Association of Diet with the Onset of Menopause in Japanese Women

Chisato Nagata, Naoyoshi Takatsuka, Norito Kawakami and Hiroyuki Shimizu

From the Department of Public Health, Gifu University School of Medicine, Gifu, Japan.


    ABSTRACT
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
A prospective study was conducted in Takayama, Gifu, Japan, to evaluate the association between diet and the onset of menopause. A total of 1,130 female residents aged 35–54 years who were premenopausal and completed a validated semiquantitative food frequency questionnaire in 1992 were contacted by mail with a follow-up questionnaire in 1998 to update information on menopause. Onset of menopause was defined as a woman's age at the last menstrual period prior to stopping menstruation for 12 months. During the 6-year study period, 296 women experienced natural menopause. The Cox proportional hazards model was used to estimate hazard ratios of the onset of menopause after controlling for age, total energy, body mass index, years of smoking, and age at which regular menstrual cycle began. The authors found that green and yellow vegetable intake was significantly inversely associated with the 6-year incidence of menopause (hazard ratio = 0.71, 95% confidence interval: 0.54, 0.95 for the highest vs. lowest tertile of intake, p for trend = 0.02). Association of carotene intake with the incidence of menopause was of borderline significance (hazard ratio = 0.78, 95% confidence interval: 0.59, 1.04, p for trend = 0.07). Am J Epidemiol 2000;152:863–7.

carotene; diet; menopause; prospective studies; vegetables; women's health

Abbreviations: CI, confidence interval; HR, hazard ratio; HRT, hormone replacement therapy.


    INTRODUCTION
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Previous studies have well described associations of age at menopause with demographic factors (1GoGo–3Go), smoking (1Go, 4Go, 5Go), and reproductive factors (3Go, 6GoGo–8Go). Results have been conflicting except for the finding that menopause occurs earlier in smokers than in nonsmokers. The inconsistent results may be due to the retrospective or cross-sectional nature of the data from most of the studies.

Few studies have addressed the association between diet and age at menopause. To our knowledge, only two studies prospectively assessed the relation of dietary factors with menopause (5Go, 9Go). One included only meat consumption and found no association (9Go); the study did not account for confounding by energy intake. The other study found no association with diet, but the dietary assessment was based on a 24-hour food recall and the sample size was small (n = 185) (5Go). By using a validated semiquantitative food frequency questionnaire, we undertook a prospective study to assess the association between diet and the onset of menopause in a larger sample of Japanese women.


    MATERIALS AND METHODS
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Women were recruited from among those who participated in the Takayama Study (10Go), designed to evaluate the role of diet and lifestyle in the subsequent development of cancer. About 92 percent of all Takayama City, Gifu, Japan, residents aged 35 years or more responded to a self-administered questionnaire that asked for basic demographic information and included items on diet, smoking and drinking habits, exercise, and reproductive history in September 1992. Dietary history was obtained by using a semiquantitative food frequency questionnaire. Participants were asked to indicate the average frequency of intake of 169 food items during the year prior to the study and the usual serving size of each item. Individual nutrient and food intake was estimated from the reported frequency of intake and portion size by using the Standard Tables of Food Composition in Japan (11Go). Questions about the frequency and duration of vitamin use were also asked but were not considered in the estimation of nutrient intakes. Detailed information on the questionnaire, including its validity and reproducibility, has been published elsewhere (10Go, 12Go).

Exercise was assessed by asking participants to indicate the average hours per week spent performing various kinds of activities during the past year. Details are described elsewhere (13Go).

A total of 6,324 women aged 35–54 years were reported to be premenopausal at baseline (September 1, 1992). Information on menopausal status was based on self-report. Of this total, census data showed that 222 women were known to be dead (n = 26) or have moved to another city (n = 196) by the end of 1996. After these exclusions, in August 1998 we randomly selected 1,500 women from those remaining who were premenopausal at baseline and sent them a questionnaire asking whether their menstrual periods had stopped during the past year and, if yes, when their last period was and what the reason was (naturally, by surgery, or by radiation/medication). Onset of natural menopause was defined as the age at the last menstrual period prior to stopping menstruation for 12 months. We sent nonrespondents the same questionnaire with a reminder letter 1 month after the first one. In all, 1,196 (79.7 percent) women responded to the questionnaire, and 23 (1.5 percent) were known to be dead (n = 2) or have moved (n = 21) after 1996. Therefore, the response rate was 81.0 percent. This study was approved by the local institutional review board, and all of the participants provided written informed consent.

To assess the association between dietary variables and the onset of natural menopause, and to adjust for potential confounding factors, we computed hazard ratios and their 95 percent confidence intervals of the incidence of menopause during the 6 years by using Cox proportional hazards models (14Go). Food and nutrient intakes were adjusted for total energy by using the method proposed by Willett (15Go) and were converted into categorical variables based on the tertiles of their distribution among the entire study population. The lowest tertile was the reference category. A hazard ratio of more than 1.00 represented a positive association with the 6-year incidence of menopause.

Each subject's time at risk was computed as the time from study entry (September 1, 1992) to the date of response to the 1998 questionnaire or the onset of natural menopause. Onset of menopause was regarded as the reported age at menopause plus 0.5 years, unless the month of the last menstruation was specified. Those who reported that their periods were stopped by surgery (n = 28) or by radiation or medication (n = 8) were regarded as censored at the reported time of menopause. The first year of the study period was excluded from our analysis to minimize the possibility that perimenopausal symptoms at women's entry into the study might have influenced their diet or their responses to the questionnaire. Therefore, 42 women who reported that they experienced menopause during the first year were excluded. Furthermore, 24 women who reported that they were postmenopausal at the end of the study period but did not report their age at menopause were excluded from analysis. Subsequently, the study comprised 1,130 women. Our sample was sufficient to detect as statistically significant (at the 5 percent level) a hazard ratio of 0.7 for the highest versus lowest tertile of intake, with 80 percent power and 26 percent of the entire population expected to become menopausal during the study period.

Age at study entry, categorized as <=39, 40–42, 43–45, 46–48, 49–51, and 52–54 years, was included as a covariate (dummy variable) in all models. The effects of potential confounders such as body mass index (kg/m2), smoking, age at menarche, parity, exercise, education, oral contraceptive use, and history of chronic diseases were examined by including them as covariates in the models. Tests for linear trends were conducted on continuous variables by using the median values of the categories. All statistical analyses were performed by using SAS software programs (16Go).


    RESULTS
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
The characteristics of the 1,130 women at study entry are presented in table 1. During the study period, 296 women experienced natural menopause and 36 women had surgical menopause. Age at natural and at surgical menopause ranged from 43 to 57 years and from 39 to 54 years, respectively.


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TABLE 1. Baseline (1992) characteristics of 1,130 premenopausal Japanese women studied to assess the association between diet and the onset of menopause

 
Among the nondietary factors considered, body mass index (hazard ratio (HR) = 0.95, 95 percent confidence interval (CI): 0.89, 1.01 for a one-unit increase), years of smoking (HR = 2.02, 95 percent CI: 1.12, 3.63 for >=10 vs. 0 years), and age at which regular menstrual cycle began (HR = 0.59, 95 percent CI: 0.36, 0.99 for >=17 vs. <=12 years) were significantly associated with the onset of menopause after we controlled for age at entry into the study. Therefore, this paper presents the hazard ratios of dietary factors after adjustment for age and these factors (table 2); however, the hazard ratios were similar to those adjusted for only age.


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TABLE 2. Hazard ratios* of menopause, by tertiles of food and nutrient intake,{dagger} for Japanese women studied to assess the association between diet and the onset of menopause, 1992–1998

 
The middle tertile of intake of vegetable protein was significantly positively associated with the onset of menopause (p = 0.007). The middle tertiles of animal fat and cholesterol intakes were significantly positively and inversely associated, respectively, with the onset of menopause (p = 0.02 and p = 0.03). However, the trends were not statistically significant for these nutrients. Carotene intake was nonsignificantly associated with menopause, and the trend was of borderline significance. Green and yellow vegetable intake was significantly inversely associated with menopause, and the trend was also statistically significant.

A total of 279 (24.7 percent) women reported taking vitamin supplements at least once a week at baseline and, among them, 12 women reported use of a beta-carotene supplement. The hazard ratios for the onset of menopause for use of any vitamin and beta-carotene supplements were 1.12 (95 percent CI: 0.86, 1.45) and 0.93 (95 percent CI: 0.34, 2.54), respectively, and were not statistically significant.

Additional adjustments were made for parity, years of education, or history of chronic diseases such as diabetes mellitus, ischemic heart disease, and hypertension. However, the results were not altered substantially.

For women using hormone replacement therapy (HRT), it is generally difficult to discern when menses truly ceases. In our study, 16 women were using HRT at baseline, and an additional 116 women started HRT use sometime during the study period. As we could not collect information on the dates that HRT use started and ceased, we reanalyzed data after excluding all of these HRT users. The results were not substantially different (HR = 0.92, 95 percent CI: 0.67, 1.26 and HR = 0.72, 95 percent CI: 0.52, 0.99 for the middle and the highest tertiles of green and yellow vegetable intake, respectively, p for trend = 0.04; and HR = 1.13, 95 percent CI: 0.82, 1.55 and HR = 0.77, 95 percent CI: 0.56, 1.07 for the middle and the highest tertiles of carotene intake, respectively, p for trend = 0.08).


    DISCUSSION
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
We found that green and yellow vegetable intake was significantly associated with the 6-year incidence of menopause. Green and yellow vegetables are rich in carotenoids. A suggestive inverse association was observed for carotene intake. An antioxidative mechanism may explain these associations. Our finding is supported by laboratory data from a study by Tarin et al., who demonstrated that dietary antioxidant supplementation prevented an age-related reduction in the ovulation rate of the mouse (17Go). High atmospheric oxygen concentrations have deleterious effects on oocyte maturation (18Go). Oxidative stress inhibits steroidogenesis in granulosa cells (19Go) and induces apoptotic cell death of granulosa cells (20Go), which may induce atresia of ovarian follicles. As Tarin et al. suggested, antioxidant supplementation may decrease the proportion of follicles undergoing follicular atresia by counteracting the potential generation of oxidative stress in oocytes and/or granulosa cells. An excess of free-radical production has also been linked to the aging process (21Go). Although menopause was thought for many years to be caused by an exhaustion of ovarian follicles, a recent literature review suggests that age-related changes in the central nervous system initiate the transition to menopause (22Go). The antioxidant activity of carotenoids may be related to the aging of the hypothalamic-pituitary-gonadal axis, which causes menopausal transition such as a change in follicle-stimulating hormone secretion (23Go).

Our previous cross-sectional survey (24Go) showed an inverse association between cholesterol intake and meno-pause. There was a concern that women may reduce their dietary intake of cholesterol after menopause. Compared with case-control studies, for example, prospective studies have the advantage of being able to collect dietary data earlier, before subjects experience menopause. Animal fat and cholesterol intakes were significantly positively and inversely related to the onset of menopause, respectively, in the present study, but the trends were not statistically significant. These observations may have no practical importance. We also failed to confirm the positive association between intake of soy products and menopause observed in our previous study.

As for the nondietary factors considered, we observed significant associations with smoking and with age at which regular menses began. These findings were compatible with those from previous studies (1Go, 4GoGo–6Go), supporting the strength of the present study.

We must consider the methodological limitations of our study. Information on menopause was based on self-report. After a long period of time, precise recall of age at menopause may be difficult. Colditz et al. (25Go) reported that 75 percent of women who were on average 7.6 years past their natural menopause recalled their age at menopause to within 1 year of the recorded data. In addition, we could not distinguish the difference in time of menopause among women who reported the same age (years) at menopause, unless they specified years and months of age at menopause. This measurement error may have affected our results. To obtain more reliable data on menopausal status, more frequent contact with study participants during the follow-up period would have been desirable. Such a design could have enabled us to include follow-up data from those who died or moved to another city during the study period. However, it is unlikely that women whose intakes of green and yellow vegetables or of carotene were higher reported an age earlier than their real age at menopause compared with those whose intakes of these dietary factors were lower.

We used a logistic model to evaluate the association of diet with menopausal status (i.e., pre- or postmenopausal) at the end of the study period, because this outcome is less likely than age at menopause to be affected by misclassification. The results strengthened our findings; for the middle and the highest tertiles, the relative risks of being postmenopausal were 1.02 (95 percent CI: 0.67, 1.55) and 0.60 (95 percent CI: 0.39, 0.92), respectively, p for trend = 0.02, for carotene intake; and 0.67 (95 percent CI: 0.33, 1.02) and 0.51 (95 percent CI: 0.33, 0.77), respectively, p for trend = 0.002, for green and yellow vegetable intake. In addition, a significant association was noted for vitamin E, which is known as an antioxidant (relative risks for the middle and the highest tertiles were 1.07 (95 percent CI: 0.71, 1.60) and 0.58 (95 percent CI: 0.38, 0.89), respectively, p for trend = 0.02).

Misclassification of dietary intake also could have influenced the results. However, it is also unlikely that this type of misclassification is directly dependent on age at menopause.

Although we presented the median values for tertiles of dietary intake, some of them may have been overestimated by our questionnaire. The mean intake estimated from the questionnaire was generally higher (<30 percent) than that estimated from 12 daily diet records.

There was a concern about including women who were still premenopausal at relatively older ages at baseline. Determinants of age at menopause may change over years. Reanalysis limited to 753 women aged less than 45 years at entry into the study showed similar estimates of hazard ratios for carotene and for green and yellow vegetables; the hazard ratios for the middle and the highest tertiles of carotene were 0.85 and 0.66, respectively, and 0.79 and 0.51, respectively, for green and yellow vegetables. Nonetheless, follow-up of younger women for a longer duration is desirable. For the older women, further subanalyses by age group revealed that the magnitudes of the hazard ratios for green and yellow vegetable intake did not differ greatly between women aged 45–49 years (n = 286) and those aged 50 years or more (n = 91); the hazard ratios were 0.94 and 0.85 for the middle and the highest tertiles, respectively, for women aged 45–49 years. The respective hazard ratios were 0.93 and 0.61 for women aged 50 years or more.

The proportion of women who died or moved during the study period was relatively small (about 5 percent). The nonresponse rate was low. Therefore, losses to follow-up of these women should not have influenced the results greatly.

In summary, our results suggest that green and yellow vegetable intake may be associated with the onset of menopause. If this relation is causal, green and yellow vegetable intake could be potentially important in the reproductive life of women. The present study was based on a sample from the general population of Japan. However, considering that the study population is relatively lean, at least compared with the US population, it may not be possible to generalize our results to other populations. The hormonal status of women might also differ among different populations. Additional prospective studies on diet and menopause in other populations are necessary.


    ACKNOWLEDGMENTS
 
This study was supported in part by grant 12670349 from the Ministry of Education, Science, Sports, and Culture in Japan.


    NOTES
 
Reprint requests to Dr. Chisato Nagata, Department of Public Health, Gifu University School of Medicine, Tsukasa-machi, Gifu 500-8705, Japan (e-mail: chisato{at}cc.gifu-u.ac.jp).


    REFERENCES
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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Received for publication August 10, 1999. Accepted for publication January 13, 2000.