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Clinical Studies |
Bowman Gray School of Medicine of Wake Forest University (M.A.E., M.K.J.), Winston-Salem, North Carolina 27157; Stanford University (M.L.S.), Palo Alto, California 94304; University of California (D.K.-S.), San Diego, California 92093; Indiana University School of Medicine (S.E.F.), Indianapolis, Indiana 46202; National Heart, Lung, and Blood Institute (M.A.W.), Bethesda, Maryland 20892; and University of California (G.A.G.), Los Angeles, California 90024
Address all correspondence and requests for reprints to: Mark A. Espeland, Ph.D., Section on Biostatistics, Bowman Gray School of Medicine, Medical Center Boulevard, Winston-Salem, North Carolina 27157-1063.
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Abstract |
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The Postmenopausal Estrogen/Progestin Interventions trial was a 3-yr, placebo-controlled, randomized clinical trial of 875 women assessing the effects on cardiovascular risk factors of four hormone regimens: oral conjugated equine estrogen (CEE) therapy (0.625 mg daily alone), CEE in combination with medroxyprogesterone acetate (2.5 mg daily), CEE in combination with medroxyprogesterone acetate (10 mg daily on days 1–12), and CEE in combination with micronized progesterone (200 mg daily on days 1–12). Women randomly assigned to CEE with or without a progestational agent averaged 1.0 kg less weight gain at the end of 3 yr (P = 0.006) than those assigned to placebo. Assignment to CEE was also associated with averages of 1.2 cm less increase in waist girth (P = 0.01) and 0.3 cm less increase in hip (P = 0.07) girth. In regression models that included weight change as a covariate, none of these differences reached statistical significance. There were no significant differences in weight or girth changes among any of the four active hormone regimens. After accounting for the effects of assignment to active hormone therapy and baseline weight, older age (P = 0.008) and higher physical activity level at baseline (P = 0.002) were also independently predictive of less weight gain. The impact of hormone therapy on weight gain was similar among subgroups, except for those defined by baseline smoking status (P = 0.04) and physical activity level at home (P = 0.02). Factors that were independently associated with smaller increases in girths were: for waist, greater overall activity (P = 0.005) and Hispanic ethnicity (P = 0.02); and for hip, work activity (P = 0.003) and greater alcohol consumption (P = 0.03). None of these factors significantly affected the observed overall relationships between estrogen and changes in girth.
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Of the reported studies, only the Postmenopausal Estrogen/Progestin Interventions (PEPI) trial has the advantages of being randomized and placebo controlled, with several estrogen/progestin regimens, and of having a large sample size with sufficient diversity in baseline characteristics to allow an exploration of factors that may influence hormone effects on weight and girth changes. PEPI investigators reported that hormone therapy was associated with an improved profile of a number of cardiovascular risk factors, including body weight (10). The purpose of this report is to provide a more comprehensive description of the PEPI weight and girth results, including characterizing separately the impacts of estrogen and the different progestin regimens, and to examine the uniformity of these effects across subgroups of participants. These subgroups were defined according to baseline factors thought to influence weight and/or girth changes among perimenopausal or postmenopausal women, including age, time since menopause, medical history (hysterectomy status and prior use of postmenopausal hormone therapy), ethnicity, and several lifestyle characteristics (activity, smoking, and alcohol intake) (9, 16, 17).
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Height (in centimeters) and weight (in kilograms) were measured while participants were wearing light clothing and no shoes; waist and hip girths were measured while women were undressed. Height and weight were measured with a standard stadiometer. On standing women, girths were measured along the horizontal plane at the level of the natural waist (narrowest circumference as viewed from the front) and at the level of the maximum extension of the buttocks (as viewed from the right side). Height, weight, and both girths were measured at baseline; during follow-up, weight was measured every 6 months, and girths were measured at 12 and 36 months. Body mass index was calculated as the ratio of height in centimeters to the square of weight in kilograms. The ratio of waist to hip girth was calculated for each participant from these measures.
Cigarette smoking (current/former/never), current alcohol intake (drinks per day), and history of hormone use (ever/never) data were collected by standardized self-report questionnaires. At baseline, participants were asked to complete a survey about their customary physical activity during the past 12 months in three domains; they were asked to classify their home (HPA), work (WPA), and leisure (LPA) activity as none, light, moderate, or heavy based on examples of each level of activity in the questionnaire (21). Each domain was examined individually. To develop an overall measure of activity, responses were assigned ranks (1 = none to 4 = heavy) and averaged across the three types of activities. For the 11% of women who did not work outside the home, this measure was computed as the average of the HPA and LPA ranks. Participants were grouped into rough tertiles according to the average ranks of their responses.
Statistical analysis
Results were first analyzed according to participant’s treatment assignment, regardless of adherence. Additional analyses were performed using only the subset of women who took at least 80% of their assigned study medications during every 6-month period based on pill counts (adherent participants). The results of these subset analyses were similar to those performed on the entire cohort and so will only be summarized briefly. Mean changes from baseline of weight and girths were computed for each scheduled data collection visit and plotted by treatment assignment. Comparisons of weights, girths, and girth ratios involved two-sided hypothesis tests based on Laird-Ware models (22) for repeated measures assessed with Wald tests (23, 24). Each comparison included all postrandomization measures (of weight, girth, or girth ratios) as dependent variables; linear models were fitted in which the visit number and each individual’s baseline measurement were included as covariates, and separate tests were made to assess treatment effects attributable to estrogen (yes/no) and type of progestin (including placebo). To portray mean differences by treatment assignment, mean changes between baseline and the last follow-up measurement for each individual were calculated and displayed. To assess the individual contribution of baseline factors to changes in weight and girth, repeated measures analyses similar to those above were performed. The consistency of effects attributable to hormone therapy across levels of these factors was described by assessing the statistical significance of two-way interaction terms. Multivariable prediction models were developed using a forward stepwise-selection algorithm in which main effects were entered and kept in the model if they reached and maintained the nominal significance level of 0.05.
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Results |
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Of the 875 women randomized to PEPI, 41% were 45–54 yr old, and the remaining were 55–65 yr old. Sixty-eight percent had not had a hysterectomy, and among these, 45% had undergone natural menopause from 1–4 yr before randomization, whereas the rest had undergone natural menopause 5–10 yr before randomization. Four percent of the participants identified themselves as African-Americans, 5% as Hispanic, 2% as Asian, 1% as Native American, and 89% as Caucasian. Forty-nine percent had never smoked cigarettes regularly, 37% were former smokers, and 14% were current smokers. Reported alcohol intake was relatively low; 32% reported no alcohol intake during the prior year, and only 17% reported averaging 1 or more alcoholic drinks/day. Fifty-six percent reported prior use of postmenopausal hormone therapy, which, by protocol, had been discontinued for at least 3 months before randomization.
The distribution of reported physical activity at home for the 875 women was 5% inactive, 45% light activity, 47% moderate activity, and 3% heavy activity. Leisure physical activity for these women was distributed as 8% inactive, 42% light, 46% moderate, and 5% heavy. Of the 875 women, 781 (89%) were employed outside of their home; their reported physical activity levels at these jobs were 19% inactive, 45% light, 33% moderate, and 3% heavy.
Table 1
lists descriptive statistics for baseline
measurements of weight, height, body mass index, waist and hip
circumferences, and mean levels of ratios formed by waist to hip
measures for the PEPI cohort. No differences among the five treatment
groups with respect to any of the baseline measures described in Table 1 or elsewhere in this report reached statistical significance
(P > 0.05).
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Table 2 lists the mean changes between baseline and
last on-study measurement (an average of 2.97 yr) of weight, girths,
and girth ratios for all women randomized to each treatment assignment.
Although the differences between the unopposed estrogen arm and placebo
tended to be slightly larger than between the three opposed estrogen
arms and placebo, this trend was minor and statistically unimportant.
When analyzed across follow-up, the types of progestin regimens
assessed in the PEPI trial had little impact on changes in weight,
girth, or girth ratios. No differences among the four active
interventions (estrogen alone and estrogen opposed by three different
progestin regimens) reached statistical significance: weight,
P = 0.74; waist, P = 0.53; hip,
P = 0.80; and waist to hip ratio, P =
0.90. Because of this, results are presented for women grouped by
active (i.e. any hormone regimen) vs. placebo
therapy.
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, there was little mean change in average weight in
the combined hormone treatment groups during the first year; these
women gained an average ± SE of 0.02 ± 0.14 kg.
Women randomized to placebo therapy had an average gain of 0.81 ±
0.32 kg over the first year. After this first year, however, both
groups gained approximately the same amount of weight (1.06 ±
0.17 kg for women assigned to estrogen vs. 1.29 ± 0.30
kg for women assigned to placebo). The differences in 3-yr weight gains
between women assigned to active vs. placebo hormones were
not significantly affected by baseline body mass index
(P = 0.49).
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, b and c, portray mean waist and hip girths across time for
women assigned to active treatment and placebo. Waist girths tended to
increased in both groups, but increased more among women assigned to
placebo (P = 0.01). The effect of CEE on the rate of
change in waist girth appeared to be sustained across the 3 yr of
follow-up; women assigned to CEE had smaller mean changes in waist
girth than those assigned to placebo CEE both during the first year
(0.70 ± 0.19 vs. 1.07 ± 0.39 cm) and across the
second and third years (0.78 ± 0.19 vs. 1.64 ±
0.32 cm). Mean hip girth remained fairly stable across all years among
women assigned to hormones and increased marginally among women
assigned to placebo (P = 0.07). During the first year,
women assigned to CEE had a mean increase in hip circumference of
0.61 ± 0.20 cm compared to 1.01 ± 0.38 cm for women
assigned to placebo. Across the subsequent 2 yr, women assigned to CEE
averaged a decrease in mean hip circumference of 0.25 ± 0.21 cm
compared to an average increase of 0.08 ± 0.35 cm in women
assigned to placebo. Three-year changes in weight and waist and hip
girths were all significantly correlated (P < 0.01),
both overall and separately among women assigned to active therapy and
placebo. In analyses in which changes in weight were statistically
controlled for in regression models, assignment to estrogen therapy had
no significant additional impact on any of the changes in girths. Assignment to active therapy appeared to shift the overall distribution of weight changes toward lesser weight gain. Women were grouped according to 3-yr changes in weight: losing 5.0 kg or more, losing 2.5–4.9 kg, remaining within 2.5 kg of baseline weight, gaining 2.5–4.9 kg, and gaining 5.0 kg or more. The percentages of women assigned to placebo in these five groups were 3.4%, 4.2%, 47.1%, 18.5%, and 26.9%; for women assigned to hormone therapy, these percentages were 7.3%, 8.3%, 52.6%, 19.2%, and 12.6%.
Waist to hip ratios tended to increase with time; however, differences between women grouped by assignment to active therapy or placebo did not reach statistical significance (P = 0.31) and appeared to be derived from those apparent at the waist.
To provide support for these intention to treat analyses, we also
performed parallel analyses on the subset of 613 (70.1%) women who
took at least 80% of their study (active and/or placebo) medications
during each 6-month interval of the trial (i.e. those that
were adherent to medication use). The patterns of treatment effects on
changes in weight (P = 0.007), waist girth
(P = 0.03), and hip girth (P = 0.02)
for this subset of women were similar to those for the entire cohort;
plots of mean changes closely approximated those in Fig. 1, and mean
3-yr changes were similar to those listed in Table 2. Women who were
nonadherers according to this definition tended to experience a smaller
impact on weight gain attributable to hormone therapy. For example,
among women who took at least 80% of their assigned medication, the
average 3-yr weight gain among the placebo group was 1.23 ± 0.51
kg greater than those assigned to active therapy. For women who did not
meet this criterion for adherence to medication assignment, the placebo
group averaged only 0.57 ± 0.68 kg greater weight gain. In the
analysis of adherers only, the effects of treatment on the mean hip
circumference were slightly more pronounced and achieved statistical
significance (P = 0.02 for adherers; P
= 0.07 for all women). To avoid redundancy, only results from the
entire cohort will be described in the rest of this report.
Roles of other factors in weight and girth changes
Table 3 shows the mean change in weight from
baseline to the last measurement of PEPI participants by treatment
assignment in subgroups defined by age, ethnicity, smoking status,
alcohol intake, and physical activity. Included in this table are
P values from regression analyses for assessing
relationships between weight change and each baseline characteristic.
Of the factors besides treatment assignment, only age
(P = 0.007), overall physical activity
(P = 0.003), leisure physical activity
(P = 0.001), and work physical activity
(P = 0.01) had statistically significant univariable
(inverse) associations with weight gain. Similar analyses were
performed for hysterectomy status, years since menopause, and prior
postmenopausal hormone therapy, which did not have statistically
significant associations with changes in weight or girths.
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Table 3 also presents the results of analyses to assess the consistency
of hormone treatment effects across subgroups based on baseline
factors. Overall, hormone treatment appeared to have fairly comparable
effects across subgroups defined by these factors, except for baseline
physical activity level at home (P = 0.02) and baseline
smoking status (P = 0.04). Active treatment appeared to
have less of an impact on the reduction of weight gain among women who
reported light activity at home, with a mean attributable reduction of
0.3 kg, than it did for women who reported other activity levels, for
which the mean attributable reductions ranged from 1.4–2.6 kg. Women
assigned to hormones gained 1.3–1.6 kg less than women assigned to
placebo if they were not current smokers. Current smokers assigned to
hormones, however, averaged weight gains of 1.1 kg more than women
assigned to placebo.
Table 4 lists mean changes in waist and hip girths
(between baseline and last measurement) for women grouped by baseline
characteristics. Significant univariable associations of baseline
characteristics with changes in waist girth were evident for ethnicity
(P = 0.006); women of Hispanic ethnicity tended to
decrease in waist girth, whereas other women tended to increase.
Greater reported activity levels were associated with smaller mean
increases in waist girth (overall, P = 0.003; at
leisure, P = 0.005; at work, P =
0.002). Changes in hip girth were inversely associated with age
(P = 0.03) and physical activity (overall,
P = 0.05; at work, P = 0.001).
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. No significant interactions were detected; the degrees to
which treatments influenced changes in girths were not significantly
different among these subgroups (data not shown).
The forward regression algorithm used to develop a multivariable
predictor model indicated that estrogen (P = 0.03),
increased overall activity (P = 0.005), and Hispanic
ethnicity (P = 0.02) were each independently associated
with smaller increases in waist girth. From the multivariable model,
hormone therapy was estimated to decrease average changes in waist
girth across the 3 yr by 0.8 ± 0.4 cm. The magnitudes of the
differences associated with activity and ethnicity were similar to the
univariable effects described in Table 4. For changes in hip girth,
inverse associations with reported activity at work (P
= 0.003) and alcohol intake (P = 0.03) had independent
statistical significance. The magnitudes of differences associated with
work activity were similar to those in Table 4; however, controlling
for activity level at work reversed the direction of the univariable
trend between changes in hip girth and alcohol intake in Table 4. In
the multivariable model, women reporting no alcoholic intake were
estimated to have average increases in hip girth 0.9 ± 0.3 cm
greater than women who reported between 0–1 alcoholic drink/day and
average increases of 0.7 ± 0.5 cm more than women who reported 1
or more alcoholic drinks/day. [This model was necessarily fitted to
only the 781 (89%) of the women who worked outside the home. When
overall activity was substituted for work-related activity, and the
analysis included all 875 participants, a similar inverse relationship
with alcohol intake was noted.] After controlling for work activity
and alcoholic intake, hormone therapy had a modest association
(P = 0.08) with smaller increases in hip girth
(estimated decrease in average changes of 0.7 ± 0.4 cm).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Results from the PEPI clinical trial suggest that postmenopausal estrogen therapy has only a modest protective effect on weight gain in the decade following menopause. These findings are consistent with other studies that reported little or no effect (13, 15, 26) and with one study that found no differences in weight between women who had or had not used estrogen therapy continuously for 15 yr or more (9). As observed differences between placebo progestin and any active progestin regimen and among the three active progestin regimens were minor, the impact on weight of the hormone therapies included in PEPI is primarily attributable to estrogen.
The lesser weight gain evident in women assigned to treatment with hormones was manifested as smaller changes in waist circumference and, to a lesser degree, in hip circumference. The timing of the effects of estrogen on weight and girth may have been different, i.e. the effect of estrogen on the rate of weight gain was only evident during the first year of follow-up, whereas its effect on the rate of change in waist circumference appeared to be sustained throughout 3 yr. However, changes in weight and girths were strongly correlated, and the effect of estrogen therapy on girth was not statistically significant in models controlling for changes in weight. Prior postmenopausal hormone therapy, hysterectomy, and time since last menopause did not appear to affect current changes in weight and girths.
Overall changes in the waist to hip ratios did not reach statistical significance, but were consistent with other reports in the literature (14, 27, 28, 29).
The magnitude of the effects of estrogen on weight were small, i.e. approximately 1 kg across 3 yr, and may have little clinical significance. Studies involving longer follow-up of women assigned to estrogen treatment would be helpful in characterizing its overall impact on girth and girth ratio. More direct measures of intraabdominal fat, for example by computed tomography or magnetic resonance imaging (25), would be useful to describe more precisely the impact of hormone therapy on fat deposition.
Age
Weight gain following menopause is thought to be a common occurrence (3, 4), and aging has also been associated with increases in weight and girths. Women in PEPI, regardless of treatment assignment, tended to gain weight and have increases in waist and hip circumferences with age. Women aged 45–54 yr had significantly greater increases in weight and in hip circumference than those aged 55–65 yr. This is in accord with a recent study by Tavani et al. (30), which showed that body mass increased with age only until 45–54 yr. The effects of hormone therapy on changes in weight and girth appeared to be fairly independent of these age effects.
As reviewed by Baumgartner et al. (31), data from the Rosetta Study and the New Mexico Aging Process Study show that older adults have higher percentages of body fat than younger adults at any age due to the loss of muscle mass with aging. Zamboni et al. (32) reported that waist to hip ratios were positively correlated with age in perimenopausal women. PEPI women, overall, tended to have increases in waist to hip ratios with time in the study. The tendency for waist to hip ratios to increase did not differ markedly with hormone use, suggesting that 3 yr of CEE therapy did not prevent postmenopausal redistribution of fat from peripheral to central sites. Two years of treatment with estradiol valerate, however, have been reported by Haarbo et al. (33) to prevent such an increase.
Physical activity
Reported overall physical activity at baseline and baseline leisure and work activities were strongly related to weight gain in the PEPI cohort, with women who reported more activity gaining less weight than less active women, a finding that is consistent with most previous reports (34). This observation did not differ between women receiving placebo vs. those receiving active hormone therapy, suggesting that estrogens do not enhance the preventive effect of overall physical activity level on postmenopausal weight gain. In contrast, although the level of baseline physical activity in the home was not associated with weight changes in the entire cohort, it may have influenced treatment effects attributable to hormone therapy; less weight gain occurred in hormone users at all levels of home activity reported, but particularly among the 50% of women reporting moderate to heavy activity at home. These observations need to be explored in depth in subsequent analyses. Overall and leisure and work physical activity levels at baseline were also significantly associated with waist and hip girth increases, with less increase occurring in more active women, whereas home-based activity was unrelated to girth changes. The differential role that physical activity at home vs. leisure or work activity played in weight and girth changes in PEPI women underscores the utility of examining separately the relationships that these domains have with weight and other cardiovascular disease risk factors in women (21).
Ethnicity
Previous studies have reported that women in ethnic minorities, including Hispanics, African-Americans, and Asians, have a higher prevalence of obesity than Caucasian women (35, 36). However, in PEPI, Hispanic women exhibited significantly smaller longitudinal changes in waist girth than women in the other ethnic groups.
Few, if any, previous studies have examined the association of hormone therapy with obesity and fat distribution by ethnicity. PEPI data indicate that the impact of hormone therapy on weight and adiposity is fairly uniform across ethnic groups; however, the relatively low numbers of these women in PEPI limit the statistical power and confidence of this conclusion.
Smoking
Cigarette smoking is associated with upper body obesity (37, 38). Smoking status, considered without respect to other factors, did not have a marked effect on longitudinal changes in weight and adiposity. However, women who were assigned to active treatment and who also smoked cigarettes did not obtain the same protection from weight gain as did those who were nonsmokers. This suggests that smoking interferes with estrogen’s effect and is consistent with the report by Keil et al. (39), who found that estrogen-using smokers in Framingham did not have a reduced risk of hip fracture, and with reports that cigarette smoking reduces the estrogen-associated risk of endometrial cancer (38).
Increased hepatic 2-hydroxylation of estrogen has been proposed as a plausible mechanism of smoking’s oral estrogen-blocking effect (40). It may be that the metabolism of estradiol is increased in smokers (41, 42). In nonobese smokers, increased smoking correlates positively with increased waist girth and negatively with hip girth and lower respiratory quotient, which is indicative of enhanced fat oxidation (38, 43, 44). Peripheral hyperinsulinism has also been reported to be a characteristic of smokers (45).
Alcohol
There was a modest trend for PEPI women who reported greater alcohol intake to gain less weight, which did not reach statistical significance. In multivariable models controlling for physical activity, these women also tended to have smaller average increases in hip circumference. Other studies have found lower weight and weight gain to be associated with higher levels of alcohol intake (46, 47). Chronic alcohol intake alters the intestinal absorption of estradiol (48) and may decrease levels of estradiol and increase levels of estrone in postmenopausal women (49). Conversely, estrogen may decrease both alcohol intake and absorption (50). In PEPI, baseline levels of reported alcohol intake were not associated significantly with differential effects of estrogen on weight and girths.
Summary
PEPI data confirm that postmenopausal hormone therapy has a modest, but detectable, effect in reducing the amount of weight typically gained by women during the decade following menopause. Randomization to any of the four active treatments reduced average 3-yr increases in weight by about half; however, the magnitudes of 3-yr effects were small and of little apparent clinical significance. The mitigating impact of hormone treatment on girth increases was most evident at the waist, but protection from increases was also observed at the hip. Opposing estrogen with MPA or MP had little effect on weight and girth changes; thus, the reduction in longitudinal weight gain and girth increases observed in PEPI can be ascribed to estrogen. These treatment effects appear to be robust across a number of patient subgroups; however, women who smoke cigarettes may experience no reduction in weight gain with estrogen therapy.
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Footnotes |
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Received September 5, 1996.
Revised January 21, 1997.
Accepted January 30, 1997.
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References |
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