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The Journal of Clinical Endocrinology & Metabolism Vol. 82, No. 2 414-417
Copyright © 1997 by The Endocrine Society


Clinical Studies

Body Weight, Body Fat Distribution, and Hormonal Replacement Therapy in Early Postmenopausal Women

M. Gambacciani, M. Ciaponi, B. Cappagli, L. Piaggesi, L. De Simone, R. Orlandi and A. R. Genazzani

Department of Obstetrics and Gynecology "Piero Fioretti," University of Pisa, and Medical Department, Schering S.p.A. (R.O.), Milan, Italy

Address all correspondence and requests for reprints to: Marco Gambacciani, M.D., Department of Obstetrics and Gynecology, University of Pisa, Via Roma 67, 56100 Pisa, Italy.


    Abstract
 Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Body weight was measured, and body fat distribution was determined by dual energy x-ray in early postmenopausal women given either oral calcium (500 mg/day; control group; n = 12) or hormonal replacement therapy (HRT), a combination of estradiol valerate (2 mg/day for 21 days) with cyproterone acetate (1 mg/day in the last 10 days of the treatment cycle; n = 15). There were no differences in basal body weight or body fat distribution in the two groups before the study. In the control group, a significant (P < 0.05) increase in body weight (from 61.8 ± 2.1 to 63.3 ± 1.9 kg after 12 months) paralleled a slight, but significant (P < 0.05), increase in total body fat mass (from 23.8 ± 2.2 to 24.7 ± 2.2 kg), with an increase in fat in the trunk (from 10.2 ± 0.4 to 11.3 ± 0.4 kg; P < 0.01) and arms (from 2.4 ± 0.5 to 2.7 ± 0.2 kg; P < 0.05). These findings demonstrate a shift to a prevalent central android fat distribution after 12 months of observation in untreated postmenopausal women. Conversely, in the HRT group, total body bone mineral showed a significant (from 1089 ± 28 to 1106 ± 29 mg/cm2; P < 0.05) increase after 12 months, with no significant increase in body weight (from 62.2 ± 1.6 to 62.7 ± 1.6 kg), and no modifications in trunk (from 10.0 ± 0.2 to 9.8 ± 0.3 kg) and arm (from 2.43 ± 0.2 to 2.5 ± 0.1 kg) fat, but a significant increase in leg fat (from 7.1 ± 0.3 to 8.3 ± 0.4 kg; P < 0.05). The present results suggest that HRT can counteract at least in part the postmenopausal increase in body weight and body fat and prevent central body fat distribution after menopause.


    Introduction
 Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 
AN INCREASED body weight, particularly the central distribution of body fat, is recognized as independent predictor of cardiovascular disease in women (1, 2, 3, 4). Circulating sex steroids can influence body fat distribution (4), and a trend to a progressive increase in body weight is often observed throughout the climacteric period. However, it remains to be determined whether those changes are related to the menopause and estrogen deficiency, to other endocrine modifications, to the aging process, or to all of these factors. The issue of body weight has a great importance regarding the acceptance of and compliance with postmenopausal hormonal replacement therapy (HRT). In fact, HRT has been commonly thought to determine an increase in body weight. This concern represents one of the greatest obstacles for the acceptance and diffusion of long term HRT, which not only can alleviate subjective symptoms, but also can prevent osteoporosis and reduce the risk of cardiovascular disease (5, 6, 7, 8, 9, 10, 11, 12). The aim of the present study was to evaluate the pattern of body weight and body fat distribution in early postmenopausal women and the effects of HRT with an oral estrogen-progestin combination.


    Materials and Methods
 Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 
The study protocol was approved by the institutional review boards and ethical committee of our University Hospital. Early postmenopausal women were recruited from the Climacteric Clinic of our department. Women participating in this study were required to have had amenorrhea for at least 6 months but for no more than 24 months. Basal plasma levels of estradiol and FSH were determined (6), and they were in the postmenopausal range for our laboratory (FSH, >40 U/L; estradiol, <25 pg/mL). Patients had no history of diabetes, eating disorders, liver disease, or other disorders known to influence calcium metabolism, and none had received glucocorticoid treatment. Women who smoked 15 or more cigarettes/week or exercised more than 6 h/week were excluded. Inclusion criteria included normal thyroid, adrenal, and renal function, as assessed by clinical, biochemical, and hormonal evaluations. None had been treated with hormones in the 6 months before observation. A group of postmenopausal women received a sole calcium supplementation (as calcium carbonate and lactogluconate at a dose of 500 mg/day; n = 12; control group) with the evening meal. The subjects included in the HRT group (n = 15) were treated with the combination of estradiol valerate (EV; 2 mg/day for 21 days) and cyproterone acetate (CPA; 1 mg/day in the last 10 days of the treatment cycle). No differences in smoking, blood pressure, education, or family history of breast cancer, osteoporosis, and cardiovascular diseases were present in the 2 groups.

The total body bone mineral (TBBM; milligrams per cm2) was measured in the supine position by dual energy x-ray absorptiometry (DEXA) using a Lunar DPX (Lunar Corp., Madison, WI), as previously reported (13, 14). Lean and adipose tissue weight and abdominal fat weight were determined from the DEXA total body scans (15, 16, 17, 18). The abdominal region of interest was determined by setting the lower horizontal border superior to the iliac crest and the upper horizontal border between T12 and L1. Lateral borders were set just outside the soft tissue. This region (named trunk) included the upper body segment fat and the android fat, excluding the fat from the gynoid regions (hips and thighs), which were measured in the region termed legs. The legs region is defined as the tissue below the oblique line passing through the hip joints. The arms region is defined by the software default readings after adjustment for the definition of legs and trunk regions. The proportion of body fat is reported as an absolute value (kilograms) and as a percentage of the soft tissue. The precision of bone scans and body fat distribution was determined by performing repeated scans in five subjects for 3 consecutive days and is expressed as the coefficient of variation. In our laboratory, the coefficient of variation is less than 1% for TBBM and 2.0% for regional tissue measurements. Body mass index (BMI) was calculated as weight (kilograms) divided by the square of the height (meters). All results are reported as the mean ± SE. Statistical analysis of the results was performed by paired Student’s t test to compare the variables in the two groups before and after treatment.


    Results
 Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 
There were no significant differences in age, plasma FSH and estradiol levels, months since menopause, body weight, or BMI in the two groups before the study (Table 1Go and 2Go). No differences in TBBM or body fat distribution were present in the two groups under basal conditions (Table 2Go). In the control group, TBBM did not show any significant modification, whereas slight, but significant (P < 0.05), increases in body weight and BMI were evident after 12 months of observation (Table 2Go). Conversely, in the HRT group, TBBM showed a slight, but significant (P < 0.05), increase after 12 months, whereas body weight and BMI did not show any significant modification (Table 2Go). The analysis of body fat distribution revealed that the total body fat weight and the percentage of total fat mass were significantly (P < 0.01) increased in the control group (Table 2Go and Fig. 1Go). No significant modification in total body fat weight or percentage of total fat mass was observed in the HRT-treated women (Table 2Go and Fig. 1Go). The regional body fat accumulation showed significant differences in the two groups. In the control group, fat weight significantly increased in both trunk (P < 0.01 vs. corresponding basal value) and arms (P < 0.05 vs. corresponding basal value) regions (Table 2Go), with a significantly (P < 0.01 vs. corresponding basal value) greater percentage of fat mass in both regions (Fig. 1Go). Conversely, in HRT-treated patients, there was an increase in fat in the legs region (P < 0.005 vs. corresponding basal value) after 12 months of treatment, but no modification in trunk or arm fat was observed (Table 2Go and Fig. 1Go).


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Table 1. Basal characteristics of postmenopausal women treated with the sole calcium supplementation (controls; n = 12) or HRT (EV + CPA; n = 15)

 

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Table 2. Selected characteristics in postmenopausal women treated with the sole calcium supplementation (controls; n = 12) or with EV + CPA (HRT); (n = 15)

 


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Figure 1. Percent fat distribution at different body sites (mean ± se) in subjects treated with calcium (controls; n = 12) or with EV and CPA (HRT; n = 15). *, P < 0.01; **, P < 0.005 (vs. corresponding basal value).

 
To evaluate the individual changes in relation to body fat distribution, we regressed the changes in regional percent fat over the basal body composition. No significant correlations between basal total body, legs, and arms fat and the final measurements after 12 months of observations were found in the control group. Conversely, in the control group, the increment in trunk fat was negatively correlated with the basal percentage of fat (y = -0.62x + 28.6; r = 0.658; P < 0.02). No significant correlations between basal regional fat distribution and the final measurements were found in the EV- plus CPA-treated group after 12 months of observations.


    Discussion
 Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 
The present results provide evidence that HRT can blunt the increase in body weight and prevent the shift to a more central, android fat distribution observed in normal women throughout the early postmenopausal period. Recently, in a large cross-sectional study, Burger et al. (19) showed a trend for an increase in BMI during the menopausal transition. In addition, Dellangeville et al. (20) reported that postmenopausal women treated with combined HRT had lower BMI than untreated control subjects. In a long term, prospective, double blind, placebo-controlled study, the PEPI trial (9), an increase in body weight during the menopause has been described. After 36 months, the body weight increase was significantly higher in untreated postmenopausal women (+2.1 kg) than in women treated with unopposed estrogens (+0.7 kg) (9). Conversely, in patients treated with different estrogen-progestin combinations, the weight gain was lower than but not significantly different from that in the placebo group (9). Our results confirm that the early postmenopausal period is associated with an increase in body weight (+1.5 kg after 12 months) that was not evident in HRT-treated women. Thus, for the effect of combined HRT, our results diverge from those reported in the PEPI trial. Our unblind study has certain limitations that could result from the shorter period of observation, and the data might be influenced by social and cultural variables. However, the differences in the HRT preparations could explain at least in part the slightly different effects on body weight gain.

In addition, the present results show that the postmenopausal increase in body weight parallels an increase in body fat and a change in body fat distribution. The assessment of body fat distribution has been traditionally estimated by anthropometric measurements, such as the waist to hip circumference ratio (WHR). However, the WHR may underestimate the abdominal fat in obese individuals, and the method is subject to errors due to the approximate individual measurements. Recently, total body DEXA measurements have been proposed and validated to measure the distribution of body fat (15, 16, 17, 18). DEXA measurements cannot discriminate between sc and intraabdominal fat. However, it has been recently shown that intraabdominal fat weight measured by computed tomography is highly correlated with abdominal, trunk fat weight measured by DEXA (21). Therefore, DEXA measurement of regional body fat distribution can be considered a useful tool for clinical studies, more valid and precise than WHR and less expensive and invasive than computerized tomography or magnetic resonance imaging (15).

In the present study, longitudinal DEXA measurements of body fat show an increase in the percentage of body fat and a shift to a central, android fat distribution in the early postmenopausal period. In fact, after 12 months of the sole calcium supplementation, early postmenopausal women experienced an increase in total body fat weight that paralleled an increase in trunk and arms (central, android) fat, whereas no augmentation in fat in the legs (gynoid) region was evidenced. This modification of body fat distribution seems to be related at least in part to the endocrinological modifications occurring during the perimenopausal period. In fact, in the EV- plus CPA-treated group after 12 months of treatment, BMI and fat mass showed only a blunted trend to increase, and the difference from basal values was not significant. Indeed, the body fat distribution maintained a typical gynoid pattern; the increase in body fat was located in the gynoid (legs) region, whereas trunk and arms fat did not increase.

As previously reported with similar oral estrogen-progestin preparations (22), the present results confirm that the administration of oral EV and CPA can prevent the effects of postmenopausal status on body fat distribution. Central body fat distribution has been associated with a series of endocrine and metabolic consequences (1, 2, 3, 4) related to an increased risk of cardiovascular disease. In this view, the observed stabilization of body weight and body fat distribution can be seen as a further protective effect of HRT against cardiovascular disease (7, 8, 9, 10). However, CPA is a unique antiandrogen progestin, and the present study cannot ascertain whether the effects on body fat should be ascribed to this specific replacement regimen or might be generalizable to all HRT. In addition, our study was not designed for and has not the power to thoroughly investigate the possible environmental and genetic influences on the individual responses to menopause and/or HRT. However, in untreated early postmenopausal women, the individual increments in trunk fat were negatively correlated with the basal percent fat, suggesting that the subjects with a less prominent android fat distribution in basal conditions are those who develop a major increment in central, android fat after the menopause. No significant correlations between basal regional fat distribution and the final measurements were found in the EV- plus CPA-treated group after 12 months of observations. These observations confirm that the changes are related to the hormonal milieu rather than to the individual basal characteristics of the women included in the two groups. Further studies are needed to ascertain the roles of individual characteristics and environmental influences on the extent and mode of body weight increase in the period immediately following the menopause.

A strong positive relation has been reported between BMD and body weight in untreated postmenopausal women; BMI along with age at menopause and the menopausal component of bone loss are the major factors in determining the extent of the involutional osteopenia at the lumbar spine (13) and the femoral neck (23). Again, the present results indeed confirm that the menopausal component of involutional osteopenia is critical. In fact, untreated postmenopausal women showed a trend to a decrease in bone density that was completely negated by EV and CPA treatement, which, in turn, induced a slight, but significant, increase in TBBM.

The EV plus CPA preparation is effective in relieving subjective symptoms and preventing postmenopausal bone loss and the impairment of lipid profile that characterize the postmenopausal years (24, 25, 26). The present study confirms and extends these data, showing that EV in combination with CPA can exert a positive effect on body fat mass and distribution. Further studies may elucidate whether this effect should be ascribed to the HRT per se or to the combination of the effects of oral EV in association with the peculiar antiandrogenic properties of CPA.


    Acknowledgments
 
We gratefully acknowledge and thank Mr. Massimiliano Telleschi for his technical assistance, and Mrs. Gabriella Campani for her secretarial assistance

Received July 12, 1996.

Revised September 16, 1996.

Accepted October 16, 1996.


    References
 Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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  5. Lindsay R. 1987 Estrogen therapy in the prevention and management of osteoporosis. Am J Obstet Gynecol. 156:1347.[Medline]
  6. Gambacciani M, Spinetti A, Taponeco F, et al. 1994 Longitudinal evaluation of premenopausal vertebral bone loss: effects of a low dose oral contraceptive preparation on bone mineral density and metabolism. Obstet Gynecol. 8:392–394.
  7. Bush TL, Barrett-Connor E. 1985 Noncontraceptive estrogen use and cardiovascular disease. Epidemiol Rev. 7:80–104.[Free Full Text]
  8. Lobo RA, Speroff L. 1994 International consensus conference on postmenopausal hormone therapy and the cardiovascular system. Fertil Steril. 61:592–595.[Medline]
  9. The Writing Group for the PEPI Trial. 1995 Effects of estrogen and estrogen/progestin regimens on heart disease risk factors in postmenopausal women. The Postmenopausal Estrogen/progestin Interventions (PEPI) trial. JAMA. 273:199–208.[Abstract]
  10. Andrews MC. 1994 Primary care for postreproductive women: further thoughts concerning steroid replacement. Am J Obstet Gynecol. 170:936–966.
  11. Ottson UB. 1984 Oral progesterone and estrogen-progesterone therapy. Effects of natural and synthetic hormones on subfractions of HDL cholesterol and liver proteins. Acta Obstet Gynecol Scand. 127:1–37.
  12. Fahraeus L, Larsson-Cohn U, Wallentin L. 1983 L-Norgestrel and progesterone have different influences on plasma lipoproteins. Eur J Clin Invest. 13:447–53.[Medline]
  13. Gambacciani M, Spinetti A, De Simone L, et al. 1993 The relative contribution of menopause and aging to postmenopausal vertebral osteopenia. J Clin Endocrinol Metab. 77:11–48-52.[Abstract]
  14. Gambacciani M, Spinetti A, Taponeco F, et al. 1995 Treatment of postmenopausal vertebral osteopenia with monofluorophosphate: a long term calcium-controlled study. Osteoporosis Int 5:467–471.
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  16. Wajchenberg BL, Bosco A, Martins Marone M, et al. 1995 Estimation of body fat and lean tissue distribution be dual energy x-ray absorptiometry and abdominal body fat evaluation by computed tomography in Cushing’s disease. J Clin Endocrinol Metab. 80:2791–2794.[Abstract]
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W. M. Kohrt, A. A. Ehsani, and S. J. Birge Jr.
HRT preserves increases in bone mineral density and reductions in body fat after a supervised exercise program
J Appl Physiol, May 1, 1998; 84(5): 1506 - 1512.
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