Feskanich D, Cho E, Schaumberg DA, Colditz GA, Hankinson SE. Menopausal and Reproductive Factors and Risk of Age-Related Macular Degeneration. Arch Ophthalmol. 2008;126(4):519-524. doi:10.1001/archopht.126.4.519
Copyright 2008 American Medical Association. All Rights Reserved. Applicable FARS/DFARS Restrictions Apply to Government Use.2008
To investigate whether estrogen exposures are associated with lower risks of age-related macular degeneration (AMD).
Postmenopausal hormone (PMH) use, past use of oral contraceptives (OCs), ages at menarche and menopause, and parity were assessed among 74 996 postmenopausal women. Over 22 years, cases of early (n = 554) and neovascular (n = 334) AMD with a visual acuity of 20/30 or worse were identified. Cox models were used to calculate the relative risk for each exposure, adjusted for smoking and other factors.
Current PMH users had a notable 48% lower risk of neovascular AMD compared with those who had never used PMH, although risk did not decline linearly with longer durations of use. Risk was lowest for PMH users who had used OCs in the past (P value for interaction, .03). In contrast, risk of early AMD was a notable 34% higher among current PMH users and OC use was unassociated with risk. The only remarkable finding for the endogenous estrogenic factors was a 26% lower risk of early AMD for parous women.
Although PMH and OC use were associated with a lower risk of neovascular AMD, no benefit was observed for early AMD. Factors influencing lifetime exposure to estrogens were not consistently associated with the disease.
Age-related macular degeneration (AMD) is the leading cause of vision loss and blindness among older adults,1 and the current US prevalence of 1.75 million is expected to increase to almost 3 million by 2020.2 Although genetics plays a key role in susceptibility to AMD,3,4 environmental factors,5 such as smoking,6 are also important. However, there are few interventions known to reduce the incidence or prevent progression of the disease.
Evidence of higher rates of AMD in women than in men7,8 and links between AMD and cardiovascular disease9- 11 suggested a role for estrogen in the etiology. Indeed, an early case-control study12 reported a 70% lower risk of neovascular AMD among current users of postmenopausal hormones (PMHs). However, a number of subsequent studies13- 21 have examined factors that contribute to estrogen exposure in relation to risk of both early and late stages of AMD, and results have been inconsistent. Most of these studies utilized cross-sectional or retrospective data, and many were too small to assess associations with confidence. Most recently, the Women's Health Initiative reported a significantly lower risk of neovascular AMD for women assigned to PMH treatment containing estrogen plus progestin,22 although case counts were too small to determine a precise measure of the extent of the benefit.
To address the limitations in previous research, we used repeated assessments of PMH use over 22 years of follow-up to conduct a large prospective analysis of the risk of early- and late-stage AMD in postmenopausal women. We also examined past use of oral contraceptives (OCs) and other menopausal and reproductive factors that contribute to lifetime estrogen exposure.
The Nurses' Health Study (NHS) began in 1976 when 121 700 female registered nurses, 30 to 55 years of age, completed a mailed questionnaire with a medical history and suspected risk factors for disease. Every 2 years, another questionnaire has been sent to update and expand this information and to identify incident diseases. For this analysis, we used 1980 as the baseline and included only the women who completed the initial diet assessment (n = 92 468). We excluded women if they reported prevalent AMD at baseline, reported a diagnosis of cancer, or failed to respond to any biennial questionnaire with an AMD assessment. Only postmenopausal women at least 50 years of age were included. Women with a natural menopause or one due to a bilateral oophorectomy were classified as postmenopausal at the age when this occurred. For women who reported that their periods ceased after a simple hysterectomy or removal of only 1 ovary, we did not classify them as postmenopausal until age 56 years if a current smoker or 54 years if a nonsmoker, the ages by which 90% of the NHS women with a natural menopause had become postmenopausal. At the 1980 baseline, there were 19 943 women in the analytic population, and the total grew to 74 996 as women became eligible.
Participants were first asked on the 1986 questionnaire to report any previous diagnosis of AMD, and subsequent diagnoses were ascertained on every later biennial questionnaire. We received 4186 reports of AMD from women who provided dietary information in 1980 and had no previous report of cancer. We attempted to contact each participant's eye physician to send us eye examination records and to complete a questionnaire that asked (per eye) for confirmation of AMD, the date of initial diagnosis, presence of diagnostic signs, and the best-corrected visual acuity. The diagnosis was denied by the eye physician for 844 of these reports, and we were unable to confirm the diagnosis for 264 women who had died or were otherwise unreachable and 775 for whom we could not obtain ocular records. Of the remaining 2303 reports, 1073 had been judged by the participant's eye physician to have AMD severe enough to cause a visual acuity of 20/30 or worse. Cases were further excluded if the date of diagnosis was before 1980 or after the end of follow-up, or if the participant was not postmenopausal or was younger than 50 years at the time of diagnosis. The remaining 970 cases of AMD were included in the analyses. Of these, 554 were classified as early AMD (drusen and/or retinal pigment epithelial [RPE] abnormalities only) and 334 as neovascular AMD (RPE detachment, choroidal neovascularization, and/or disciform scar). Cases of geographic atrophy (n = 82) were too few to analyze separately. To validate our confirmation of AMD, we obtained 30° color stereo photographs from 180 cases, of which 143 were of sufficient quality to grade. Two retinal specialists independently judged 95% of the early cases and 92% of the advanced cases to be definite or probable AMD.
At cohort initiation, women who reported that they were a current or past user of PMHs or OCs were asked for their total duration of use of each medication. Subsequent biennial questionnaires updated the status of OC use and requested months of PMH use since the previous questionnaire. At each 2-year follow-up cycle, we calculated the total duration of use and time since last use. Women were also asked for the brand name and/or type of their PMH preparation.
Every biennial questionnaire asked participants whether their menstrual periods had ceased, their age at that event, and the reason for cessation (natural or surgical). Self-reported menopause and age at menopause were found to be highly accurate in this cohort.23 Age at menarche was reported on the initial 1976 questionnaire, and the number of births was ascertained through the 1984 questionnaire. We calculated reproductive years and the time between ages of menarche and menopause.
Smoking, body weight, and hypertension were assessed on every biennial questionnaire, and recreational activity was reported in 1980 and on 8 subsequent questionnaires. Dietary factors that were associated with AMD in previous reports from the NHS24- 27 (ie, daily intakes of lutein plus zeaxanthin, alcohol, fruit, and fish) were measured with a food frequency questionnaire in 1980 and at least every 4 years thereafter.
For each participant, follow-up began at the return of her 1980 questionnaire or the first questionnaire on which she was classified as postmenopausal and was at least 50 years of age. Follow-up ended with a report of AMD, a report of cancer, lack of any further questionnaire response, death, or end of follow-up on June 1, 2002. A total of 972 218 person-years were accrued from the 74 996 women. Follow-up time was allocated to the exposure and covariate variables at the beginning of each 2-year questionnaire cycle.
Cox proportional hazards models were used to compute relative risks of AMD for each exposure category compared with a reference category, using age in months as the time variable. The multivariate models included all assessed risk factors, and the exogenous and endogenous estrogen exposures were also adjusted for one another. In models of past PMH use, duration, and time since quitting were mutually adjusted because these variables are negatively correlated (Pearson correlation, −0.26). To assess dose-response effects, P values for linear trend were calculated using continuous values. Interaction between PMH use and OC use was assessed with the P value of the multiplicative term in a model with the main effects.
After adjusting for age differences, current PMH users were more likely to have used OCs in the past (52%) compared with past users of PMHs (39%) and those who had never used PMHs (never users) (32%) (Table 1). They also had a lower mean body mass index (calculated as weight in kilograms divided by height in meters squared), were less likely to be a smoker, and had accrued fewer pack-years if they had ever smoked. Women who never used PMHs were unlikely to have had menopause resulting from removal of their ovaries and/or uterus, and, if parous, had a higher mean number of children. Age at menopause and reproductive years, calculated only among the women with a natural menopause or one resulting from a bilateral oophorectomy, were highest among the never PMH users.
Risk of early AMD was a significant 34% higher among current PMH users (relative risk [RR] = 1.34; 95% confidence interval [CI], 1.06-1.68) compared with never users after adjusting for age and the other exposures and potential risk factors (Table 2). The increased risk was evident only with 3 or more years of use. Risk was elevated for both the estrogen-only and estrogen-plus-progestin preparations. There was no indication of a lasting effect in past users, nor was there any evidence that risk decreased linearly with longer time since last use (P = .11). Risk of early AMD was highest in past PMH users with less than 3 years of use and declined with longer durations of past use (P = .03). Use of OCs was not associated with risk of early AMD in these postmenopausal women.
For neovascular AMD, risk was a significant 48% lower for current PMH users (RR = 0.52; 95% CI, 0.38-0.71) in the multivariate model, but there was no evidence that risk declined with longer use (P = .47) (Table 2). Estrogen-only and estrogen-plus-progestin preparations provided equal benefit. As a whole, past PMH users experienced a nonsignificant 15% lower risk of neovascular AMD, with an attenuation of benefit with greater time since last use (P = .07). In a post hoc analysis, risk was a significant 34% lower (RR = 0.66; 95% CI, 0.47-0.94) for up to 15 years since the last PMH use. Past OC use was also inversely associated with risk of neovascular AMD when compared with never users, although the result did not reach statistical significance (RR = 0.79; 95% CI, 0.60-1.04). Although PMH and OC use were controlled for one another in the multivariate models, we also analyzed the 2 together as a cross-classified variable because the potential for confounding was high. Women who were current or past users of PMHs but had never used OCs had a 21% lower risk of neovascular AMD compared with women who had never used either medication, and risk dropped further to be a notable 56% lower for ever users of PMHs who had used OCs in the past. No benefit was observed for past OC users who never used PMHs during menopausal years. The interaction between PMH and OC use was significant (P = .03).
The associations between PMH use and risk of AMD were robust when stratified by several other risk factors. Current PMH use conferred a decreased risk of neovascular AMD and an increased risk of early AMD for women in the following strata: age younger than 70 years and age 70 years or older; menopause that was natural, menopause after removal of 2 ovaries, and menopause after removal of the uterus only and/or 1 ovary; body mass index less than 25 and 25 or greater; and past and current smokers and those who had never smoked.
The only significant finding for the endogenous estrogenic factors was a 26% lower risk of early AMD for parous women (RR = 0.74; 95% CI, 0.55-0.99) (Table 3). Risk did not decline with increasing number of children (P = .21). We also observed 2 opposite, though weak, associations for the early and late stages of disease: women who became postmenopausal after removal of both ovaries had a lower risk of early AMD and a higher risk of neovascular AMD compared with women whose menopause occurred naturally; and lower risks were associated with older ages at menarche for early AMD but with younger ages for neovascular AMD.
In this cohort of postmenopausal women, current PMH use was associated with a 34% higher risk of early signs of AMD but a 48% lower risk of the late-stage neovascular form of the disease. Past OC use during premenopausal years provided additional benefit for neovascular AMD, suggesting lifetime or long-term exposure to estrogen as the most relevant exposure. However, other results did not support this hypothesis, including no observation of a lower risk with longer durations of PMH use, older age at menopause, or longer reproductive years.
Few previous studies have had a sufficient number of late-stage AMD outcomes to report an association for PMH use with confidence, but most supported our finding of a beneficial effect. Although based on only 20 cases, recent results from the Women's Health Initiative22 showed a significant 71% lower risk of neovascular AMD for the women treated with estrogen plus progestin for an average of 5 years compared with the group taking a placebo. Two case-control studies also reported lower risks of neovascular AMD for current PMH users.12,14 However, no benefit of PMH use was found for late-stage AMD in 2 cohort studies,13,15 although case numbers were too low to assess the association.
The effects of estrogens are mediated through specific nuclear receptors, and both estrogen receptors α and β have been detected in the retina and RPE.28,29 There are several mechanisms by which estrogen may work to protect against AMD. With increasing age, oxidative stress contributes to the degeneration of RPE through cell apoptosis,30 and estrogen may be involved in the regulation of RPE cell function to promote their survival.31 Various estrogen compounds, found both naturally and in PMH preparations, have been shown to be potent antioxidants.32 Most other suspected environmental factors for AMD, including exposure to sunlight, cigarette smoking, and consumption of antioxidant nutrients, have oxidative stress as a common denominator. It has also been proposed that AMD shares a pathogenic process with atherosclerosis, evidenced by the accumulation of lipid in the sclera and in the Bruch membrane, which progressively increases the stiffness of these tissues and impairs choroidal blood flow.10,33 A population-based study34 has reported wider arteriole diameters in the retina in women compared with age-equivalent men, although the lack of an observed difference in retinal arteriolar diameters in current PMH users and never users of PMH35 casts doubt as to whether this may be attributed to estrogen exposure. Estrogens may also exert biological function by regulating the expression of genes relevant in the turnover of extracellular matrix such that an estrogen deficiency predisposes to accumulation of collagens and other proteins between the RPE and Bruch membrane.36 In the retina, estrogen can also downregulate the genetic expression of YKL-40,37 an inflammatory marker that plays a role in angiogenesis and may promote development of neovascular AMD.
The increased risk of early AMD among the women in this cohort who had been using PMHs for at least 3 years was an unexpected observation. Other estrogen exposures did not support this finding, including no association with OC use or with reproductive years. To our knowledge, no previous research has reported an increased risk of early AMD for PMH users or for other estrogen-related exposures. Rather, several studies have reported a lower risk with PMH use,19,21,22 OC use,21 longer reproductive years,13 and early menarche.18 Because drusen may not progress or may even fade over time,38 it is possible that risk factors differ for early AMD that does advance to later stages. However, we expected consistency in our results because our definition of early AMD required a visual acuity of 20/30 or worse to minimize identification of cases that would not be enduring.
It is possible that our contradictory results for early and neovascular AMD are attributable to misclassification of our self-reported diagnoses, although cases were confirmed with ocular records and information provided by the participant's eye physician. Misclassification would more likely be caused by differences between the confirmed cases and the 25% of the reported diagnoses for whom we were unable to obtain medical records. However, PMH use in this group (39%) was not very different from that in our confirmed cases (34%). Because our cases were identified and classified when first diagnosed, it is possible that the conflicting results were an artifact of the data, occurring because PMH users received eye examinations at an earlier age than nonusers and therefore had their condition diagnosed at an earlier stage of disease. Although we could not assess this directly with available data, the high percentage of both current users of PMHs (83%) and those who had never used them (78%) who reported in 1990 that they had had an eye examination within the past 2 years does not support this possibility.
The prospective collection of exposure data and the large number of AMD cases are the primary strengths of this study. With repeated assessments over the 22 years of follow-up, we were able to examine PMH use in more detail than in previous studies, including analyses of duration of use and time since last use. Assessment of other factors that contribute to lifetime estrogen exposure provided additional information for determining the strength of our observations. Although we controlled our analyses for other risk factors for AMD, it is possible that a healthier lifestyle and earlier screenings for eye disease among PMH users are at least partially responsible for the observed results. To minimize this possibility, we limited our analysis to women who had had at least 1 eye examination during the follow-up period, and we required all women who were cases in this study to have had a visual acuity loss of at least 20/30 owing to AMD.
In conclusion, current use of PMH and previous use of OC were associated with lower risks of neovascular AMD in this cohort of postmenopausal women. However, the endogenous factors did not support a benefit from lifetime estrogen exposure. The higher risk of early AMD among PMH users was unexpected and in apparent conflict with the observed inverse association for neovascular AMD. Taken together, these findings suggest a role for estrogen in the pathogenesis of AMD that requires further research in specific early and late signs of disease.
Correspondence: Diane Feskanich, ScD, Brigham and Women's Hospital and Harvard Medical School, Channing Laboratory, 181 Longwood Ave, Boston, MA 02115 (firstname.lastname@example.org).
Submitted for Publication: March 30, 2007; final revision received August 17, 2007; accepted September 30, 2007.
Financial Disclosure: None reported.
Funding/Support: This research was supported by grants CA87979 and EY09611 from the National Institutes of Health.