1 Department of Epidemiology and Preventive Medicine, University of California, Davis, Davis, CA.
2 Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA.
3 New England Research Institutes, Watertown, MA.
4 Division of Geriatrics, University of California Los Angeles, Los Angeles, CA.
5 Department of Epidemiology, University of Michigan, Ann Arbor, MI.
6 Department of Preventive Medicine and Community Health, University of Medicine and DentistryNew Jersey Medical School, Newark, NJ.
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ABSTRACT |
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age of onset; ethnic groups; life style; menopause; proportional hazards models; risk factors; smoking
Abbreviations: BMI, body mass index;; SWAN, Study of Women's Health Across the Nation.
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INTRODUCTION |
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Age at natural menopause has also been related to all-cause mortality. In one US population-based study, women who experienced nonsurgical menopause prior to age 40 years had a 50 percent higher mortality rate than those reporting menopause at age 50 years or older (4). Women whose nonsurgical menopause occurred between ages 40 and 50 years had no increased mortality compared with those whose menopause occurred at an older age. Another community-based cohort study reported a 95 percent increase in all-cause mortality associated with nonsurgical menopause occurring before age 40 years compared with menopause at age 50 years or older (2
). However, women aged 4049 years at menopause were also at a 35 percent higher risk of mortality compared with women aged 50 years or older at natural menopause. Several complex causes may underlie the observed relation between earlier age at menopause and mortality, including genetic factors, behavioral and environmental exposures, hormonal mechanisms, and health-related factors. Understanding the associations of these factors with age at natural menopause may help to elucidate the mechanisms underlying the relation of age at menopause to morbidity and mortality.
Most estimates of age at natural menopause are based on samples of Caucasian women in western societies, although one international study of 18,997 women from 11 countries found the median age at natural menopause to be 50 years (range, 4952 years) (7). A few studies of non-Caucasian women, conducted primarily outside the United States, have reported younger ages at menopause than those for Caucasian women. The better-designed studies suggest that Africans (8
, 9
), African Americans (10
, 11
), and Hispanics of Mexican descent (12
) have an earlier age at menopause than Caucasian women do, while Japanese (13
) and Malaysian (14
) women report a median age at menopause similar to that for women of European descent.
The most consistent finding regarding behavioral factors has been that for smokers, menopause occurs 12 years earlier than for nonsmokers (10, 15
19
). With varying consistency, studies have found that an earlier natural menopause is also associated with less education (20
, 21
), low social class (15
, 22
), nulliparity or having fewer children (21
, 23
, 24
), never having used oral contraceptives (21
, 22
, 25
), and low relative weight (18
, 26
). Being on a weight reduction diet has also been associated with earlier menopause (10
). Most of these factors may affect the hypothalamic-pituitary-gonadal axis and its regulation of gonadotropins and sex steroid hormones.
Many prior studies have not had sufficiently large sample sizes to provide stable estimates of age at menopause (10, 27
), did not control statistically for confounding variables, or used inappropriate statistical techniques. In the present study, we analyzed data from a large, multicenter study (Study of Women's Health Across the Nation (SWAN)) of a multiracial/multiethnic sample of women to examine the independent association of a number of factors with age at natural menopause by using multivariate survival statistical techniques to adjust simultaneously for the effects of multiple factors.
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MATERIALS AND METHODS |
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A two-stage recruitment process was used. First, during 19951997, a cross-sectional survey was conducted, by telephone at most sites and in person for about half of the women at two sites (with African Americans as their minority sample), to assess eligibility for enrollment into a cohort study and to collect health, reproductive, demographic, and lifestyle data. Eligibility criteria for the cross-sectional survey were as follows: age 4055 years, self-designated as one of the targeted racial/ethnic groups for the site, residence near one of the seven clinic sites, speaker of English or one of the other selected languages (Spanish, Japanese, Cantonese), and able to give verbal consent. Community-based sampling from established lists of populations at five sites and random digit dialing, combined with a "snowball" approach at two sites (28) (those with the Hispanic and Japanese minority samples), were used. In the snowball technique, women first identified by using a list-based or random-digit-dialing technique were asked for the names and contact information of other women who met the eligibility criteria; these women in turn were contacted, were screened for eligibility, and were asked for the names of other appropriate women. This process continued until a sufficient number of eligible women was identified. In the second stage of the study, a longitudinal cohort was recruited from those women screened and found eligible in the cross-sectional survey. A total of 16,065 women participated in the cross-sectional survey, 3,150 of whom enrolled in the cohort study.
Data collection
Assessment of the outcome (age at menopause). Natural menopause was defined according to the World Health Organization (29) as at least 12 consecutive months of amenorrhea not due to surgery or other obvious cause, such as extreme weight loss. Women who reported that they had had a hysterectomy or oophorectomy (unilateral vs. bilateral was not specified, since in pretests women could not distinguish between the two) were asked the year of surgery; age at surgery was computed by subtracting birth year from the year of surgery. Women not reporting such surgery were asked whether they had menstruated in the past 12 months. Among those with 12 or more months of amenorrhea, women whose periods had not stopped because of surgery, medical treatment, pregnancy, breastfeeding, or severe weight loss were defined as naturally postmenopausal (29
). These women were asked in what year their last menstrual period had occurred; their year of birth was subtracted from this year to obtain age at menopause. Menopausal status was defined as surgical amenorrhea if menses had stopped as a result of hysterectomy and/or oophorectomy, naturally postmenopausal if menses had stopped for at least 12 months without surgery, late perimenopause if menses had occurred in the past 12 months but not in the last 3 months, early perimenopause if menses had occurred in the past 3 months but had become less predictable, and premenopause if menses had occurred in the past 3 months with no decreased predictability.
Independent variables. All independent variables of interest were obtained by self-report during the interview. Included were demographic factors (age, race/ethnicity, educational attainment, employment, marital status, number of children, and ability to pay for basics, i.e., food, shelter, clothing, and heat), lifestyle factors (smoking, physical activity), and health-related factors (height and weight (converted to body mass index (BMI): weight in kilograms/height in meters2), ever having been told by a health care provider that she had heart disease, cancer, hypertension, or diabetes).
Primary race/ethnicity was self-defined as Black or African American, non-Hispanic Caucasian, Chinese or Chinese American, Japanese or Japanese American, or Hispanic (Central American, Cuban or Cuban American, Dominican, Mexican or Mexican American, Puerto Rican, South American, Spanish, or other Hispanic). Respondents could also specify "other," "mixed," or no primary ethnic affiliation. Since most extant literature regarding age at menopause is based on non-Hispanic Caucasians, they were used as the reference group.
Cigarette smoking was categorized as never, former, or current smoker and number of cigarettes currently smoked per day, based on modified American Thoracic Society questions (30). Physical activity was assessed with one global question about activity level relative to other women of the respondent's age (31
).
Data analyses
Approach. Menstrual status groups were compared with respect to key demographic, lifestyle, and health characteristics by using chi-square statistics. We performed bivariate Kaplan-Meier survival analyses (32) and Cox proportional hazards regression analyses (33
) to evaluate the relation of categorical and of continuous variables, respectively, to age at menopause. Variables found in bivariate analyses to be related (p < 0.15), or suggested by previous literature to be related, to age at natural menopause were included in the multivariate Cox proportional hazards analyses.
Exclusions. Women whose menstrual periods had stopped because of medication, radiotherapy, pregnancy or lactation, or extreme weight change (n = 311) were excluded from the present analyses. Also excluded were women whose data on current menstrual status (n = 109) or whose information on any covariate (n = 1,141) was missing. Women who identified their primary race/ethnicity as "mixed" or "other" (n = 1,694) constituted a heterogeneous group whose results could not be interpreted clearly and were thus excluded. The remaining sample size used in this analysis was 14,620.
Cox proportional hazards modeling. Cox proportional hazards models were estimated to assess associations of age at natural menopause with independent variables. Women not currently using reproductive hormones who were not surgically or naturally menopausal were censored at their current age.
Women who had had a hysterectomy and/or oophorectomy (n = 3,069) were censored at their age at surgery, since surgery masks the age at which a woman would become menopausal in the absence of this surgery (34). (We did not have information on whether oophorectomy was unilateral or bilateral.) We also conducted analyses by excluding these women; the result was that overall age at menopause was reduced by 0.4 years and all point estimates changed less than 10 percent (data not shown). Including these women and censoring them assumes that, given their covariate information, the distribution of their "true" age at natural menopause (which cannot be observed) is the same as that for naturally menopausal women. Their inclusion is important because they are not a random subsample of middle-aged women (35
40
); excluding them could lead to biased results. They also constitute a nonnegligible proportion of the population (41
, 42
), and their data may be informative regarding the timing of natural menopause.
Women who had used hormones, including oral contraceptives, in the past 3 months ("current users," n = 1,151) were initially considered in two ways, first by excluding them (10) and then by leaving them in the analysis and censoring at the age computed by subtracting the total number of years of hormone use from their current age. The results of these two approaches did not differ, but the latter approach provided a slightly better model fit; thus, its results are presented in this paper. Data on women whose menopause preceded hormone use were included as menopausal events.
Continuous variables (e.g., parity, BMI) were initially maintained in multivariable models as continuous variables. For ease of interpretation, this paper reports hazard ratios by categories of these variables. For categorical variables, a conceptually logical referent level was selected for comparison. All other levels of ordinal (e.g., educational level) variables were coded as dummy variables, rather than assuming rankings in the models.
Dummy indicator variables for field site were included in the multivariable models (43). For each of the three racial/ethnic groups studied at a single site only (Chinese, Hispanic, and Japanese), the coefficients reflect a direct comparison with the Caucasians at the same site only. Interactions between site and race/ethnicity for these three groups could not be estimated given the study design. Four sites interviewed African Americans and Caucasians, enabling us to examine interactions between race/ethnicity and site for these two racial/ethnic groups, that is, whether the racial/ethnic difference in age at menopause varied across these four sites. We also examined interaction terms for smoking with race/ethnicity, BMI, history of use of oral contraceptives, parity, education, employment, marital status, site, or history of heart disease. Goodness of fit of the multivariate Cox models was assessed by using the link test (44
, 45
).
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RESULTS |
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DISCUSSION |
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Race/ethnicity
Unlike our study, prior studies have reported that age at menopause for Japanese women was similar to that for Caucasian women (51, 52
). One study of 2,221 Japanese women reported a median age at menopause of 50.4 years (13
). Another study of 400 Malaysian women reported a similar median age at menopause of 50.7 years (14
). However, a study of 2,354 Thai women aged 4559 years, sampled from Bangkok health centers in lower-middle socioeconomic status areas, reported a median age at menopause of 49.5 years (53
). Filipino Malay women were reported to be an average age of 4748 years at menopause (54
), although the methods used in both of these latter studies may have biased their results toward lower estimates.
Several studies have reported that Latina women experience natural menopause about 2 years earlier than Caucasian women, but we found no difference after adjustment for covariates. For Mexican women, median ages at menopause have been reported to be 48.2 years (12) and 47 years (22
), although the latter study was based on only currently menopausal women and was thus likely to underestimate median menopausal age. Peruvian and Mayan women, despite their high parity, have also been reported to experience menopause earlier, ranging from age 45 to 47 years (49
, 55
).
Two previous studies also suggested that African-American women experience menopause 612 months earlier than Caucasians, with a median age of 49.3 years for African Americans in both studies (10, 11
), in contrast to our study showing no difference between African Americans and Caucasians, possibly because of the age group of our sample or greater censoring of African Americans because of more surgical menopause. Studies in South Africa (8
) and Ghana (9
) also reported an earlier age at menopause for African compared with Caucasian women, but a small Nigerian study reported the average age at menopause to be 52.8 years (56
).
Smoking
The results of the present study add to a growing body of literature showing that current, but not former, smoking is associated with earlier age at natural menopause after adjustment for confounding factors. Women who smoke stop menstruating 12 years earlier than comparable nonsmokers (10, 15
, 19
, 20
, 46
48
, 50
, 57
59
) and may have a shorter perimenopause (27
). Some studies have reported that heavy smokers have an earlier menopause than light smokers (15
, 18
, 60
, 61
). However, we observed no dose-response effect of smoking, consistent with at least one other study (19
). Previous studies have shown that former smokers have no or only a slightly earlier age at menopause than never smokers (18
, 19
, 62
), suggesting that the effect of smoking may not be permanent, a finding inconsistent with a toxic effect leading to atrophy of ovarian follicles. Polycyclic aromatic hydrocarbons in cigarette smoke are toxic to ovarian follicles (63
, 64
) and could result in their loss and thus in earlier menopause in smokers. Greater prevalence of hysterectomy among premenopausal smokers than nonsmokers (60
, 65
) does not account for the earlier menopause in smokers (66
).
Socioeconomic status
We found that lower educational attainment and nonemployment were significantly, independently associated with earlier age at menopause, although difficulty paying for basics was not. Several previous studies indicate that lower educational attainment and/or socioeconomic status, often determined by occupational status of the woman or her husband, is associated with earlier age at menopause (15, 20
, 21
, 50
), although the findings are not wholly consistent (10
). Social and physical stress are also associated with amenorrhea and reproductive dysfunction (67
, 68
), and low socio-economic status or low educational level may be markers for elevated stress.
Marital status and parity
In our study, separated/divorced/widowed women had an earlier menopause than women who were married or were living as married. For parous women, age at natural menopause occurred significantly later than for nulliparous women, concurring with the results of most previous work (10, 15
, 21
, 23
25
, 27
, 50
, 69
). We observed a trend of increasing age at menopause with increasing number of livebirths, but the trend was not strongly monotonic, unlike that in some previous reports (24
). Since onset of menopause is theorized to be related to the rate of loss of oocytes and thus to the occurrence of ovulatory cycles (21
, 23
, 70
), the proposed mechanism by which parity and use of oral contraceptives may result in later age at natural menopause is by reducing ovulatory cycles earlier in life and thus preserving oocytes longer, resulting in later menopause.
Oral contraceptive use
We found that prior use of oral contraceptives was associated with earlier age at natural menopause, although no relation with increasing duration of use was observed. This finding is consistent with those of some prior prospective studies (49, 50
) but inconsistent with other results (10
, 24
) that either did not use survival analyses or did not control for the effects of covariates.
Body mass
In the present study, BMI and physical activity were not related to age at natural menopause. Although some studies have observed that women with lower BMI had an earlier natural menopause (18, 26
, 69
), other work has not confirmed this finding (10
). In primates and humans, caloric restriction and nutritional deficiencies are associated with amenorrhea (71
73
). The production of estrone in adipose tissue, which is greater in more-obese women, may result in higher levels of circulating estrogens that may contribute to longer reproductive functioning. Obesity, however, has also been associated with inadequate ovarian function (74
).
Heart disease
We found that women who had heart disease were significantly younger at natural menopause, consistent with prior reports showing a protective effect of later age at natural menopause on heart disease morbidity and mortality (34, 75
). However, given the cross-sectional nature of our data, we are uncertain whether natural menopause preceded a diagnosis of heart disease. When we did not include this variable in the multivariate model, none of the findings changed more than 10 percent. Interestingly, 45 percent of the women reporting heart disease had had a hysterectomy and/or oophorectomy, thus resulting in a high proportion of censored women with this condition. Recent work (76
) shows an estrogen receptor polymorphism to be associated with earlier menopause and with surgical menopause. Unlike some (77
, 78
) but not all (79
) studies, age at natural menopause was not related to diabetes or to hypertension in our study.
Strengths and limitations
Our use of multivariate survival analyses (which included and censored women who were still menstruating, had surgical amenorrhea, or were currently using female hormones) enabled systematic examination of the relation of a number of independent variables to age at natural menopause. However, because of the limited time available for the cross-sectional interview, data were not collected on important details such as ages at which reproductive hormones were used and on other potentially important factors such as age at menarche, age at maternal or sibling menopause, history of long or short or irregular menstrual cycles, diet (such as consumption of fat, cholesterol, meat, and phytoestrogens), and alcohol and caffeine consumption (10, 21
, 24
, 50
, 80
, 81
). All of these factors will be studied prospectively in the SWAN cohort, with results available within the next few years. In addition, in the cross-sectional portion of SWAN, we had recalled data on only the year of the final menstrual period and lacked knowledge regarding timing of the factors examined relative to the final period. Furthermore, we had information on only the year of the final menstrual period (surgical or natural); thus, our estimates of age may have been inaccurate by up to 1 year, either older or younger, a source of variability that will be reduced in the cohort portion of SWAN. A final limitation is the varied sampling methods used by the study sites, necessitated by difficulties in achieving the needed sample size of minority populations, making use of formal estimation procedures inappropriate. Thus, the present confidence intervals should be interpreted with caution.
Nonetheless, the present study is one of the largest, is comprised of one of the most diverse study populations, and has been analyzed by using the most comprehensive statistical methods. Thus, the findings regarding the relations with race/ethnicity, current smoking, parity, use of oral contraceptives, educational attainment, and unemployment, and the lack of association with BMI, are likely to be robust and suggest that multifactorial host (possibly genetic) and environmental factors are involved in a likely complex mechanism to determine onset of menopause.
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ACKNOWLEDGMENTS |
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Clinical Centers: University of Michigan, Ann Arbor, Ann Arbor, Michigan (U01 NR04061, Dr. MaryFran Sowers, Principal Investigator (PI)); Massachusetts General Hospital, Boston, Massachusetts (U01 AG12531, Dr. Robert Neer, PI in 19941999; Dr. Joel Finkelstein, current PI); Rush University, Rush-PresbyterianSt. Luke's Medical Center, Chicago, Illinois (U01 AG12505, Dr. Lynda Powell, PI); University of California, Davis/Kaiser, Davis, California (U01 AG12554, Dr. Ellen Gold, PI); University of California, Los Angeles, Los Angeles, California (U01 A12539, Dr. Gail Greendale, PI); University of Medicine and DentistryNew Jersey Medical School, Newark, New Jersey (U01 AG12535, Dr. Gerson Weiss, PI); and University of Pittsburgh, Pittsburgh, Pennsylvania (U01 AG12546, Dr. Karen Matthews, PI). Central Laboratory: University of Michigan, Ann Arbor, Ann Arbor, Michigan (U01 AG12495, Central Ligand Assay Satellite Services, Dr. Rees Midgley, PI). Coordinating Center: New England Research Institutes, Watertown, Massachusetts (U01 AG12553, Dr. Sonja McKinlay, PI). Project Officers: Drs. Taylor Harden, Carol Hudgings, Marcia Ory, and Sheryl Sherman. Steering Committee Chair: Dr. Jennifer L. Kelsey, currently; Dr. Christopher Gallagher, 19941996.
The manuscript was reviewed by the Publications and Presentations Committee of SWAN and has its endorsement.
The authors thank the study staff at each site. They also acknowledge the statistical programming assistance of Yan Luo and Marianne O'Neill Rasor.
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NOTES |
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REFERENCES |
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