (9Go, 10Go).

To our knowledge, no population-based study has been performed to investigate this possible protective effect of female sex hormones, of which age at menopause is one indicator, on primary open-angle glaucoma. Thus, the purpose of the current study was to test our hypothesis and to determine whether age at menopause is associated with the prevalence of primary open-angle glaucoma.


    MATERIALS AND METHODS
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Population
The Rotterdam Study is a population-based prospective follow-up study of residents of a suburb of Rotterdam, the Netherlands, aged >=55 years in which chronic cardiovascular, neurologic, locomotor, and ophthalmologic diseases are being investigated (11Go). The present cross-sectional study was performed with baseline data, which were collected from 1990 to mid-1993. The study was approved by the Medical Ethics Committee of Erasmus University (Rotterdam), and written informed consent was obtained from all participants.

Of all eligible residents (n = 10,275) who were invited to take part in the study, 7,983 subjects (78 percent) participated in an extensive home interview (table 1). Because the ophthalmic part of the Rotterdam Study started later than the other three sections, 6,872 subjects were eligible for the ophthalmologic study. Of the 6,756 subjects who participated in the eye examination, 4,032 were female. Nursing home residents (n = 366) were excluded, because visual field testing could not be carried out. Independently living women for whom we had no data on optic disc parameters (n = 24) or on visual field testing of at least one eye (n = 111) were also excluded. In addition, women who were premenopausal or who could not remember the date or cause of their last menstrual period (n = 189) were excluded. Complete menopausal and ophthalmologic data were available on 3,342 women.


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TABLE 1. Procedure used to select the study population in the baseline phase of the Rotterdam Study, 1990–1993

 
In the present study, women who reported experiencing menopause after stopping the use of oral contraceptives (n = 173) were excluded, because for these women true age at menopause was not known. Women who stopped menstruating after taking medication (n = 91) were also excluded, because data on the use and effects of medications with a specific influence on menopause were not available at the time of the analyses. The present analysis included 2,469 women who experienced a natural menopause and 609 women who experienced menopause after surgery or irradiation therapy.

Interview
Data on menopause, menarche, and use of hormone replacement therapy were obtained by self-report during the home interview, which was conducted by a trained research assistant. For women with natural menopause, age at menopause was defined as self-reported age at the time of last menstruation. For all women reporting menopause after gynecologic surgery or radiation therapy and for those reporting any other operations before age 50 that might have led to menopause, information on the exact date and type of operation was verified using general practitioners' records, which included correspondence from medical specialists. Data on the use of hormone replacement therapy were likewise validated. Age at menarche was defined as age at the date of the first menstrual period, and duration of exposure to endogenous sex hormones was defined as the difference in years between menarche and menopause.

Measurements
The complete eye examination included testing of visual acuity, ocular refraction, and visual fields, measurement of intraocular pressure, and slit-lamp examination, as well as indirect ophthalmoscopy (4Go). For intraocular pressure, three measurements were taken and the median was used (12Go).

For assessment of the optic disc, stereo transparencies from both eyes were digitized and analyzed using the module for retinal nerve fiber layer height of the Topcon image analyzer Imagenet (4Go, 13Go). Disc area, vertical cup:disc ratio, and the smallest neural rim width were automatically calculated from the topographic data (14Go). Visual field testing was performed as described by Wolfs et al. (4Go).

Visual field grading and classification
Six graders (three senior ophthalmologists, two residents, and one perimetrist) independently graded all Goldmann visual field charts according to shape and localization of the defect (4Go). The graders were masked with regard to other clinical data such as medical history or optic disc characteristics. The cause of the visual field defect was determined using data from the home interview, ophthalmologic examination, and neurologic assessment and additional information obtained from the medical records of general practitioners and specialists. Glaucomatous visual field loss was defined as a visual field defect compatible with nerve fiber bundle defects (nasal step, paracentral defect, arcuate scotoma, temporal nerve fiber bundle defect, remaining peripheral island and a central remnant) after exclusion of other retinal or neuroophthalmologic causes.

Diagnosis
At baseline, pseudoexfoliative glaucoma was not explicitly ruled out; thus, a few cases with this syndrome might have been included. Therefore, we will refer to the disease status of the subjects as open-angle glaucoma instead of primary open-angle glaucoma. Open-angle glaucoma was classified into three categories: definite, probable, and possible (4Go). For the current analysis, we included only patients with definite and probable open-angle glaucoma.

Definite open-angle glaucoma was defined as the presence of a glaucomatous visual field defect in combination with a possible or probable glaucomatous optic neuropathy, based on the 97.5th and 99.5th percentiles of the distributions of the measurements in this population, respectively. The 97.5th percentile for vertical cup:disc ratio was 0.7, that for asymmetry between the vertical cup:disc ratios of both eyes was 0.2, and that for minimal neural rim width was 0.10. For the 99.5th percentile, these values were 0.8, 0.3, and 0.05, respectively. Probable open-angle glaucoma was defined either as the presence of glaucomatous visual field loss in the absence of a possible glaucomatous optic neuropathy or as a probable glaucomatous optic neuropathy, without glaucomatous visual field loss.

Intraocular pressure was not included in our criteria for the diagnosis of open-angle glaucoma, but elevated intra-ocular pressure was included in the analysis because of its importance as a risk factor for open-angle glaucoma (15Go). We considered the intraocular pressure elevated when applanation tonometry was over 21 mmHg in one or both eyes or when treatment had been given to lower the intra-ocular pressure.

Data analysis
We studied the association between age at menopause and open-angle glaucoma in the following ways. First, we compared baseline characteristics between the women included in the analysis and those excluded from the analysis because of missing data. For this, both logistic and linear multivariate regression analyses were used. Next, women were stratified into three categories according to age at menopause: <45 years, 45–49 years, and >=50 years. The last group was regarded as the reference group. Odds ratios and 95 percent confidence intervals were calculated for definite and probable open-angle glaucoma and for elevated intraocular pressure, by age at menopause, using multivariate logistic regression analysis.

Relative risks were then calculated for women who had experienced either natural or artificial menopause. To examine the effect of ovarian estrogen production, we made a distinction in the artificial menopause group between women whose menopause started after irradiation therapy or bilateral oophorectomy and those whose menopause resulted from hysterectomy with or without unilateral oophorectomy. In all analyses, adjustments were made for age, hypertension, diabetes mellitus, use of hormone replacement therapy at any time, and duration of hormone replacement therapy (in months) (15Go).


    RESULTS
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Baseline characteristics of the women who were included in the analyses and those who were excluded from the analyses are shown in table 2. Excluded women were older. In these women, systolic blood pressure was higher after age adjustment, and percentage of women who had ever used hormone replacement therapy was lower. Mean age at menopause, mean vertical cup:disc ratio in the right eye, and duration of use of hormone replacement therapy did not differ between the groups.


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TABLE 2. Age-adjusted baseline characteristics of women included in analyses and women excluded from analyses (because of complete and incomplete ophthalmologic and menopausal data, respectively), The Rotterdam Study, 1990–1993

 
Characteristics of women who experienced a natural menopause are given by age category in table 3. Age at the time of examination ranged from 55 years to 94.5 years (mean = 68.8 years), and age at menopause varied from 30 years to 60 years (mean = 49.7 years). Women whose meno-pause occurred before age 45 were older; a higher percentage of them had used hormone replacement therapy at some time, and a higher percentage had used it for at least 1 year. In these women, the prevalence of definite and probable open-angle glaucoma and of elevated intraocular pressure was higher.


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TABLE 3. Characteristics of women with natural menopause, by age group, The Rotterdam Study, 1990–1993

 
Definite (n = 13) and probable open-angle glaucoma based on either a glaucomatous visual field defect (n = 14) or a glaucomatous optic neuropathy (n = 51) was diagnosed in 78 subjects (table 4). Women who experienced menopause before the age of 45 years had a significantly higher risk of open-angle glaucoma (odds ratio (OR) = 2.6; 95 percent confidence interval (CI): 1.5, 4.8) than the reference group. Women who experienced menopause between the ages of 45 and 49 years did not have a significantly increased odds ratio (OR = 1.1; 95 percent CI: 0.7, 2.0). When we considered the small number of cases with definite open-angle glaucoma (n = 13), the odds ratio for women with menopause before age 45 was 3.5 (95 percent CI: 0.8, 14.8) and that for women with menopause between ages 45 and 49 was 1.8 (95 percent CI: 0.5, 6.7). We next examined the relation between age at menopause and probable open-angle glaucoma, based on a glaucomatous visual field defect or a glaucomatous optic neuropathy (table 5). The odds ratio for women with menopause before age 45 was 2.5 (95 percent CI: 1.3, 4.8) and that for women with menopause at age 45–49 years was 1.0 (95 percent CI: 0.6, 1.9), in comparison with the reference group.


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TABLE 4. Odds ratios for definite and probable* open-angle glaucoma, by age at natural menopause, The Rotterdam Study, 1990–1993

 

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TABLE 5. Odds ratios for probable* open-angle glaucoma, by age at natural menopause, The Rotterdam Study, 1990–1993

 
Duration of lifetime exposure to endogenous sex hormones ranged from 15 years to 49 years (mean = 36.1 years). The odds ratio for open-angle glaucoma decreased significantly by 5 percent per year of exposure to endogenous sex hormones (OR = 0.95; 95 percent CI: 0.90, 0.99) and by 6 percent per year for each year of age at menopause (OR = 0.94; 95 percent CI: 0.90, 0.99). Additional adjustment for use of hormone replacement therapy did not markedly change our estimates.

There were 609 women who had experienced an artificial menopause. Among women who had experienced menopause after irradiation therapy or bilateral oophorectomy with or without hysterectomy (n = 209), definite or probable open-angle glaucoma was diagnosed in seven women: four women with menopause at or after age 50 and three women with menopause between ages 45 and 49 years. Open-angle glaucoma was not present in the women who had experienced menopause before age 45. In the category of women who had undergone a hysterectomy with or without unilateral oophorectomy (n = 400), these numbers were one, two, and five, respectively. Numbers were too small among women with an artificial menopause to calculate odds ratios. When we analyzed all women, regardless of cause of menopause (n = 3,078), the odds ratio for open-angle glaucoma was 1.8 (95 percent CI: 1.0, 3.0) among women with menopause before age 45 and 1.1 (95 percent CI: 0.7, 1.9) among women with menopause at age 45–49, in comparison with the reference group. In all analyses, additional adjustments for use of hormone replacement therapy, hypertension, diabetes, and elevated intraocular pressure did not markedly change our results.

Hormone replacement therapy
Among women with natural menopause or menopause after irradiation therapy or bilateral oophorectomy (n = 2,678), 188 women had taken hormone replacement therapy for some period of time. Mean duration of use was 2.5 years (maximum = 24 years). Of women who used hormone replacement therapy, three had definite or probable open-angle glaucoma. The risk of open-angle glaucoma was lower in women who had used hormone replacement therapy than in women who never had, but this estimate was not significant (OR = 0.54 (95 percent CI: 0.17, 1.74), adjusted for age and age at menopause).

Intraocular pressure
The odds ratio for elevated intraocular pressure among women who experienced either natural or artificial menopause before age 45 years was 1.2 (95 percent CI: 0.8, 1.8), and the odds ratio among those with menopause between ages 45 and 49 years was 0.8 (95 percent CI: 0.6, 1.1), in comparison with the reference group (table 6). Additional adjustments for hypertension and hormone replacement therapy did not change the odds ratios.


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TABLE 6. Odds ratios for elevated intraocular pressure, by category of age at natural menopause, for women with natural menopause and women who experienced artifical menopause after undergoing irradiation therapy or bilateral oophorectomy, The Rotterdam Study, 1990–1993

 

    DISCUSSION
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
In this population-based study, women who experienced an early natural menopause had an increased risk of open-angle glaucoma. In interpreting this finding, some methodological issues must be addressed.

Women included in the present analysis may have differed from those excluded. We excluded subjects with incomplete ophthalmologic or menopausal data; these women were mostly older and living in a nursing home, where visual field screening was not possible. After we adjusted for age, there was no difference in most baseline characteristics between the two groups, but the percentage of use of hormone replacement therapy was lower and the mean systolic blood pressure was higher in the group of excluded subjects. Since age is an important risk factor for open-angle glaucoma, exclusion of an older set of women probably causes underestimation of the prevalence of the disease. Mean age at menopause and mean vertical cup:disc ratio were comparable in the two groups; therefore, we do not think selection bias had a large effect on our results.

Data on age and cause of menopause were self-reported. The distribution of ages at menopause in our study was comparable to the distributions reported by two leading studies on age at menopause in the Netherlands (16Go, 17Go). Still, misclassification could have occurred because of the time period between age at menopause and age at examination. Since we have no reason to assume that women with open-angle glaucoma would have reported an earlier age at menopause, misclassification would have been nondifferential, and this would have given an underestimation of the true effect.

The main finding of our study was that women who had a natural menopause before the age of 45 had a significantly higher risk of open-angle glaucoma than those who had a natural menopause at age 50 or above. This is in agreement with our hypothesis that female endogenous sex hormones protect against open-angle glaucoma. However, the risk was not significantly elevated among women who experienced menopause between the ages of 45 and 49 years. This can be explained by a smaller contrast in hormonal status between the two groups. Probably only very early menopause is relevant for an increased risk of open-angle glaucoma. We cannot exclude the possibility that the small number of cases rendered our findings insignificant. When we considered only definite open-angle glaucoma, both in women who had menopause before age 45 and in those who had menopause between ages 45 and 49, the odds ratios were increased. The small number of cases probably explains the lack of significance in this analysis.

Another variable of possible importance is the interval between menarche and menopause. We studied the relation between menarche and open-angle glaucoma (1-year-later menarche: OR = 1.05; 95 percent CI: 0.92, 1.19). The reason for such a small effect and wide confidence intervals could be misclassification due to inaccurate assessment of age at menarche. Possibly, in contrast to cessation of hormonal activity during middle age, the start of hormonal activity in youth has no effect or a weaker effect on risk of open-angle glaucoma. We also studied the interval between menarche and menopause, but this gave us results similar to those for age at menopause. For these reasons, we chose age at menopause as our indicator of exposure to endogenous female hormones. For analyses including other parameters of endogenous or exogenous exposure to hormones, such as artificial menopause and use of hormone replacement therapy, the data should be interpreted with care, since the numbers of cases in these categories were small.

There was no significant difference in risk of elevated intraocular pressure between women in different categories of age at menopause. This finding was expected from our hypothesis. No appreciable difference in risk was predicted, because any hypothesized pressure-lowering effect of estrogens and progestogens would be a direct effect, independent of age at menopause. In the literature, evidence is found for a direct effect of endogenous hormonal changes on aqueous humor circulation: Most authors agree that in pregnancy, with altered hormonal status, intraocular pressure decreases significantly (18GoGo–20Go). This reversible effect is most likely explained by an increased outflow facility through the trabecular meshwork (19Go).

The relation between primary open-angle glaucoma and gender is still controversial. In the Baltimore Eye Survey (21Go), the Beaver Dam Eye Study (22Go), and the Blue Mountains Eye Study (23Go), no significant difference was found between prevalences of primary open-angle glaucoma in men and women. However, in the Framingham Eye Study (24Go), the Barbados Eye Study (3Go), and the Rotterdam Study (4Go), up to a twofold higher prevalence was found in men. Many differences between these studies have been discussed (4Go). The change over time in use of hormone replacement therapy, and thus a protective effect of exogenous sex hormones, could explain the gender difference.

Several biologic mechanisms could explain the association between early menopause and open-angle glaucoma. It may be assumed that the decrease in estrogen and progesterone levels after menopause may play a key role, and therefore biologic mechanisms influenced by these hormones may be involved. It is known that estradiol increases endothelial nitric oxide levels by enhancing the activity of the enzyme nitric oxide synthase III (25GoGoGo–28Go). Several investigators have reported that nitric oxide induces a decrease in intraocular pressure--for example, by relaxation of the trabecular meshwork (29GoGoGo–32Go). Moreover, as a vasodilator, nitric oxide may have an effect on the blood supply of the optic nerve and the basal vascular tone in uveal, retinal, and choroidal circulation (32GoGoGoGoGo–37Go).

There is evidence that progesterone has the properties of a glucocorticoid antagonist (38Go). Glucocorticoids are known to elevate intraocular pressure (39Go, 40Go). Progesterone may inhibit the ocular hypertensive effect of endogenous glucocorticoids by competing for the receptor binding site. These receptors have been located in human trabecular meshwork cells (41Go) and rabbit iris-ciliary body cells (42Go), binding both glucocorticoids and progesterone.

In the population-based Rotterdam Study, age at natural menopause was associated with the presence of open-angle glaucoma. For both etiologic and therapeutic reasons, further research into the effects of endogenous and exogenous exposure to female sex hormones would be of interest.


    ACKNOWLEDGMENTS
 
This work was supported by the Nestor program (Ministry of Health and Ministry of Education, the Netherlands); Stichting Zorg Onderzoek Nederland; Topcon Europe BV; the Netherlands Society for Prevention of Blindness; Stichting Fondsenwervingsacties Volksgezondheid; Haagsch Oogheel-kundig Fonds; Landelijke Stichting voor Blinden en Slecht-zienden; Stichting Blindenhulp; Rotterdamse Vereniging voor Blindenbelangen; G. P. Verhagen Stichting; Stichting voor Ooglijders; the Optimix Foundation; Stichting ROOS; and the Edmond and Marianne Blaauw Foundation.

The authors thank Ada Hooghart and Corina Brussee for assistance with data collection.


    NOTES
 
Correspondence to Prof. P. T. V. M. de Jong, The Netherlands Ophthalmic Research Institute, Meibergdreef 47, 1105 BA Amsterdam, the Netherlands (e-mail: p.dejong{at}ioi.knaw.nl).


    REFERENCES
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 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
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Received for publication March 1, 2000. Accepted for publication November 29, 2000.