Medical Research Council National Survey of Health and Development, Department of Epidemiology and Public Health, Royal Free and University College Medical School, London WC1E 6BT, UK
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Abstract |
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Key words: birth cohort/birthweight/breastfeeding/childhood growth/menopause
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Introduction |
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Since a woman is born with an exhaustible and non-renewable supply of ovarian follicles, the peak number of follicles attained in utero or the number retained at birth have been proposed as the most important determinants of age at menopause (Ginsberg, 1991; Finch and Kirkwood, 2000
). Very little is known about factors that determine the size of the initial pool of primordial follicles or about the subsequent rate of depletion in early postnatal life before ovulation begins (Finch and Kirkwood, 2000
).
There is now considerable evidence that a number of chronic diseases are influenced by growth during the intrauterine period (Barker, 1994). Given that the pool of primordial follicles is formed during fetal development, it is plausible that retarded growth in utero could have a detrimental effect on the number of these follicles (te Velde et al., 1998
) and therefore potentially lead to an earlier menopause (Cresswell et al., 1997
). Few epidemiological studies have investigated the hypothesis. A cohort study of women in Hertfordshire, England (Cresswell et al., 1997
) and a twin study in Australia (Treloar et al., 2000
) have shown that lower birthweight was associated with later, rather than earlier, age at menopause, although in neither case was the association statistically significant. Low weight at 1 year was found to be associated with an earlier menopause in the Hertfordshire cohort (Cresswell et al., 1997
). It is plausible that postnatal growth is associated with the extent of loss of follicles during childhood. Early life nutrition and socioeconomic conditions may be important in this respect since childhood growth trajectories may be influenced by such factors.
The MRC National Survey of Health and Development (NSHD), a birth cohort study where women have been followed up annually through the menopause, provides an ideal opportunity to investigate the hypothesis that early growth, either pre- or postnatal, influences age at menopause. The NSHD has detailed data regarding timing of the perimenopause and menopause, hysterectomy operations and hormone replacement therapy (HRT) use. It also has prospective measures of birthweight and height and weight throughout childhood, information on social conditions in early life and breastfeeding in infancy. In addition, a wealth of information on potential confounding factors throughout the life course has been collected.
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Materials and methods |
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Women experiencing cessation of periods other than by a natural menopause were identified from the health questionnaires where they were asked to provide dates of hysterectomy or bilateral oophorectomy operations. A complete record of HRT use was also collected. The use of the majority of such preparations causes bleeding among post-menopausal women so it was not possible to define age at menopause, according to the definition of menopause based on cessation of menstruation used here, if HRT started before cessation of menstrual cycles was reported.
Explanatory variables
Birthweight of cohort members to the nearest quarter of a pound was extracted from medical records within a few weeks of delivery and converted into kilograms. Birthweight was categorized into a low birthweight group (2500 g) and three further groups (25013000, 30013500 and
3501 g). Height and weight measured at 2 years was chosen for the analysis as they were the earliest postnatal measures of growth in the NSHD. Height and weight at age 7 years were also considered as these are the last premenarcheal measures for all the cohort.
Information on duration of breastfeeding was obtained from mother's reports to health visitors when the survey members were 2 years of age, and was here categorized into never breastfed, breastfed for 3 months, 46 months and
7 months. Father's social class and crowding in the household were used as markers of socioeconomic status in childhood. Social class was assigned from father's occupation when the survey member was 4 years of age, or if this was unknown, from the father's occupation when the survey member was 11 years of age or at the time of birth of the survey member. Those from non-manual and manual origins were distinguished for the purposes of the analysis. A measure of `crowding' at age 2 years was defined using the number of persons per room, with `crowded' being defined as two or more persons per room.
Potential confounding variables
Potential confounders, identified because of their possible association with age at menopause, were parity, smoking, body mass index (BMI), adult socioeconomic status and experience of a unilateral oophorectomy operation. Records of all live births have been collected throughout the adult life of the cohort. Smoking and BMI were defined using information given when the cohort were 36 years of age since this represents a premenopausal measure for all the cohort. Occurrences of unilateral oophorectomy (n = 26) were reported in the women's health questionnaires. Socioeconomic status was represented by spouse's occupational social class, based on the current or most recent occupation at the 43 year follow-up, and the women's own educational qualifications by the age of 26 years.
Statistical methods
Cox's proportional hazard models (Cox, 1972) were used to obtain estimates of the hazard ratio for the risk factors. Follow-up time was in months since age 25 years and was until menopause (n = 412), or, if no date of menopause was available, until the date of one of the following events: hysterectomy (or bilateral oophorectomy) (n = 290), start of HRT use (n = 414) or last returned questionnaire if pre-menopausal or peri-menopausal at that time (n = 398). Follow-up was treated as censored if the event was not menopause. Where the date of menopause was not specified to the nearest month, the mid point of the year of menopause was taken. The small number of women (n = 32) whose periods stopped for other surgical reasons (usually endometrial ablation) or medical treatment (for example, chemotherapy) before the menopause, and those who had or were taking oral contraceptives (n = 23) or for whom data were not complete (n = 3), were omitted.
The assumption of proportional hazards was checked both by inspection of plots and by the use of time-dependent covariates. Initially, unadjusted estimates of the hazard ratio for birthweight and each height and weight measure compared with a baseline category were obtained, as well as estimates for duration of breastfeeding and the socioeconomic indicators. Childhood heights and weights were split into quarters of the distribution. Tests for linear trend across the ordered categorical variables were carried out. Models including both birthweight and childhood heights and weights were then investigated in order to assess the relative importance of prenatal and postnatal growth (Lucas et al., 1999). Tests for interactions between birthweight and childhood heights and weights were carried out by testing whether any linear effect of later measures varied systematically across categories of birthweight. The early life socioeconomic factors and breastfeeding were added to the model judged to represent the effects on menopausal age of early growth. Finally, the influence of all the potential adult confounders was assessed.
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Results |
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In the model including both birthweight and weight at age 2 years, the effect of weight at 2 years is strengthened (test for linear trend P = 0.06). The influence of weight at age 2 years is confounded with height at 2 years. No evidence of any interaction between the growth variables were found. Hence, birthweight and weight at 2 years are considered in further models. For parsimony, social class was omitted from further models as investigation (results not shown) suggested that crowding and social class were confounded with each other.
Breastfeeding and crowding were added to the growth model. In the subgroup of women restricted to those who have full early life information (n = 1238), the unadjusted effect of crowding was weaker (Table II, unadjusted column) than that observed in the unrestricted sample (Table I
). This effect was further reduced after adjustment. Little change was observed in the estimates for breastfeeding in the full model, while the linear effect of weight at 2 years became stronger (P = 0.04) with a 25% lower hazard rate in the top compared with the bottom group (Table II
).
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Of these adult variables, only parity had a strong association (P < 0.001) with age at menopause, with women with no children having an earlier menopause than women with children.
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Discussion |
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The possibility that the effect of weight at 2 years represents a postnatal influence on ovarian function remains. The effect was strengthened after adjustment for birthweight indicating that it was growth between birth and 2 years that is important. The fact that weight was attenuated in a model including height at 2 years suggests that the important aspect of size is difficult to distinguish. Additional analyses found no trend in menopausal age across categories of BMI at age 2 years, suggesting that adiposity is not the important factor. There was no association with body size measures at 7 years, suggesting that any effect is occurring early in postnatal development. Although 2 years is the first age after birth at which body size was measured, the effect of breastfeeding on age at menopause may be a marker of the effect of earlier postnatal growth. In this cohort, breastfeeding has previously been found to influence adult leg length but not trunk length, a finding likely to indicate an effect on early growth (Wadsworth et al., 2002). A study in New Guinea found that women who were currently undernourished and smaller in adult height and weight reached menopause 4 years earlier than a better nourished sample (Scragg, 1973
). This could reflect the effects of lifelong poor nutrition and poor growth, as opposed to adult nutrition, on reproductive ageing. The association with breastfeeding may indicate the importance of early nutrition in relation to ovarian development.
Few studies have considered early socioeconomic conditions in relation to age at menopause (Shinberg, 1998; Hardy et al., 2000
). In the unadjusted analyses those of a lower socioeconomic status in childhood had an earlier menopause, but the effect was much weaker in the adjusted model. This was due to the reduction in the size of the unadjusted effect in the restricted sample as well as to confounding with the growth and nutrition variables. A study of Wisconsin women (Shinberg, 1998
) observed an effect of parental occupation. Women whose fathers were farmers had a later menopause compared with women whose fathers were not and it was suggested that this may be a result of a different lifestyle including nutrition. Alternatively it might be that stress (Bromberger et al., 1997
), either early in life or across the life course, may be responsible for any social class differences in age at menopause.
All the early life influences identified are relatively small. Given the observed relationships between childhood growth and breastfeeding (Wadsworth et al., 2002), it is interesting that the effect of weight at age 2 years gets stronger rather than weaker after adjustment. This, together with the previously observed relationship between low cognitive function and earlier menopause in this cohort (Richards et al., 1999
), suggests that there may be a number of independent pathways from childhood risk to age at menopause. All variables considered are proxy measures for the underlying biological mechanism or mechanisms and hence further research needs to consider what such processes might be and how best they can be measured. The lack of many strong adult environmental risk factors for age at menopause supports further exploration of early life influences on ovarian ageing.
The estimated median age at menopause in this cohort cannot yet be obtained, as not enough women have reached menopause. The estimate will thus be greater than 52 years and 7 months (1 year prior to current maximum follow-up), later than the most reliable estimates of median age at menopause from Western industrialized countries of between 50 and 52 years (McKinlay, 1996). There has been considerable debate as to whether there has been a secular increase in the age at menopause. Data have shown an increase between the mid-nineteenth and the mid-twentieth century (Flint, 1978
), but it has been argued that this is a result of improving methodology in the study of menopausal age (McKinlay et al., 1992
). An increasing trend would be consistent with the improvement in early nutrition and better childhood growth of recent cohorts of women, although any increase may have been masked by the effects of an increased prevalence during the twentieth century of the main adult risk factors for early menopause of nulliparity and cigarette smoking (Swerdlow et al., 2001
). The increased use of HRT and the increased number of hysterectomy operations may have influenced the more recent estimates of menopausal age. A greater proportion of women were using HRT in the NSHD compared with most previously studied populations. This results in the follow-up of more women being censored, and, since women are likely to be approaching the menopause at the time that they start HRT use, the estimated median age may be biased upwards. In a competing risks framework (Farewell, 1979
; Hardy et al., 2000
), the median age at first event (either menopause or start of HRT use) in the NSHD is 50 years and 5 months, supporting this possibility.
The increased popularity in HRT use will be a constant problem in epidemiological investigation of the natural menopause if menstrual change is the indicator of menopausal status. The results presented in this paper can only be interpreted under the conditions existing in the study and may not be applicable to populations with different patterns of HRT use. Replication of the findings would be valuable in samples with lower HRT use. Since the NSHD is a prospective study, birthweight was obtained from medical records soon after birth and childhood heights and weights were measured. Confounding variable information was also obtained at follow-ups prior to menopause and hence was less subject to recall problems than if collected concurrently with menopausal status.
The independent associations of weight at age 2 years and breastfeeding suggest that early life factors acting in utero or in early childhood may play some part in determining a woman's age at menopause. The potential importance of a life course approach in understanding the menopause is thus highlighted (Hardy and Kuh, 2002). The previous inconsistency in the findings on adult behavioural and social factors and the age at menopause may be due, at least in part, to a failure to account for earlier life factors.
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Acknowledgements |
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Notes |
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References |
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Submitted on December 11, 2001; resubmitted on March 18, 2002; accepted on May 9, 2002.