From the Epidemiology and Surveillance Research Department, American Cancer Society, Atlanta, GA
Reprint requests to Dr. Carmen Rodriguez, American Cancer Society, 1599 Clifton Road, N.E., Atlanta, GA 30329-4251 (e-mail: Carmen.Rodriguez{at}cancer.org).
Received for publication September 8, 2004. Accepted for publication June 27, 2005.
![]() |
ABSTRACT |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
menopause; mortality; osteoporosis; prospective studies
![]() |
INTRODUCTION |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
There is epidemiologic evidence from five (48
) of six (4
9
) studies for a slightly higher mortality rate among women with a younger age at menopause. However, the increase in mortality was statistically significant in only one study (8
). The largest study, a prospective cohort of 19,731 Norwegian women followed for 37 years, found a higher risk of all-cause mortality associated with a younger age at menopause, but findings for cause-specific mortality were not reported (7
).
Few studies have assessed which specific causes of death may be contributing to the increased mortality associated with earlier menopause. Four (6, 8
10
) of five (5
, 6
, 8
10
) studies reported an increased risk of death from coronary heart disease or cardiovascular disease with younger age at menopause, although none of these associations reached statistical significance. The Nurses' Health Study reported a statistically significant increased risk of coronary heart disease incidence with younger age at menopause (11
). Other than a positive correlation between age at menopause and risks of breast and endometrial cancer (12
, 13
), most studies have found no relation between specific cancers and age at menopause (12
16
). To our knowledge, no studies have examined the association between age at menopause and any other specific causes of death. Importantly, most previous studies on this topic did not adequately account for a possible influence of cigarette smoking and hormone replacement therapy use.
We conducted an investigation in a large cohort of US women who experienced a natural menopause, had never smoked, and had never used hormone replacement therapy, to determine the relation between age at menopause and the risk of death from any cause and specific causes.
![]() |
MATERIALS AND METHODS |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
The vital status of study participants was determined from the month of enrollment through December 31, 2002, using two approaches. Volunteers made personal inquiries in September 1984, 1986, and 1988 to determine whether their enrollees were alive or dead and to record the date and place of all deaths (17). Automated linkage with the National Death Index was used to extend follow-up through December 31, 2002, and to identify deaths among 13,219 women (2 percent) lost to follow-up between 1982 and 1988 (17
). At completion of mortality follow-up in December 2002, 184,718 women (27.3 percent) had died, 489,495 (72.4 percent) were still living, and 2,040 women (0.3 percent) were dropped from follow-up on September 1, 1988, because of insufficient data for National Death Index linkage. Death certificates including codes for multiple causes of death were obtained for 98.4 percent of all women known to have died.
Underlying causes of death were coded from the death certificates according to the International Classification of Diseases, Ninth Revision (ICD-9) (18) and Tenth Revision (ICD-10) (19
). For cause-specific analyses, we grouped the observed deaths into nine main diagnostic categories: coronary heart disease (ICD-9 codes 410.0414.9, ICD-10 codes I20.0I25.9); stroke (ICD-9 codes 430.0438.9, ICD-10 codes I60.0I69.9); other circulatory diseases (ICD-9 codes 390.0405.9, 415.0429.9, and 440.0459.9; ICD-10 codes I00.0I19.9, I26.0I59.9, and I70.0I99.9); all cancer (ICD-9 codes 140.0195.9 and 199.0208.9, ICD-10 codes C00.0C76.9 and C80.0C97.9); respiratory diseases (ICD-9 codes 460.0519.9, ICD-10 codes J00.0J98.9); digestive diseases (ICD-9 codes 520.0579.9, ICD-10 codes K00.0K92.9); genitourinary diseases (ICD-9 codes 580.0629.9, ICD-10 codes N00.0N98.9); external causes (ICD-9 codes E80.0E99.9, ICD-10 codes V01.0Y89.9); and all other causes.
We excluded from the analysis 187,124 women who were not postmenopausal at baseline, 169,489 who may have experienced menopause as a consequence of ovarian surgery or hysterectomy, 49,042 who reported having had a surgery- or radiation-induced menopause, and 61,531 with a missing, invalid, or extreme (before age 40 or after 55 years) reported age at menopause. We further excluded 84,820 women who ever used hormone replacement therapy and 56,093 who ever smoked cigarettes. Cigarette smoking is the most important confounding factor in studies of age at menopause and mortality; smoking decreases a woman's age at menopause by an average of approximately 2 years (20, 21
), and confounding by smoking remained after controlling for smoking in a multivariate model in a study of age at menopause and coronary heart disease (11
). After these exclusions, the analytical cohort consisted of 68,154 women who had experienced a natural menopause and who had not used tobacco or hormone replacement therapy.
Age at menopause was grouped into 5-year categories (4044, 4549, and 5054 years) based on previous epidemiologic studies (4, 5
, 8
, 9
, 11
, 22
, 23
). We tested the linear trends by modeling the medians of the categories for age at menopause as continuous variables.
Cox proportional hazards models were used to compute rate ratios, adjusting for potential confounders. All Cox models were stratified on single year of age at enrollment, and multivariate models were further adjusted for partial year of age. This partial-year variable was created by subtracting a woman's exact age, calculated from her birthday and her date of interview, from her age rounded to the nearest year, and this variable was included as a continuous variable in our multivariate models. Multivariate models were further adjusted for race (White, Black, other), marital status (married, not married/missing), body mass index (weight (kg)/height (m)2) (<25, 25<30, 30, missing), age (years) at menarche (<12,
12, missing), parity (no livebirths, any livebirths, missing), educational level (high school graduate or less, some college, college graduate or more, missing), alcohol consumption (none, former drinker, current
1 drink/day, 23 drinks/day,
4 drinks/day, missing), oral contraceptive use (ever, never, missing), and exercise (none, slight, moderate, heavy, missing). To examine potential effect modification, we modeled multiplicative interaction terms between age at menopause (in 5-year categories) and each covariate. We tested the significance of each interaction by use of the likelihood ratio test, except for the interaction with attained age that was assessed by the Wald
2 test.
![]() |
RESULTS |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
|
|
|
Cancer was the only cause of death for which mortality rates were lower among women with a younger age at menopause. This association was solely due to breast and ovarian cancer deaths (table 3).
Stratified analyses by attained age showed that the increased risk of all-cause mortality with a younger age at menopause was limited to women aged 75 years or older (table 4), because of a strong decreased risk of cancer mortality associated with a younger age at menopause among women younger than 75 years of age. There was no interaction between attained age and any other specific cause of death (table 4). We found no effect modification with any of the following factors: body mass index, alcohol intake, level of education, parity, or exercise.
|
![]() |
DISCUSSION |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Our results for all-cause and coronary heart disease mortality are consistent with those of most previous studies on these topics (48
), and the magnitude of the association is very similar to those reported by the largest previous prospective studies on age at menopause and all-cause mortality (7
) and coronary heart disease mortality (10
). Although the magnitude of the increased risk of coronary heart disease mortality observed in our cohort is modest, it contributes to the overall increase in mortality because 23 percent of the observed deaths were due to coronary heart disease. One of the strengths of our study is the ability to assess the association between specific causes of death in relation to age at menopause.
The association between age at menopause and mortality was limited to older women, contrary to what has been reported in a previous study conducted in Norway (7). Differences by age in the overall association between age at menopause and mortality may be due to a different distribution of causes of death in younger versus older women. The most common cause of death among women younger than 75 years of age in our study was cancer, and cancer was the only specific cause of death for which there was a significant interaction by attained age.
Several biologic mechanisms would support the observed association between younger age at menopause and risk of death from coronary heart disease, respiratory and genitourinary disease, and external causes. First, estrogen receptors are found in most tissues including vascular endothelial cells, smooth muscle cells, myocardial cells, bone, bladder, urethra, and ovary (2, 24
), indicating that all of these tissues may be affected by a decrease in estrogen like that observed in postmenopausal women. Second, estrogen may play a role in the maintenance of immune function; it has been shown that women who underwent surgically induced menopause developed impaired immune function that returned once they were given estrogen replacement therapy (25
). Finally, the observed increases in mortality from respiratory and genitourinary diseases and external causes could also be mediated by osteoporosis. Low estrogen levels are associated with a decrease in bone density and osteoporosis, which often leads to fractures (1
). Common complications of osteoporotic fracture include pneumonia and urinary tract infections (26
29
). Little work has been done to determine the specific causes of death that contribute to excess mortality following osteoporotic fracture, but a few studies of postfracture mortality have indicated that pneumonia, cardiovascular diseases, and renal diseases, including urinary tract infections, have been among the causes of death observed postfracture (30
35
). One study, in particular, indicated that the rate ratio of observed to expected pneumonia deaths among women during the first year after hip fracture was 7.46 (95 percent confidence interval (CI): 6.51, 8.55) and remained high during the second year after hip fracture (RR = 4.00, 95 percent CI: 3.46, 4.62) (35
). Similarly, this study found that the rate ratio of observed to expected renal disease deaths during the second year after hip fracture was 9.36 (95 percent CI: 7.17, 12.22) (35
).
Our questionnaire did not include questions about bone density, osteoporosis, or history of fracture, so we are limited in our ability to explore this hypothesis. However, a subset of the women in the CPS-II cohort were recruited into the CPS-II Nutrition Cohort in 1992, and these women were given a follow-up survey in 1997 (36) that included a question on whether a physician had ever diagnosed them with osteoporosis. Among the 8,226 women who completed the 1997 questionnaire, the age-adjusted prevalence of osteoporosis was higher in women who experienced menopause at a younger age (27 percent for menopause at ages 4044 compared with 20 percent for menopause at ages 5054 years). This is consistent with the hypothesis that the increased mortality associated with a younger age at menopause in our cohort could be partly mediated by osteoporosis.
Strengths of this study include the prospective design and the large sample size, which allowed us to restrict our cohort to women who had never smoked and who had never taken hormone replacement therapy. Additionally, we were able to look at specific causes of death rather than just overall mortality. We were limited, however, by the fact that age at menopause was self-reported and was collected retrospectively, likely resulting in some misclassification of age at menopause. Although misclassification of reported age at menopause may be differential, as suggested by Rockhill et al. (37), with older women falsely reporting a younger age at menopause, we believe that our results are not significantly biased, because we controlled tightly for age and have fit our models using age as the time axis, as well as using calendar time as the time axis. In both models, the results were identical. Finally, although we did have a large sample size, statistical power was still somewhat limited when the specific causes of death were examined.
In summary, results from this study and other studies suggest that a younger age at menopause is associated with a small increase in all-cause mortality and that mortality from coronary heart disease and other causes, such as respiratory disease, genitourinary disease, and external causes, may contribute to the increased mortality.
![]() |
ACKNOWLEDGMENTS |
---|
![]() |
References |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
|