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American Journal of Epidemiology Advance Access published online on March 21, 2008
American Journal of Epidemiology, doi:10.1093/aje/kwn046
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American Journal of Epidemiology © The Author 2008. Published by the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oxfordjournals.org.

Original Contribution

Predictors of the Timing of Natural Menopause in the Multiethnic Cohort Study

Katherine DeLellis Henderson1, Leslie Bernstein1, Brian Henderson2, Laurence Kolonel3 and Malcolm C. Pike2

1 Department of Cancer Etiology, City of Hope National Medical Center, Duarte, CA
2 Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA
3 Cancer Research Center of Hawaii, University of Hawaii, Honolulu, HI

Correspondence to Dr. Katherine DeLellis Henderson, Division of Population Sciences, Department of Cancer Etiology, City of Hope National Medical Center, 1500 East Duarte Road, Duarte, CA 91010 (e-mail: khenderson{at}coh.org).

Received for publication August 3, 2007. Accepted for publication February 11, 2008.


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 
The timing of natural menopause has implications for several health endpoints; in particular, it is a risk factor for breast cancer. The authors investigated factors influencing the timing of natural menopause among 95,704 women with a mean age of 59.7 years (10th–90th percentile range, 47.0–71.0) in five racial/ethnic groups in the Multiethnic Cohort Study, including non-Latina Whites, Japanese Americans, African Americans, Native Hawai'ians, and Latinas. The authors investigated whether race/ethnicity and several lifestyle and reproductive characteristics were associated with the timing of natural menopause. Race/ethnicity was a significant independent predictor of the timing of natural menopause. Other factors, including smoking, age at menarche, parity, and body mass index, did not significantly alter the race/ethnicity-specific hazard ratios. Relative to non-Latina Whites, natural menopause occurred earlier among Latinas (US-born Latinas: hazard ratio (HR) = 1.10, 95% confidence interval (CI): 1.07, 1.14; non-US-born Latinas: HR = 1.25, 95% CI: 1.21, 1.30) and later among Japanese Americans (HR = 0.93, 95% CI: 0.90, 0.95). These results support the hypothesis that the timing of natural menopause is driven by a combination of genetic, reproductive, and lifestyle factors.

cohort studies; continental population groups; epidemiologic factors; menopause

Abbreviations: CI, confidence interval; HR, hazard ratio


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 
The timing of natural menopause is an important risk factor for breast cancer. Women who experience later natural menopause have higher rates of breast cancer than do women with earlier natural menopause. In 1972, Trichopoulos et al. (1) reported that women who had experienced natural menopause at age 55 years or older had a twofold greater risk of breast cancer than women who had experienced natural menopause before age 45 years. In 1983, Pike et al. (2) proposed a breast cancer risk model that reflected the exposure of breast tissue to hormones over the life span; according to this model, the age-related increase in breast cancer risk begins to decelerate distinctly at menopause. This age-incidence curve and the role of the timing of natural menopause as a breast cancer risk factor have since been firmly established (see reviews by Bernstein (3) and Hankinson et al. (4)).

The biologic mechanism that accounts for the association between the relative timing of menopause and breast cancer risk is hypothesized to be hormonal. Circulating levels of estradiol and progesterone, hormones produced by the ovary during ovulatory menstrual cycles which have been associated with breast cancer risk (5), decline markedly during the menopausal transition. The breast tissue of a woman who experiences menopause later will have greater cumulative exposure to these hormones than the breast tissue of a woman who experiences menopause earlier.

Lifestyle and reproductive factors such as smoking and parity have been associated with the timing of natural menopause; however, the variance in age at natural menopause that is explained by such factors is estimated to be low, less than 10 percent (6). This finding, in combination with observational studies implicating familial factors in the timing of natural menopause (7, 8) and twin studies showing significant heritability for age at natural menopause (9–12), has supported the hypothesis that the timing of natural menopause is a heritable trait.

Despite a growing body of evidence showing that the timing of natural menopause is likely to be a heritable trait, the relative timing of natural menopause across racial/ethnic groups has not been established. Some investigators have reported that American women of African ancestry experience natural menopause earlier than American non-Latina Whites (13–16); others have reported that American women of Asian ancestry experience natural menopause later than American non-Latina Whites (13, 17, 18). The Multiethnic Cohort Study is a population-based study of non-Latina Whites, Latinas, African Americans, Native Hawai'ians, and Japanese Americans in Hawai'i and Los Angeles, California, that provides an excellent resource for examining the effect of race/ethnicity in the timing of natural menopause while controlling for a variety of other factors.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 References
 
Participants in the Multiethnic Cohort Study were recruited between 1993 and 1996 through targeted mailings to men and women aged 45–74 years. A total of 215,251 men and women completed a self-administered baseline questionnaire that obtained information on medical history, family cancer history, diet, medication usage, physical activity, smoking history, alcohol intake, and women's reproductive history, including menopausal status and hormone use. A description of the methods used to create the cohort and the characteristics of cohort members has been published elsewhere (19). The proposal for this work was approved by the institutional review boards of the University of Southern California and the University of Hawai'i. Informed consent was obtained in writing from cohort participants, as per the protocol.

A total of 103,893 female African-American, Japanese-American, Native Hawai'ian, Latina, and non-Latina White cohort members with no history of breast, ovarian, or endometrial cancer were eligible for this study. Of these, 95,704 women with a mean age of 59.7 years (10th–90th percentile range, 47.0–71.0) had valid nonmissing data for the variables of interest and were included in the final analysis (table 1). Only data from the baseline questionnaire were used in the current analysis.


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  		TABLE 1. Characteristics of subjects by racial/ethnic group (N = 95,704), Multiethnic Cohort Study, 1993–1996

 
A woman was considered postmenopausal if her menstrual periods had stopped naturally or if she had undergone a hysterectomy or bilateral oophorectomy. Women in the second category were censored in this analysis, as were premenopausal women. For 1,452 women who were missing data on age at menopause but for whom we had data on when they began using hormone therapy, the age at initiation of hormone therapy was assigned as the age of menopause.

Age at menopause was recorded in the baseline questionnaire in four categories: <45, 45–49, 50–54, and ≥55 years. Women who were older at baseline than the maximum age of the selected category were assigned an event age at the midpoint of the category (43, 47, 52, or 57 years). If a subject's age at baseline was within the category she selected for her age at natural menopause, her event age was calculated as the midpoint between the start of the category and her age at baseline. Premenopausal subjects were assigned a censoring age in a parallel manner. For example, a 53-year-old premenopausal woman was censored at age 51.5 years, the midpoint between her age at menopause and the start of the corresponding age-at-menopause category.

Categories of age at hysterectomy or bilateral oophorectomy were <45, 45–49, and ≥50 years. Subjects reporting menopause by surgery in one of the first two categories (<45 years or 45–49 years) were assigned a censoring age in a manner parallel to the manner in which naturally menopausal subjects were assigned an event age. Women with surgical menopause whose age at baseline was older than the highest age of the self-reported age-at-surgery category were assigned a censoring age at the midpoint of the self-reported age-at-surgery category (43 years or 47 years). If a subject's age at baseline fell within the category she selected for her age at surgery, the censoring age was calculated as the midpoint between the start of the category and her baseline age. Subjects reporting menopause by surgery in the highest category (≥50 years) were treated in a different manner, because the age at natural menopause had one additional category on the upper end (≥55 years). Subjects between 50 and 54 years of age at baseline were assigned a censoring age at the midpoint between their baseline age and 50 years. Subjects aged 55–57 years at baseline were censored at the midpoint between their baseline age and 55 years, and those older than 57 years at baseline were censored at age 57 years.

In addition to race/ethnicity, we considered the following factors, on which data were collected at baseline, as potential predictors of the timing of natural menopause: smoking history, age at menarche, age at first full-term pregnancy, parity, years of oral contraceptive use, and body mass index (weight (kg)/height (m)2). Table 1 shows the categories used for each of these factors. Smoking history was defined by a six-level variable that separated women whose smoking might have been temporally relevant to menopause (never smoker, smoker who started smoking after age 45 years, smoker who quit before age 45 years and smoked ≤10 cigarettes per day, smoker who quit before age 45 years and smoked >10 cigarettes per day, current smoker at age 45 years who smoked ≤10 cigarettes per day, and current smoker at age 45 years who smoked >10 cigarettes per day). Body mass index was categorized according to World Health Organization guidelines (<20, 20–24.9, 25–29.9, or ≥30) (20).

We used univariable and multivariable Cox proportional hazards regression with age as the time metric (21) to assess the association (hazard ratio) between exposure and outcome variables. Subjects were considered to have entered the study at birth and remained under follow-up until they completed the baseline questionnaire (when they joined the Multiethnic Cohort Study) or until one of the following events occurred: natural menopause (event) or surgery resulting in the end of menses, including hysterectomy and/or bilateral oophorectomy (censored observation). Thus, women who were premenopausal at baseline were censored at the age at which they joined the cohort. Analyses were performed using PROC TPHREG in SAS, version 9.1 (SAS Institute, Inc., Cary, North Carolina). A hazard ratio less than 1.0 indicates that natural menopause for the exposed group occurred later than it did in the unexposed (referent) group.

A series of univariable analyses were performed in which a model with each single variable of interest was tested by likelihood ratio test against a model that fitted only an intercept term. Variables showing statistically significant associations with timing of natural menopause in univariable analyses were subsequently tested for independent associations in a multivariable model. We fitted a series of multivariable failure-time models in which a woman failed at the time of natural menopause and which included both race/ethnicity and smoking to determine the factors associated with the relative timing of natural menopause. A forward stepwise regression approach was used, with variables entering the model when at least one of the categories had a p value less than 0.01. Once a full model was identified, a backward stepwise regression approach was used, with variables being excluded when no category had a p value less than 0.01. Trend tests for ordinal variables were performed by fitting as a single variable the ordinal categories of increasing exposure. A test for interaction with race/ethnicity was performed on each covariate retained in the final model. All statistical significance levels (p values) quoted are two-sided. An alpha level of 0.05 was used as the threshold for statistical significance, unless otherwise explicitly stated.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 References
 
The study population included a substantial proportion of Japanese-American (27.8 percent), non-Latina White (25.4 percent), Latina (20.8 percent), and African-American (18.8 percent) women (table 1). In addition, 7.2 percent were Native Hawai'ians. Of the Latinas, 48.5 percent had been born outside of the United States. A chi-squared test for the difference in the proportions of subjects by racial/ethnic group for each variable shown in table 1 was statistically significant (all p's ≤ 0.01). In characterizing the study population, African Americans tended to be somewhat heavier and to have earlier first full-term pregnancies and were more likely to have undergone surgical menopause (hysterectomy and/or bilateral oophorectomy (43.1 percent)) than women in any of the other racial/ethnic groups. In table 1, participants in the category of surgical menopause by bilateral oophorectomy may also have had a hysterectomy, whereas participants categorized as having undergone surgical menopause by hysterectomy had only ever had a hysterectomy. Native Hawai'ians were the youngest of the racial/ethnic groups and were relatively overweight. Japanese Americans were leaner, were less likely to smoke (as were the non-US-born Latinas), and had a later age at first full-term pregnancy than women in other racial/ethnic groups. A greater proportion of non-Latina Whites were nulliparous than women in other racial/ethnic groups. Non-US-born Latinas had later ages at menarche than US-born Latinas.

In the univariable analyses, race/ethnicity and smoking were significantly associated with the timing of natural menopause (data not shown). Thus, in testing of additional variables, we retained race/ethnicity and smoking in the models. Age at menarche, age at first full-term pregnancy, parity, years of oral contraceptive use, and body mass index were significantly associated with relative timing of natural menopause in univariable analyses with race/ethnicity and smoking forced into the model. Of these factors, age at menarche, parity, and body mass index were significantly independently associated with relative timing of natural menopause in the multivariable model, in addition to race/ethnicity and smoking (table 2).


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  		TABLE 2. Multivariable Cox proportional hazards ratios for the relative timing of natural menopause, Multiethnic Cohort Study, 1993–1996

 
In table 2, the independent effect of race/ethnicity in the timing of natural menopause in the multivariable model is evident. Latinas, particularly those not born in the United States, experienced significantly earlier menopause than did non-Latina Whites (non-US-born Latinas: hazard ratio (HR) = 1.25, 95 percent confidence interval (CI): 1.21, 1.30; US-born Latinas: HR = 1.10, 95 percent CI: 1.07, 1.14). Native Hawai'ians showed a borderline-significant effect that pointed in the same direction as the effect for Latinas (HR = 1.05, 95 percent CI: 1.01, 1.09). African Americans did not differ significantly from non-Latina Whites (HR = 0.99, 95 percent CI: 0.96, 1.02). Japanese Americans experienced later menopause than non-Latina Whites (HR = 0.93, 95 percent CI: 0.90, 0.95). Race/ethnicity-specific hazard ratios were obtained from a series of models in which race and smoking were forced in and into which each covariate associated with the timing of natural menopause was added individually. A comparison of these models showed no alteration in the race/ethnicity-specific hazard ratios (data not shown).


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
References
 
Age at natural menopause in the developed world is approximately normally distributed, ranging between 40 years and 58 years, with an approximate mean of 51.4 years (22). This broad range may be due to real differences in age at natural menopause, driven by variation in an incompletely defined set of predictors. It may also be attributed to methodological issues, including differing or problematic methods of classification of menopausal status, use of convenience samples such as hospital patients, potentially inaccurate recall in retrospective assessment of age at event and covariate information, inconsistent treatment of hormone therapy users, lack of data on demographic and physiologic covariates, and paucity of data on diverse populations (see reviews by the World Health Organization (23) and Crawford (24)). In the current study, we investigated a host of lifestyle and reproductive variables that may influence the timing of natural menopause in the large, population-based Multiethnic Cohort Study cohort. In this racially/ethnically diverse study of over 90,000 women, Japanese-American race/ethnicity was independently associated with relatively late natural menopause and Latinas were found to experience relatively early natural menopause, with those born in the United States experiencing the event later than those born outside the United States. Adjustment for other factors did not significantly alter the magnitude of these racial/ethnic effects.

Most previous studies that assessed predictors of the timing of natural menopause did not address whether the timing of natural menopause differed by race/ethnicity, because of the predominance of European ancestry in the study populations (6, 25–31). The findings of one prospective study (13) and three cross-sectional studies (14–16) suggested that African-American women experienced natural menopause earlier than non-Latina Whites; Gold et al. (17) reported that Japanese Americans experienced menopause later than non-Latina Whites. None of these findings were conclusive.

The independent racial/ethnic effect reported in this study does not discount the hypothesis that age at natural menopause is a heritable trait. Torgerson et al. (8) reported an association between age at natural menopause and maternal age at natural menopause in a study of 551 women. Investigators have reported heritability estimates for age at natural menopause that have ranged from 31 percent to 63 percent (11, 12, 32, 33). Genome-wide linkage studies with age at natural menopause as a continuous quantitative phenotype have identified several loci with strong signals (34, 35). Other studies have suggested associations with single nucleotide polymorphisms in genes in several pathways (36–41).

Of all environmental factors studied previously, smoking has been most consistently associated with the timing of natural menopause (17, 42–48). We have reported a dose-response relation between timing and amount of smoking and age at natural menopause that is consistent with evidence from a quantitative review (49). The mechanism by which smoking affects the timing of natural menopause is not fully understood, and it is likely to involve more than one pathway (50–53).

Reproductive factors, particularly those hypothesized to influence ovulation or follicle attrition, are somewhat controversial with respect to timing of natural menopause. The direction of our results regarding age at menarche (54) and parity (13, 25, 27, 48) is consistent with previous reports. In our data, it appears that women with a low body mass index (body mass index <20) have an earlier age at natural menopause than heavier women. In the postmenopausal period, women with a high body mass index have higher circulating levels of estrogen than leaner women through the increased aromatization of androstenedione that occurs in body fat (55). It is possible, in women transitioning through menopause (i.e., perimenopausal women), that some additional adipose-tissue-derived estrogen may support the continuation of menstrual cycles in heavier women relative to leaner women.

The current study had several strengths. The multiethnic design enabled us to attempt to address whether the timing of natural menopause differed by racial/ethnic group. Extensive information from the baseline questionnaire offered us the opportunity to assess racial/ethnic variation in the timing of natural menopause while controlling for a number of potentially confounding factors. Use of a failure-time modeling approach enabled us to avoid excluding a large proportion of subjects.

However, this analysis was potentially limited by several factors. In particular, this is a cross-sectional data set and it may contain errors in recall. For example, we might predict that increased error in recall would be associated with increasing age or decreasing socioeconomic status. To assess this quantitatively, we conducted an analysis limited to women who were less than 60 years of age at baseline. We also tested the addition of an attained education variable (high school or less, some college/vocational school, college graduation or higher) as a surrogate for socioeconomic status. Finally, we limited the analysis to women with an education in the higher two categories. With no method did any of the race/ethnicity-specific hazard ratios change by more than 10 percent. These results argue against differential recall by age and socioeconomic status.

Another limitation stems from the fact that the variable for age at natural menopause was categorical, which prevents the easy translation of the hazard ratios into a difference in years or months. However, to provide an idea of what a hazard ratio means in terms of months, we used a method published by Krailo et al. (56). Assuming a median age at natural menopause of 50 years, a hazard ratio of 1.25, corresponding to the largest multivariate race/ethnicity-specific hazard ratio reported herein, which was specific to the non-US-born Latinas, would translate into a difference of 0.72 years or 8.64 months. In addition, there was a small group of women (n = 1,452; 1.5 percent of the total) who were missing data on age at menopause but for whom we had data on when they began using hormone therapy. For these women, we defined age at menopause as the age at which they reported starting the use of hormone therapy. By definition, these women will tend to have been assigned a menopausal age lower than their true age at menopause. This would mean that groups with higher proportions of such women would appear to have had an earlier menopause. We tested whether our coding was biasing our results in several ways, including 1) entering an indicator variable (1 = age at menopause assigned as age at first use of hormone therapy, 0 = age at menopause known) in the final multivariable model, 2) censoring the women with an age at menopause assigned as age at first use of hormone therapy at the age at first use of hormone therapy, and 3) excluding all of the women with an age at menopause assigned as age at first use of hormone therapy. There was no significant change in the race/ethnicity-specific hazard ratios, indicating that our coding did not produce material bias.

The categorical nature of these data also posed a problem in choosing a method for assignment of censoring ages. We tested methods extensively. For example, for women older than 55 years at baseline who reported an age at surgical menopause of 50 years or older, we tested several methods, including one in which we assigned a censoring age based on the relative distribution of the timing of natural menopause by race/ethnicity. The estimates for the race/ethnicity-specific hazard ratios did not change significantly from those shown for any of these different methods.

Another possible limitation of our data was our measure of body mass index. Since we did not have access to body mass index as a time-dependent variable, we relied on body mass index at baseline as an approximation of relevant body mass index. We find no conclusive prospective evidence in the literature for an independent effect of menopause on body mass index. In fact, we consider this an interesting future research question. However, there is evidence that weight in women increases with age (55). Thus, the participants who enrolled at older ages (postmenopausal women) will have tended to have higher body mass indices than they had at the age of menopause. For older women, body mass indices will have been overestimated in the model. Measurement bias would be possible if, for example, older women, with overestimated body mass indices, also tended to report later menopause than younger women. These women would then appear to have a higher body mass index and later menopause. However, in a sensitivity analysis excluding women over age 60 years, we found no evidence of bias in race-specific estimates by age.

Use of the failure-time modeling approach to assess predictors of the timing of menopause in this large, multiethnic sample provided us with ample statistical power to detect small differences in the hazard ratios for timing of natural menopause between strata. We were able to show a significant racial/ethnic difference in the timing of natural menopause that was independent of adjustment for potential confounders, and we have provided confirmatory evidence for factors hypothesized to be associated with the timing of natural menopause that had heretofore remained controversial in the literature. These findings support the hypothesis that the timing of natural menopause is driven by a combination of genetic, reproductive, and lifestyle factors.


   ACKNOWLEDGMENTS
 
This work was supported by National Cancer Institute grants CA63464 and CA54281.

Conflict of interest: none declared.


   References
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 

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S. L. Mumford and R. Hasan
Re: "Predictors of the Timing of Natural Menopause in the Multiethnic Cohort Study"
Am. J. Epidemiol., November 1, 2008; 168(9): 1091 - 1091.
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K. DeLellis Henderson, L. Bernstein, B. Henderson, L. Kolonel, and M. Pike
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Age at Menopause Differs -- a Little -- by Race and Ethnicity
Journal Watch Women's Health, July 24, 2008; 2008(724): 7 - 7.
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