PAPER. HM Macdonald 1 *, SA New 2, MK Campbell 3 and DM Reid 1. Introduction

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1 (2003) 27, & 2003 Nature Publishing Group All rights reserved /03 $ PAPER Longitudinal changes in weight in perimenopausal and early postmenopausal women: effects of dietary energy intake, energy expenditure, dietary calcium intake and hormone replacement therapy HM Macdonald 1 *, SA New 2, MK Campbell 3 and DM Reid 1 1 Department of Medicine and Therapeutics, University of Aberdeen, Medical School Buildings, Foresterhill, Aberdeen, UK; 2 Centre for Nutrition and Food Safety, School of Biomedical and Life Sciences, University of Surrey, Guildford, Surrey, UK; and 3 Health Services Research Unit, University of Aberdeen Medical School, Foresterhill, Aberdeen, UK OBJECTIVE: To investigate whether energy intake or energy expenditure affects 5 7 y weight gain in perimenopausal and early postmenopausal women, and whether hormone replacement therapy (HRT) use or dietary calcium (Ca) intake are contributory factors. DESIGN: Longitudinal, observational study of healthy women around the menopause. SUBJECTS: A total of 1064 initially premenopausal women, selected from a random population of 5119 women aged y at baseline. In all, 907 women (85.2%) returned y later for repeat measurements. Of these, 36% were postmenopausal (no HRT) and 45% had taken HRT, and 898 women completed the questionnaires. MEASUREMENTS: Weight, height, estimation of energy intake by food frequency questionnaire and physical activity level (PAL) by questionnaire. RESULTS: Change in PAL influenced weight change explaining 4.4% (P ¼ 0.001) of the variation. Alterations in dietary energy intake also had a small but significant effect (0.6% P ¼ 0.013). Dietary Ca intake had no effect on weight or weight change. CONCLUSION: Mean weight had increased and was influenced more by reduced energy expenditure rather than increased energy intake. HRT and dietary Ca intake did not influence weight gain. (2003) 27, doi: /sj.ijo Keywords: weight gain; menopause; physical activity level; dietary energy intake; HRT; calcium Introduction The prevalence of obesity in Scotland is increasing 1 with an epidemic reported in Scottish children, 2 but little is known about women specifically in the fifth and sixth decade of life. The period following the menopause is often characterized by weight gain. 3,4 In an American population, this appeared to be a result of decreased leisure time exercise rather than increased energy intake as estimated by 24 h recall, 5 and a smaller study showed decreased energy expenditure in *Correspondence: Dr H Macdonald, Osteoporosis Research Unit, Victoria Pavilion, Woolmanhill Hospital, Aberdeen AB25 1LD, UK. h.macdonald@abdn.ac.uk Received 1 October 2002; revised 23 December 2002; accepted 9 January 2003 women who became postmenopausal compared to agematched women who remained premenopausal. 6 Many women are concerned about weight gain at this period and assume hormone replacement therapy (HRT) to be a causal factor. Indeed, this was one of the reasons, along with return of regular periods, given for stopping HRT in a group of 400 postmenopausal women aged y who were recommended HRT following screening for osteoporosis. 7 Low calcium (Ca) intake has also been associated with increased body weight in young adult women, 8,9 but whether this was attributable to a lack of Ca itself or reflected a deficiency or excess of other components in the diet is uncertain. It has been suggested from analysis of data from observational studies and controlled trials that 300 mg increment of daily Ca intake is associated with a kg reduction in adult body weight. 10,11

2 670 This longitudinal study was undertaken to observe weight change in women around the time of the menopausal transition (including HRT users and nonusers); to explore how each side of the energy balance equation (ie energy intake estimated by food frequency questionnaire (FFQ) and expenditure) affect weight change during this period; and to determine whether dietary Ca has any influence on weight gain. Methods Subjects In , 1064 Causcasian women (mean age7s.d., y) were selected from a randomly selected population osteoporosis screening programme of 5119 women living within a 25 mile radius of Aberdeen, Grampian Region, Scotland. 12,13 These women were not suffering from any condition or taking any medication that would interfere with their bone metabolism. Most of the women were premenopausal at the time of their bone scan, but 70 women who were enroled for a study on bone metabolism towards the end of the study were of mixed menopausal status. None had taken HRT at the time of their original assessment. They completed an FFQ in 1993 and the findings of this baseline, cross-sectional work have been published. 14,15 In , the women (now aged 5472 y) were recalled and completed the FFQ for a second time. A total of 907 women returned (85% response rate) and 898 women completed the FFQ. Five women were excluded from the statistical analysis; one who had become wheelchair bound and one whose dietary Ca intake was particularly high, and three who were taking bisphosphonates. Of those women who did not return after 5 y, 66 (6.2%) had moved away from the area and 91 (8.6%) did not want to attend for assessment again. Menopausal status was unavailable for four women. Written informed consent was obtained for all the women and the study was approved by the Grampian Research Ethics Committee. Energy intake and expenditure Energy intake was measured shortly after the baseline visit (in 1993) and at the follow-up visit (6 y later) by FFQ that had been validated using 7-day weighed intakes 16 and serum levels of antioxidants. 17 The questionnaire was based on the Caerphilly questionnaire 18 that was used for the Scottish Heart Health study. 19,20 Physical activity levels (PALs) were obtained using the same questions as used for the Scottish Heart Health Study, 21 and these data contributed to the WHO Monitoring Trends and Determinants in Cardiovascular Disease (MONICA) survey. The PAL is calculated from the number of hours in a 24-h period that women generally carry out heavy, moderate or light activities and how many hours are spent sleeping or resting in bed. These questions were asked separately for working (including housework) and nonworking days. PAL is a unitless variable defined as the ratio of energy expenditure divided by the basal metabolic rate (BMR), which is calculated from Schofield equations. 22 Based on European data, the equation for females aged y, is BMR ¼ weight (standard error of estimate 0.47). Ca intake was calculated as the crude nutrient and either energy adjusted using the residual method 23 or standardized to a daily diet of 8 MJ (by dividing the crude nutrient by energy intake in MJ and multiplying by 8), which is the average energy requirement for women in this age range (51 59 y), again based on Schofield equations. 22 Statistical analysis Analyses were performed using SPSS version 9.0 (SPSS Inc., Chicago, 2000). Comparisons between the baseline and follow-up data were made using paired t-tests for continuous variables. Differences between the different menopausal/ HRT groups were examined by one-way analysis of variance (with Bonferroni post hoc test). The w 2 test was used for categorical variables. All P-values quoted are two-tailed. Stepwise multiple regression analysis was used to assess independent predictors of weight change. Measurements The women were weighed on both occasions wearing light clothing and no shoes on a set of balance scales (Seca, Hamburg, Germany) calibrated to 0.05 kg. The scales were calibrated at 4-month intervals during the measurement periods, using weights up to 70 kg. Height and sitting height were measured with a stadiometer (Holtain Ltd, Crymych, UK). Body mass index (BMI) was calculated as the weight (kg) divided by the height squared (m 2 ). Overweight was defined as BMI425 kg/m 2 and obesity as BMI 430 kg/m 2. Information on health, use of medication, menopausal status (including hysterectomy and oopherectomy) and HRT use (defined as oestrogen or oestrogen/progestogen use) was collected by questionnaire and detailed face-to-face questioning of each volunteer during the visit. Results The anthropometric characteristics at baseline and follow-up are shown for all the women who returned for a second bone scan (Table 1). On average, the women gained weight, lost height and accordingly increased their BMI. All differences were significant by paired t-tests (Po0.001), although it should be noted that the decrease in mean height was extremely small (0.7 cm). Energy intake (Po0.001) and physical activity (Po0.025) also decreased significantly between the two assessments. The change in energy-adjusted dietary Ca intake, although statistically significant, was probably of no biological significance and more likely reflects errors inherent in dietary methodology. At the baseline visit, 49 women had taken Ca supplements and at

3 Table 1 Anthropometric measurements and bone mineral density at baseline and follow-up (5 7 y) visit 671 Baseline Final (after 5 7 y) Change (final-baseline) Mean7s.d. Mean7s.d. Mean7s.d. Paired t-test P-value a N 902 Age (y) Weight (kg) o0.001 Height (cm) o0.001 BMI (kg/m 2 ) o0.001 N 893 Ca intake diet only (mg/day) Dietary Ca standardized to 8 MJ (mg/day) Total Ca intake (diet+supplements) (mg/day) Total Ca (diet+supplements) standardised to 8 MJ (mg/day) o0.001 Energy intake (MJ) o0.001 Physical activity level (PAL) a After transformation to normality if required. the follow-up visit 68 women had taken Ca supplements, but only 18 women reported taking Ca supplements both at baseline and follow-up. The prevalence of overweight and obesity was 38.1 and 16.0% at the second visit compared to 25.3 and 9.8%, respectively, at baseline. Menopausal status At the time of the baseline measurements, 93% women were regularly menstruating. At 5 7 y, the women were categorized into five different groups; only 51 (6%) were now regularly menstruating and were described as premenopausal; a further 117 (13%) had irregular menses and were defined as perimenopausal. For 92 of the latter women, who gave more details, the period of irregular menses ranged from 2 to 60 months with a mean7s.d. of months. Women who had not menstruated in the last year and had never taken HRT (n ¼ 328, 36%) were classified as being postmenopausal by WHO criteria. 24 The fourth and fifth groups were past and present HRT-users (115 (13%) and 284 (32%) women, respectively). Of those currently taking HRT, 273 women gave precise details on dates of usage: 9.5% women had taken HRT for less than 1 y and for the rest, the median time of usage was 4.4 y (mean y). For the past HRT-users, 98 (out of 113) women gave dates of usage and 56% women had used HRT for less than 1 y. The remaining women had taken HRT for a median of 3 y (mean y). For the postmenopausal women who had not taken HRT, the number of years past menopause ranged from 1 to 12 y (mean7s.d y). A total of 49 women had a hysterectomy: six women reported one ovary removed and 27 had two ovaries removed. The majority of these were on HRT (n ¼ 25), but seven women had ceased HRT and six women had never taken HRT. The remaining women did not provide further details. The demographics of the subjects split according to menopausal status and HRT use are given in Table 2. The women in the pre- and perimenopausal groups were significantly younger than the postmenopausal women and the current or past HRT users (one-way ANOVA Po0.001). There appeared to be slightly more smokers among past HRT users. Women taking HRT included a higher percentage who had previously taken oral contraceptives, compared to postmenopausal never users. There were small but significant differences between the groups in terms of height and weight. Current HRT users were lighter and their BMI was lower compared to the other groups, and BMI was marginally greater for the premenopausal group. Weight change All groups of women regardless of menopausal status or HRT use increased their mean weight by between 2.9 and 4.5 kg (Table 3). This increase in weight was significant for each group (Po0.001). Although the past HRT users appeared to have gained more weight compared to the other groups, this was not statistically significant by ANOVA. Over 10% of women (n ¼ 104) claimed to be on a weightreducing diet, and 99 of these reported the length of time they had been on a diet. Over half (52%) had been dieting for less than 6 months and 14% women had been dieting for more than 7 y. There was no significant difference in mean weight gain between women who were on a diet and those who not, although those on a diet were heavier ( kg compared to kg). There was also no significant difference in energy intake at baseline (8.272 MJ a day for both groups) and surprisingly no significant difference in energy intake at follow-up ( MJ for the dieters compared to for the nondieters, P ¼ 0.478). All the groups, except the past HRT users, had slightly decreased their mean dietary energy intake. The mean energy intake of the past HRT users had slightly increased,

4 672 Table 2 Volunteer characteristics at follow-up visit (proportion or mean7s.d. unless otherwise indicated) Premenopausal Perimenopausal Postmenopausal Past HRT-users Present HRT-users N P w 2 Current smokers 7 (14%) 16 (14%) 50 (15%) 31 (27%) 55 (19%) Gave up smoking since last visit 2 (4%) 4 (3.4%) 13 (4.0%) 3 (2.6%) 13 (4.6%) Previous contraceptive use 34 (67%) 84 (72%) 199 (62%) 73 (66%) 211 (76%) Educational status (1, 2, 3) a 10%, 43%, 47% 8%, 38%, 54% 7%, 35%, 58% 10%, 27%, 63% 13%, 29%, 58% Premenopausal Perimenopausal Postmenopausal Past HRT Present HRT P ANOVA Age at follow-up (y) o0.001 Time since baseline scan (y) o0.001 Weight at follow-up (kg) o0.001 Weight at baseline (kg) o0.010 Height at follow-up (cm) Height at baseline (cm) Follow up BMI (kg/m 2 ) Baseline BMI (kg/m 2 ) Sitting height (cm) Sitting height/height (%) a Ascertained at baseline visit: 1Funiversity degree, 2Fother professional/technical qualification, 3Fsecondary school education only. Table 3 Mean annual percentage change for weight, and energy intake differences according to menopausal group Premenopausal Perimenopausal Postmenopausal Past HRT use Present HRT use N P ANOVA Difference weight (kg) Percentage weight change (%) Annual weight change (%/y) N Energy intake difference (MJ) N PAL difference and this was significantly different from present HRT users (P ¼ with Bonferroni post hoc test). PAL had decreased for most groups and this may in part explain the increase in weight. The effect of dietary energy intake, change in energy intake, PAL and change in PAL according to quintiles of weight change are shown in Figures 1 and 2. The lowest fifth of women had lost weight (mean decrease 3 kg), the second fifth had gained a mean of 1 kg, and this progressively increased with each category until the top fifth where the mean weight gain was 10 kg. There was little difference between the groups in terms of energy intake (as reported in the FFQ). However, there is a clear progression of decreasing PAL with increasing weight gain. Furthermore, there was an increase in mean PAL since the first visit for the weightlosing group, little change for the moderate weight-gaining groups and a decrease in PAL for the top two weight-gaining groups. Multiple regression analysis showed that difference in PAL between the baseline and follow-up visit, baseline weight, smoking status and, to a lesser extent, difference in energy intake were independent significant predictors of weight change (Table 4). Including a variable for women who were on a weight-reducing diet did not affect these results and was not shown to be a significant predictor of weight change. With regard to menopausal status and HRT use, including these variables in the regression did not add significantly to the model. Furthermore, when the two largest groups, postmenopausal (no HRT) and current HRT users were examined separately, in both cases it was found that differences in PAL, baseline weight and smoking were significant predictors of annualized weight gain accounting for 4.7, 5.1 and 4.4%, respectively, for postmenopausal no HRT users, and 4.4, 2.0 and 3.2%, respectively, for current HRT users. Also, the number of years past menopause was not found to be a significant predictor of weight gain in the postmenopausal (no HRT) group, neither was the number of years on HRT a predictor of weight change for the current HRT users. Hysterectomy or ovaries removed did add

5 a 8.4 P=0.503 a 2.1 P< Energy intake (MJ) Physical Activity Level b Difference in Energy Intake (MJ) Quintiles of Annual Weight Change (%/y) P=0.189 b Difference in Physical Activity Level Quintiles of Annual Weight Change (%/y) P< Quintiles of Annual Weight Change (%/y) Figure 1 Dietary energy intake and change energy intake since the baseline visit by quintiles of weight change Quintiles of Annual Weight Change (%/y) Figure 2 Physical activity level and change in physical activity level since the baseline visit by quintiles of weight change. Table 4 Results of multiple regression analyses to identify independent predictors of weight change Final model for annual percentage change in weight Each stage of model building Independent variable Unstandardized beta 95% CI for beta P Additional variation explained (%) Constant to o0.001 PAL difference to o Baseline weight to o Energy difference to Smoking status a 2.6 Dummy variable: ceased smoking to o0.001 Dummy variable: current smoker to Total 10.2 a Reference category: nonsmoker. From age, baseline weight and height, PAL or PAL difference, and energy intake or energy intake difference. Smoking status was included as two dummy variables: for current smokers and for women who ceased smoking since last visit, compared to non-smokers.

6 674 significantly to the model, and excluding these affected women from the analysis did not affect the outcome of the regression model. Dietary Ca intake (either crude nutrient, nutrient density or energy adjusted) had no significant effect on weight change or weight when included in a linear regression model. Furthermore, there was no difference in weight change between different quartiles of Ca intake. Women in the lowest quartile (Q1) were in fact significantly lighter than those in the highest quartile (Q4) (baseline: 62.4 kg Q1, 65.6 kg for Q4, P ¼ Follow-up: and 65.2 kg Q1, 68.8 kg Q4, P ¼ 0.007), but this difference disappeared after adjustment or standardization for dietary energy intake. Also total Ca intake (diet plus dietary supplements) had no influence on weight change or weight. Discussion Weight changes Our study shows, conclusively in a larger study of women in their fifth and sixth decade, that the majority of women gained weight, regardless of their menopausal status and use of HRT. Even our small group of women who remained premenopausal at follow-up were found to have gained weight, consistent with a previous 3-y study of 484 women aged y, 5 indicating that the weight gain is not because of the menopause per se and is in agreement with other studies The prevalence of overweight and obesity had increased over 50 and 60%, respectively, in the 6 y since the first visit. In 1995, there was a prevalence of 32% overweight and 17% obese nationally in Scotland, 28 although there were regional differences, with Grampian Region having the greatest overall prevalence of overweight and obesity. 29 The percentage of obese women was comparable to that observed at the second visit (16%), but our study found a greater prevalence of overweight (38%). Interestingly in Glasgow, the prevalence of overweight and obesity in 1995 was greatest in the y age range compared to younger age groups. 29 Between 1995 and 1998, obesity had increased nationally in Scotland by 3% with a total of 54% of women being overweight or obese, 1 similar to our total figure of 56%. The weight gain in our study population did not appear to be primarily explained by an increase in energy intake (at least with regard to reported eating habits). Change in PAL was the major predictor of weight gain. However, together with smoking, these factors only accounted for 10.2% of the total variation. This may be because the tools we use for measuring energy intake and expenditure are simply not sensitive enough. The questionnaire may slightly overestimate PAL as calculated using Schofield equations 22 compared to results of an analysis of doubly labelled water measurements. 30 These showed that seated work with discretion/requirement to move around with little or no strenuous activity was consistent with a PAL of and that standing work (eg housewife, shop assistant) requires more energy expenditure equivalent to PAL between 1.8 and 1.9. Our mean results are 1.88 and 1.86 at baseline and follow-up visits respectively, which is at the higher end of these activities. Energy intake data were obtained from analysis of our FFQ. It is known that there can be under-reporting especially in overweight individuals. 31 The questionnaire relies on standard portion sizes and there will be some foods that are not covered by the FFQ. However, the mean energy intake to BMR ratio was comparable or better than that found in other studies which use FFQ (1.43 at baseline and 1.36 at followup). There may be other explanations for weight gain. A decrease in lean body mass around the menopause would result in a decrease in energy expenditure leading to weight gain, if energy intakes were not reduced sufficiently (or PALs increased) to compensate for this. 32 Hence, a change in body composition around the menopause could be responsible for weight gain. Loss of muscle mass has been suggested as an explanation for increased femoral neck loss of bone during the perimenopause. 33 Although Schofield equations are available for four different groups of adult women (o30; 30 59, and over 75 y), there is no information on BMR levels specifically for peri- and early postmenopausal women. One might expect the BMR for these to be different from BMR for premenopausal women, given the above, as BMR is dependent on body composition. However, if a change in body composition does influence weight change, then we would have expected to observe differences in weight gain between postmenopausal women who did not use HRT and current HRT users, which we did not observe. Age-related decline in growth hormone and growth hormone binding protein may also influence weight change, 34 and previous illness could account for weight loss or less weight gain, but these data had not been collected. It is likely that specific genotypes may be associated with weight change, via a number of mechanisms, including eating patterns that have been shown to be heritable. 35 It is also possible that previous exposure to environmental factors, gene environment interactions and, as found with heart disease and stroke, intrauterine programming may influence susceptibility to weight gain. 36 HRT use and weight change One of the concerns expressed by women about HRT is that it will lead to weight gain. However, it has been reported that HRT may in fact decrease the amount of weight gained during the decade following the menopause, 37 and a Cochrane review 38 concluded that there was no evidence of an effect of unopposed oestrogen or combined oestrogen on body weight over and above that normally noted at the menopause. Elderly women (aged y) from the Rancho Bernardo study who used HRT (continuously or intermittently) had lower BMI than never users at baseline, but there

7 was no difference between users and nonusers at 15 y followup. 39 Our results also show that HRT users were lighter at baseline and in our case current users were also lighter at follow-up 5 7 y later. Although some similarly designed studies showed that HRT was associated with decreased weight gain, we did not observe this. Perhaps there is a greater spread of socioeconomic class in the HRT group of our study, since a wide range of women would have been made more aware of the benefits of HRT, as a result of having a bone scan, whereas normally this information might be restricted to more educated women. The past HRT-users group was the only group to increase their dietary energy intake. Whether past HRT users increased their dietary intake after the HRT was stopped or whether weight gain occurred while taking HRT, and might have been one of the reasons for discontinuing its use is not known. Women might have increased their dietary energy intake as a result of giving up smoking, since smoking cessation was shown to be associated with weight gain in perimenopausal and early postmenopausal women. 40 However, although there were slightly more smokers in this group, only three women in this group had given up smoking since the first visit. Ca intake and weight change Although it has been reported that Ca intake is associated with reduced body weight, 11 we did not find any relation between dietary energy intake and weight change. However, the Ca intake of the women in our study was quite high with a mean intake over 1000 mg/day and even that of the lowest quartile was around 800 mg/day. It had been hypothesized that low Ca intake results in fat accumulation (supported by in vitro experiments in which low Ca caused adipocytes to switch from lipolysis to lipogenesis). 8 However, high Ca intake may reduce absorption of fat, 41,42 which may in itself result in less weight gain, and vice versa. Therefore, the effect of Ca on weight loss may also depend on other components in the diet that influence how much Ca is absorbed. There are limitations to this study in that weight was not the primary end point, and energy intake and expenditure were assessed by questionnaire. Nevertheless it appears that for women in the north of Scotland, mean weight increases around the fifth and sixth decade and is influenced more by reduced energy expenditure rather than increased energy intake for both HRT users- and nonusers. Also, HRT use and dietary Ca intake did not appear to influence weight gain. Acknowledgements We are grateful to David Grubb of the Rowett Research Unit for running the ORACLE programme to analyse our food frequency and physical activity questionnaire. We are also very grateful for the hard work of the radiographers and research nurses at the Osteoporosis Research Unit, and to all the women who kindly participated in the study. We gratefully acknowledge the UK Department of Health and the Medical Research Council for project grant support for HMM and to the Arthritis Research Campaign (ARC) for continuing infrastructure support for DMR. The Health Services Research Unit is funded by the Chief Scientist Office of the Scottish Executive Health Department. Any views expressed are ours. References 1 Shaw A, McMann A, Field J. Scottish health survey Scottish Executive Department of Health: Edinburgh; Reilly JJ, Lord A, Bunker VW, Prentice AM, Coward WA, Thomas AJ, Briggs RS. Energy balance in healthy elderly women. Br J Nutr 1993; 69: Manson JE, Colditz GA, Stampfer MJ, Willett WC, Rosner B, Monson RR, Speizer FE, Hennekens CH. A prospective study of obesity and risk of coronary heart disease in women. N Engl J Med 1990; 322: Matthews KA, Meilahn E, Kuller LH, Kelsey SF, Caggiula AW, Wing RR. Menopause and risk factors for coronary heart disease. N Engl J Med 1989; 321: Wing RR, Matthews KA, Kuller LH, Meilahn EN, Platinga PL. Weight gain at the time of menopause. Arch Intern Med 1991; 51: Poehlman ET, Toth MJ, Gardner AW. Changes in energy balance and body composition at menopause: a controlled longitudinal study. Ann Intern Med 1995; 123: Ryan PJ, Harrison R, Blake GM, Fogelman I. Compliance with hormone replacement therapy (HRT) after screening for postmenopausal osteoporosis. Br J Obstet Gynaecol 1992; 99: Zemel MB, Shi H, Greer B, Dirienzo D, Zemel PC. Regulation of adiposity by dietary calcium. FASEB J 2000; 14: Lovejoy JC, Champagne CM, Smith SR, de Jonge L, Xie H. Ethnic differences in dietary intakes, physical activity, and energy expenditure in middle-aged, premenopausal women: the Healthy Transitions Study. Am J Clin Nutr 2001; 74: Heaney RP, Davies KM, Barger-Lux MJ. Calcium and weight: clinical studies. J Am Coll Nutr 2002; 21: 152S 155S. 11 Davies KM, Heaney RP, Recker RR, Barger-Lux MJ, Lappe JM. Calcium intake and body weight. J Clin Endocrinol Metab 2000; 85: Garton MJ, Torgerson DJ, Donaldson C, Russell IT, Reid DM. Recruitment methods of screening programmes: trial of a new method within a regional osteoporosis study. BMJ 1992; 305: Torgerson DJ, Garton MJ, Donaldson C, Russell IT, Reid DM. Recruitment methods for screening programmes: trial of an improved method within a regional osteoporosis study. BMJ 1993; 307: New SA, Bolton-Smith C, Grubb DA, Reid DM. Nutritional influences on bone mineral density: a cross-sectional study in menopausal women. Am J Clin Nutr 1997; 65: New SA, Robins SP, Campbell MK, Martin JC, Garton MJ, Bolton Smith C, Grubb DA, Lee SJ, Reid DM. Dietary influences on bone metabolismffurther evidence of a positive link between fruit and vegetable consumption and bone health? Am J Clin Nutr 2000; 71: New SA, Bolton-Smith C. Development of a food frequency questionnaire. Proc Nutr Soc 1993; 52: 330A. 17 Bodner CH, Soutar A, New SA, Scaife AR, Byres M, Henderson GD, Brown K, Godden DJ. Validation of a food frequency questionnaire for use in a Scottish population: correlation of antioxidant vitamin intakes with biochemical measures. J Hum Nutr Diet 1998; 11: Yarnell JWG, Fehily AM, Milbank JE, Sweetnam PM, Walker CL. A short dietary questionnaire for use in an epidemiological study: 675

8 676 comparison with weighed dietary records. Hum Nutr Appl Nutr 1983; 37: A Bolton-Smith C, Woodward M, Tunstall-Pedoe H. The Scottish Heart Health study. Dietary intake by food frequency questionnaire and odds ratios for coronary heart disease risk. I The macronutrients. Eur J Clin Nutr 1992; 46: Bolton-Smith C, Woodward M, Tunstall-Pedoe H. The Scottish Heart Health study. Dietary intake by food frequency questionnaire and odds ratios for coronary heart disease risk. II The antioxidant vitamins and fibre. Eur J Clin Nutr 1992; 46: Tunstall-Pedoe H, Smith WCS, Crombie IK, Tavendale R. Coronary risk factor and lifestyle variation across Scotland: results from the Scottish Heart Health Study. Scot Med J 1989; 34: Department of Health. Dietary reference values for food energy and nutrients for the United Kingdom. HMSO: London; Willett WC, Howe GR, Kushi LH. Adjustment for total energy intake in epidemiologic studies. Am J Clin Nutr 1997; 65: 1220S 1228S. 24 WHO Scientific Group. Research on the menopause in the 1990s. World Health Organization: Geneva; Crawford SL, Casey VA, Avis NE, McKinlay SM. A longitudinal study of weight and the menopause transition: results from the Massachusetts Women s Health Study. Menopause 2000; 7: Davies KM, Heaney RP, Recker RR, Barger-Lux MJ, Lappe JM. Hormones, weight change and menopause. Int J Obes Relat Metab Disord 2001; 25: Guthrie JR, Dennerstein L, Dudley EC. Weight gain and the menopause: a 5-year prospective study. Climacteric 1999; 2: Dong W, Erin B. Scotand s Health: Scottish Health Survey Scottish Office Department of Health: Edinburgh; Scottish Intercollegiate Guidelines Network (SIGN). Obesity in Scotland. Implementing prevention with weight management. SIGN: Edinburgh; Black AE, Coward WA, Cole CJ, Prentice AM. Human energy expenditure in affluent societies: an analysis of 574 doublylabelled water measurements. Eur J Clin Nutr 1996; 50: Prentice AM, Black AE, Coward WA, Cole TJ. Energy expenditure in overweight and obese adults in affluent societies: an analysis of 319 doubly-labelled water measurements. Eur J Clin Nutr 1996; 50: Panotopoulos G, Raison J, Ruiz JC, Guy-Grand B, Basdevant A. Weight gain at the time of the menopause. Hum Reprod 1997; 12: Sowers M, Crutchfield M, Bandekar R, Randolph JF, Shapiro B, Schork MA, Jannausch M. Bone mineral density and its change in pre- and perimenopausal white women: the Michigan Bone Health Study. J Bone Miner Res 1998; 13: Maheshwari H, Sharma L, Baumann G. Decline of plasma growth hormone binding protein in old age. J Clin Endocrinol Metab 1996; 81: de Castro JM. Heritability of diurnal changes in food intake in free-living humans. Nutrition 2001; 17: Barker DJ. Intrauterine programming of coronary heart disease and stroke. Acta Paediatr Suppl 1997; 423: Espeland MA, Stefanick ML, Kritz-Silverstein D, Fineberg SE, Waclawiw MA, James MK, Greendale GA. Effect of postmenopausal hormone therapy on body weight and waist and hip girths. J Clin Endocrinol Metab 1997; 82: Norman RJ, Flight IH, Rees MC. Oestrogen and progestogen hormone replacement therapy for peri- menopausal and postmenopausal women: weight and body fat distribution. Cochrane Database System Rev 2003; AB Kritz-Silverstein D, Barrett-Connor E. Long-term menopausal hormone use, obesity, and fat distribution in older women. JAMA 1996; 275: Burnette MM, Meilahn E, Wing RR, Kuller LH. Smoking cessation, weight gain, and changes in cardiovascular risk factors during menopause: the Healthy Women Study. Am J Public Health 1998; 88: Newmark HL, Wargovich MJ, Bruce WR. Colon cancer and dietary fat, phosphate, and calcium: a hypothesis. J Natl Cancer Inst 84; 72: Suzuki K, Suzuki K, Mitsuoka T. Effect of low-fat, high-fat, and fiber-supplemented high-fat diets on colon cancer risk factors in feces of healthy subjects. Nutr Cancer 92; 18: