Postmenopausal
Hormone Replacement Therapy Prevents Central Distribution of Body Fat After Menopause Jens Haarbo, Ulla Marslew, Anders Gotfredsen, and Claus Christiansen
The reduction in cardiovascular risk induced by hormone replacement therapy is only partly explained by changes in serum lipids and lipoproteins. As body composition and body fat distribution in particular are independent predictors of cardiovascular disease, we investigated the effect of postmenopausal hormone therapy on body composition parameters directly measured. Sixty-two early postmenopausal women were followed up for 2 years in a prospective, randomized, placebo-controlled study. We found that combined estrogen-progestogen therapy prevented the increase in abdominal fat after menopause (P < .05), and that this effect was independent of the effect on serum lipids and lipoproteins. The therapy reduced postmenopausal bone loss significantly (P < .OOl), whereas it did not have a statistically significant influence on total body fat mass or total lean body mass. The findings of the present study suggest that some of the protective impact of postmenopausal hormone therapy on cardiovascular disease may be explained by the effect on body composition, in particular abdominal fat. Copyright 0 7991 by W.B. Saunders Company
C
ARDIOVASCULAR disease is currently the leading cause of death and disability in Western societies. It accounts for almost 500,000 deaths per year among women in the United States alone.’ Several epidemiologic studies hate shown that estrogen replacement therapy may prevent or reduce coronary heart disease in postmenopausal women.‘.’ This favorable effect is only partly explained by the action of estrogen on serum lipids and lipoproteins, which indicates that estrogen possesses additional benefits,’ for instance on carbohydrate metabolism, coagulation factors, blood pressure, the prostacyclin/thromboxane balance, and through direct action on the arterial wall.4,5The attenuating effect of estrogen on atherogenesis is, however, poorly understood. The central distribution of body fat has recently been recognized as an independent predictor of cardiovascular disease in women.‘,’ As estrogen may partly be responsible for the peripheral (gynoid) distribution of body fat in pre:nenopausal women, menopause may induce a more ccnaral distribution of the body fat, and thus contribute to the increased risk of cardiovascular disease after menopause. ‘I Theoretically, estrogen therapy could reverse this possible shift in the distribution of body fat and thereby constitute an important mechanism by which estrogen eserts a part of its protective effect against cardiovascular disease that is independent of its action on serum lipids and lipoproteins. We have therefore in a randomized, prospective, and controlled study investigated the influence of menopause and hormone replacement therapy on body composition in
early postmenopausal
women.
MATERIALS
AND METHODS
and medical and laboratory screening procedures as being a representative sample of healthy Danish postmenopausal women aged 45 to 55 years, who had passed natural menopause 6 months to 3 years previously.’ Seventy-five women entered the study; none had diseases or medications known to influence body composition. They were blindly allocated to treatment with estradiol valerate 2 mg (E,V) either continuously combined with cyproterone acetate 1 mg (CPA) or sequentially combined with levonorgestrel 75 kg (LNG), or placebo. They did not receive calcium supplementation.
Sixty-two women (83%) completed the study period of 2 years. Only data from these women were used in the calculations. All participants gave their informed consent, in accordance with the Helsinki Declaration II, and the trial was approved by the Ethical Committee of Copenhagen County. Body wt was measured to the nearest 0.1 kg in light indoor clothing, without shoes, and height to the nearest 0.5 cm with the subject standing erect, without shoes. Body mass index (BMI) was calculated as body wt (kg) divided by the squared height (m’). The body consists of soft tissue and bone (total body bone mineral [TBBM]). The soft tissues are composed of fat mass (FM) and lean tissue mass (LTM). Lean body mass (LBM) is the sum of the LTM and TBBM. The percentage of total body fat was calculated as the FM divided by the sum of FM, LTM, and TBBM. These components were measured initially by dual photon (“jGd) absorptiometry (DPA)‘” and after 2 years by dual energy X-ray absorptiometry (DEXA).” The precision errors (coefficient of variation percentage [CV%]) of the DPA measurements of the LTM, FM, and TBBM are 2.1% (0.9 kg), 7.6% (1.1 kg), and 2.4%‘. respectively. The accuracy errors are of the same magnitude.“’ The precision errors (CV%) of the DEXA measurements are for LTM, FM, and TBBM: 3.1% (1.4 kg); 6.4% (1.1 kg); and 1.2% (0.03 kg).” The abdominal fat percentage (AF%) including both subcutaneous and intra-abdominal fat (the present technique cannot separate these compartments) was initially measured with DPA in an area 15 cm broad between the upper edge of the second lumbar vertebra and the lower edge of the fourth lumbar vertebra.‘j and after 2 years with DEXA. The precision errors (CV%) of the AF% measurements with DPA and DEXA were 9% and 7%, respectively.” In our laboratory. the DEXA scanner (not available at the beginning of the present study) replaced the DPA scanner to improve precision and because it was a more convenient measurement procedure.“,” The DPA results are presented both as raw values and as values corrected according to an earlier established regression between DPA and DEXA.‘” Blood samples for serum lipids and lipoproteins were taken before randomization and every 3 months for 2 years during the
The subjects were selected by means of a questionnaire
Metabol/sm, Vol40,
No 12 (December), 1991: pp 1323-1326
From the Depariment of Clinical Chemistry, University of Copenhagen, Glostrup Hospital, Glostrup, Denmark. Supported by a grant from Statens Sundhed.widenskabeiige Forskningsrd, Copenhagen, Denmark. Address reprint requests to Dr Jens Haarbo, Department qf Clinical Chemistry, University of Copenhagen, Glostncp Hospital. Denmark. Copyright 0 1991 by W B. Saunders Company 0026-049519114012-0017$03.OOlO
1323
HAARBO ET AL
1324
estrogen-progestogen period. High-density lipoprotein (HDL)cholesterol was separated from chylomicrons, and low-density lipoprotein (LDL)-cholesterol, very low-density lipoprotein (VLDL)-cholesterol by a phosphotungstate-MgCI, precipitation technique.14 Serum total cholesterol, triglycerides, and HDLcholesterol were determined enzymatically by Chem I (Technicon Instruments, Tarrytown, NY). LDL-cholesterol was then estimated as described by Friedewald et al.”
Statistics Student’s t test for paired and unpaired data and one-way ANOVA were used to compare the groups. The relation between the change in AF% and the mean change in serum lipids and lipoproteins during the 2 years of the study (calculated as the mean difference between the initial value [NO%] and the following eight measurements) was investigated by calculation of parametric correlation coefficients. These analyses were performed with the Statistical Analysis System (SAS). RESULTS
Table 1 shows the clinical data of the three groups as well as serum lipids and lipoproteins. The groups were well matched. Table 2 gives the parameters for body composition (FM, LBM, TBBM, AF%) for the three groups. No significant differences between the groups were observed. The two hormone replacement groups were thereafter pooled to improve the statistical power of the study. No significant differences in these parameters (Tables 1 and 2) were seen when the combined hormone group was compared with the placebo group. The AF% remained virtually unchanged in the estrogenprogestogen group, whereas it increased significantly (5.5%) in the placebo group (P < .OS), an increase that was also significantly different from the result in the estrogen-progestogen group (P < .05) (Fig 1). The total body fat percentage tended to increase in the placebo group (1.3% corresponding to about 1 kg), whereas it was unchanged in the estrogen-progestogen group (Fig 1). LBM tended to decrease in the placebo group (0.64 kg rt 0.4 [mean +- SEMI) and remained unchanged in the estrogenprogestogen group (-0.01 kg 2 0.3). The differences in total body fat percentage and LBM did not, however, reach statistical significance. In addition, the estrogen-progestogen group had unchanged TBBM values, whereas in the placebo group it decreased significantly (4.5%) (Fig 2). This difference was highly statistically significant (P < .OOl).
Table 2. Body Composition Was Measured Initially With DPA and After 2 Years With DEXA (Mean f 1 SD) EZV/LNG
E,VICPA
Placebo
17.5 + 6.9
FM (kg) DPA
18.4 ? 6.2
21.1 + 8.6
DPA (corrected)
20.4 2 6.5
23.3 2 9.4
19.5 + 7.5
DEXA
20.9 2 6.8
23.5 2 7.4
20.4 2 6.5
LBM (kg) DPA
45.4 2 3.1
45.5 + 5.2
46.6 ? 3.6
DPA (corrected)
43.3 2 3.3
43.5 f 5.6
44.7 2 3.9
DEXA
43.9 & 4.1
43.3 + 4.8
44.0 f 3.8
TggM (g) DPA
3,240 + 334
3,215 2 429
3,323 f 374
DPA (corrected)
3,757 * 293
3,735 * 377
3,830 + 328
DEXA
3,807 2 423
3,723 + 549
3,658 2 458
AF % DPA
28.3 t 11.3
32.7 +- 13.6
25.5 ? 10.0
DPA (corrected)
31.5 2 12.4
36.4 r 14.9
28.5 2 11.0
DEXA
33.2 5 8.8
36.4 & 9.3
34.2 2 9.1
-
NOTE. The DPA results are also given after transformation to DEXA equivalents
(DPA [corrected])
according
to an earlier established
regression equation. There were no statistically significant differences between groups in any of the body composition
parameters
in the
Table.
The estrogen-progestogen therapy reduced the serum concentrations of total cholesterol (8.5%) and LDLcholesterol (13%) as compared with the placebo group (P < .OOl), whereas HDL-cholesterol and triglycerides did not change differently during the a-year study period. The change in AF% was not statistically significantly related to the mean change in serum lipids or lipoproteins (P > .05) (r values: serum total cholesterol, .15; serum triglycerides, .Ol; serum LDL-cholesterol, .22; serum HDL-cholesterol, -.07). DISCUSSION
The present randomized placebo-controlled study suggests that hormone replacement therapy prevents the increase in abdominal fat that occurs after menopause. This finding may be of considerable importance, as the abdominal distribution of fat is an important independent predictor of cardiovascular disease.’ The beneficial effect of estrogen on atherogenesis may therefore partly be explained by the prevention of abdominal fat.
Table 1. Initial Clinical Findings, Serum Lipids, and Lipoproteins (Mean + SD) E,V/LNG (n = 19)
E,V/CPA (n = 19)
Placebo (n = 24)
22.4 2 9.9
20.9 z 8.4
17.6 r 8.6
Height (cm)
163.2 + 5.0
164.3 + 5.6
163.4 + 5.5
Weight (kg)
65.1 + 9.2
67.1 ?z 11.5
64.5 2 8.1
8MI (kg/m’)
24.4 + 3.2
24.8 + 3.7
24.2 f 3.6
Total cholesterol (mmol/L)
6.7 ? 1.3
6.1 ? 0.7
6.0 r 1.2
Triglycerides (mmol/L)
1.1 + 0.5
1.0 t 0.5
1.0 f 0.5
HDL-cholesterol (mmol/L)
1.8 f 0.5
1.7 f 0.4
1.9 & 0.3
LDL-cholesterol (mmol/L)
4.5 + 1.4
4.0 2 0.8
3.7 -+ 1.1
Menopausal age (mo)
Fig 1. Change in AF% and total body fat percentage (FAT%) in the estrogen-progestogen group (0) and placebo group (0). lP < .05.
1325
HORMONE THERAPY AND BODY COMPOSITION
ATBBM
(g)
t
50
does,
ever,
increase
contribute
to highlighting
the rather
large
study.
The howin
AF%. Our data demonstrated a 4.5% loss from TBBM during the 2 early postmenopausal years. This change, which is in agreement with earlier data,“.” could be prevented by treatment with a combination of estrogen and progestogen. Such treatment regimens have already proved effective in the prevention of postmenopausal osteoporosis in the total skeleton and in any local region of the skeleton.“-” It has been noted that the results obtained with DPA and DEXA are not identical and in longitudinal studies the data must be converted when data are initially obtained with DPA and thereafter with DEXA.” Wahner et al” and Kelly et al” found slopes of 0.97 and 0.84, respectively, in regressions of spinal bone mineral density measured by DPA (Lunar DP3) versus DEXA (Hologic QDR). In a previous study of healthy subjects WC found the following regression relationships: FM,,,, = 1.09 FM,,,,, + 0.28: = 0.88 LBM,,,,, = 1.07 . LBM,,,,% - 5.34; TBBM,,,, TBBM,,, + 913.” Obviously, if DEXA and DPA results arc to be compared, one of the sets of data should be corrected according to regressions such as those given above. We chose to correct our data into DEXA equivalents. The results should be interpreted with caution, as any data convertion by means of regression equations introduces an error. However, such an error may disguise a true relation, and so the P values of the present study would probably have been even smaller had DEXA been available at the beginning of the study. The nonsignificant relation between the change in AF% and the cumulated change in serum lipids and lipoproteins is consistent with previous findings, which indicate that abdominal fat is related to serum lipids and also has an independent effect on cardiovascular disease.‘.’ Furthermore, the estrogen-mediated antiatherogcnic effect is only partly explained by the effect on serum lipids and lipoproteins.‘.’ The abdominal fat as measured by the present technique cannot be separated into subcutaneous and various intra-abdominal fat depots. However, previous studies suggest that intra-abdominal fat is the significant predictor of cardiovascular disease. Furthermore, an underlying disturbance in the metabolism of sex steroids. glucocorticoids, lipoproteins, or insulin may explain some of the relations between intra-abdominal fat and cardiovascular disease.LU~l’ In conclusion, the present study suggests that combined estrogen-progestogen therapy prevents abdominal fat and bone loss after menopause, and may maintain the premenopausal relation between FM and LBM. the (regional)
_I
-5:: “r-,,i*
- 100
level of statistical significance in the present small change in the total body fat percentage
\
1
”
-200 I
0 Fig 2. Change in TBBM in the estrogen-progestogen placebo group (0). ***P < ,001.
1 2 years group (0) and
The estrogenic effect on the distribution of body fat may partly be explained by effects on lipoprotein lipase activity, lipolytic responsiveness, and sensitivity of femoral and abdominal adipocytes.‘b.‘7 It has thus been demonstrated that premenopausal women, in contrast to postmenopausal women, have higher lipolytic activity in the abdominal adipose tissue and higher activity of lipoprotein lipase in the femoral adipose tissue.‘6.‘7 In addition, postmenopausal estrogen therapy has been shown to increase the activity of lipoprotein lipase in the femorogluteal region, which could bring about accumulation of triglycerides.16 Estrogen depletion, for instance, during menopause may therefore influence these mechanisms. This could lead to a relative increase in abdominal fat, which, as well as being an independent cardiovascular risk factor in itself, is also associated with diabetes mellitus, an atherogenic lipid and lipoprotein profile, and hypertension.6.‘X.‘9 All of these are associated with an increased risk for cardiovascular disease. Qur data suggest that postmenopausal estrogen-progestogen therapy may prevent the increase in total body FM and the decrease in LBM seen in the placebo group, although these differences were not statistically significant. These findings are consistent with those of previous studies, which have indicated that hormone replacement therapy prevents the increase in total body FM, as well as the decrease in skin collagen.*“~” These menopause-related changes in body composition seem to be relatively small (about 1 kg over 2 years) and would not therefore reach the
REFERENCES 1. Bush TL, Fried LP, Barrett-Connor E: Cholesterol, lipoproteins, and coronary heart disease in women. Clin Chem 34:B60870. 1988 2. Bush TL. Barrett-Connor E, Cowan LD, et al: Cardiovascular mor:ality and xoncontraceptive use of estrogen in women: Results
from the lipid research clinics program follow-up study. Circulation 75:1102-1109. 1987 3. Stampfer MJ, Willett WC. Colditz GA. et al: A prospective study of postmenopausal estrogen therapy and coronary heart disease. N Engl J Med 313:1044-1049, 1985
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4. Bush TL, Barrett-Connor E: Noncontraceptive estrogen use and cardiovascular disease. Epidemiol Rev 7:80-104,1985 5. Haarbo J, Leth-Espensen P, Stender S, et al: Estrogen monotherapy and combined estrogen-progestogen replacement therapy attenuate aortic accumulation of cholesterol in ovariectomized cholesterol-fed rabbits. J Clin Invest 87:1274-1279, 1991 6. Haarbo J, Hassager C, Schlemmer A, et al: The influence of smoking, body fat distribution, and alcohol consumption on serum lipids, lipoproteins, and apolipoproteins in early postmenopausal women. Atherosclerosis 84:239-244, 1990 7. Lapidus L, Bengtsson C, Larsson B, et al: Distribution of adipose tissue and risk of cardiovascular disease and death: A 12 year follow up of participants in the population study of women in Gothenburg, Sweden. Br Med J 289:1257-1261,1984 8. Witteman JCM, Grobbee DE, Kok FJ, et al: Increased risk of atherosclerosis in women after the menopause. Br Med J 298:642644,1989 9. Marslew U, Riis BJ, Christiansen C: Progestogens: therapeutic and adverse effects in early postmenopausal women. Maturitas 13:7-16,199l 10. Gotfredsen A, Jensen J, Borg J, et al: Measurement of lean body mass and total body fat using dual photon absorptiometty. Metabolism 3588-93, 1986 11. Mazess RB, Barden HS, Bisek JP, et al: Dual-energy x-ray absorptiometry for total-body and regional bone-mineral and soft-tissue composition. Am J Clin Nutr 51:1106-1112, 1990 12. Haarbo J, Gotfredsen A, Hassager C, et al: Validation of body composition measurement by dual energy x-ray absorptiometry (DEXA). Clin Phys 11:331-341,199l 13. Schlemmer A, Hassager C, Haarbo J, et al: Direct measurement of abdominal fat by dual photon absorptimetry. Int J Obes 14:603-611, 1990 14. Draeger B, Wahlefeld AW, Ziegenhorn J: Eine praktikable Methode zur HDL-Cholesterin-Bestimmung. Lab Med 6:198-202, 1982 15. Friedewald WT, Levy RI, Frederickson DS: Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin Chem 18:499502,1972 16. Rebuff&Strive M, Liinnroth P, M&in P, et al: Regional adipose tissue metabolism in men and postmenopausal women. Int J Obes 11:347-355,1987 17. Rebuff&Strive M, Eldh J, Hafstrom L-O, et al: Metabolism of mammary, abdominal, and femoral adipocytes in women before and after the menopause. Metabolism 35:792-797,1986
HAARBOET
AL
18. Evans DJ, Hoffmann RG, Kalkhoff RK, et al: Relationship of body fat topography to insulin sensitivity and metabolic profiles in premenopausal women. Metabolism 33:68-75,1984 19. Weinsier RL, Norris DJ, Birch R, et al: The relative contribution of body fat pattern to blood pressure level. Hypertension 7:578-585,1985 20. Hassager C, Christiansen C: Estrogenigestagen therapy changes soft tissue body composition in postmenopausal women. Metabolism 38:662-665,1989 21. Brincat M, Moniz CF, Kabalan S, et al: Decline in skin collagen content and metacarpal index after the menopause and its prevention with sex hormone replacement. Br J Obstet Gynaecol 94:126-129,1987 22. Nilas L, Christiansen C: Rates of bone loss in normal women: evidence of accelerated trabecular bone loss after the menopause. Eur J Clin Invest 18:529-534,1988 23. Gotfredsen A, Riis BJ, Christiansen C: Total and local bone mineral during estrogen treatment: A placebo controlled trial. Bone Miner 1:167-173,1986 24. Gotfredsen A, Nilas L, Riis BJ, et al: Bone changes occurring spontaneously and caused by oestrogen in early postmenopausal women: a local or generalized phenomenon? Br Med J 292:1098-1100, 1986 25. Riis BJ, Thomsen K, Strom V, et al: The effect of percutaneous estradiol and natural progesterone on postmenopausal bone loss. Am J Obstet Gynecol156:61-65,1987 26. Riis BJ, Jensen J, Christiansen C: Cyproterone acetate, an alternative gestagen in postmenopausal oestrogenigestagen therapy. Clin Endocrinol26:327-334, 1987 27. Wahner HW, Dunn WL, Brown ML, et al: Comparison of dual-energy x-ray/absorptiometry and dual photon absorptiometry for bone mineral measurements of the lumbar spine. Mayo Clin Proc 63:1075-1084,1988 28. Kelly TL, Slovik DM, Schoenfeld DA, et al: Quantitative digital radiography versus dual photon absorptiometry of the lumbar spine. J Clin Endocrinol Metab 67:839-844,1988 29. Evans DJ, Hoffmann RG, Kalkhoff RK, et al: Relationship of androgenic activity to body fat topography, fat cell morphology, and metabolic aberrations in premenopausal women. J Clin Endocrinol Metab 57:304-310,1983 30. Desprts J-P, Moorjani S, Ferland M, et al: Adipose tissue distribution and plasma lipoprotein levels in obese women. Importance of intra-abdominal fat. Arteriosclerosis 9:203-210,1989 31. Despres J-P, Moorjani S, Lupien PJ, et al: Regional distribution of body fat, plasma lipoproteins, and cardiovascular disease. Arteriosclerosis 10:497-511, 1990
Hormone Replacement Therapy Prevents Central Distribution of Body Fat After Menopause Jens Haarbo, Ulla Marslew, Anders Gotfredsen, and Claus Christiansen
The reduction in cardiovascular risk induced by hormone replacement therapy is only partly explained by changes in serum lipids and lipoproteins. As body composition and body fat distribution in particular are independent predictors of cardiovascular disease, we investigated the effect of postmenopausal hormone therapy on body composition parameters directly measured. Sixty-two early postmenopausal women were followed up for 2 years in a prospective, randomized, placebo-controlled study. We found that combined estrogen-progestogen therapy prevented the increase in abdominal fat after menopause (P < .05), and that this effect was independent of the effect on serum lipids and lipoproteins. The therapy reduced postmenopausal bone loss significantly (P < .OOl), whereas it did not have a statistically significant influence on total body fat mass or total lean body mass. The findings of the present study suggest that some of the protective impact of postmenopausal hormone therapy on cardiovascular disease may be explained by the effect on body composition, in particular abdominal fat. Copyright 0 7991 by W.B. Saunders Company
C
ARDIOVASCULAR disease is currently the leading cause of death and disability in Western societies. It accounts for almost 500,000 deaths per year among women in the United States alone.’ Several epidemiologic studies hate shown that estrogen replacement therapy may prevent or reduce coronary heart disease in postmenopausal women.‘.’ This favorable effect is only partly explained by the action of estrogen on serum lipids and lipoproteins, which indicates that estrogen possesses additional benefits,’ for instance on carbohydrate metabolism, coagulation factors, blood pressure, the prostacyclin/thromboxane balance, and through direct action on the arterial wall.4,5The attenuating effect of estrogen on atherogenesis is, however, poorly understood. The central distribution of body fat has recently been recognized as an independent predictor of cardiovascular disease in women.‘,’ As estrogen may partly be responsible for the peripheral (gynoid) distribution of body fat in pre:nenopausal women, menopause may induce a more ccnaral distribution of the body fat, and thus contribute to the increased risk of cardiovascular disease after menopause. ‘I Theoretically, estrogen therapy could reverse this possible shift in the distribution of body fat and thereby constitute an important mechanism by which estrogen eserts a part of its protective effect against cardiovascular disease that is independent of its action on serum lipids and lipoproteins. We have therefore in a randomized, prospective, and controlled study investigated the influence of menopause and hormone replacement therapy on body composition in
early postmenopausal
women.
MATERIALS
AND METHODS
and medical and laboratory screening procedures as being a representative sample of healthy Danish postmenopausal women aged 45 to 55 years, who had passed natural menopause 6 months to 3 years previously.’ Seventy-five women entered the study; none had diseases or medications known to influence body composition. They were blindly allocated to treatment with estradiol valerate 2 mg (E,V) either continuously combined with cyproterone acetate 1 mg (CPA) or sequentially combined with levonorgestrel 75 kg (LNG), or placebo. They did not receive calcium supplementation.
Sixty-two women (83%) completed the study period of 2 years. Only data from these women were used in the calculations. All participants gave their informed consent, in accordance with the Helsinki Declaration II, and the trial was approved by the Ethical Committee of Copenhagen County. Body wt was measured to the nearest 0.1 kg in light indoor clothing, without shoes, and height to the nearest 0.5 cm with the subject standing erect, without shoes. Body mass index (BMI) was calculated as body wt (kg) divided by the squared height (m’). The body consists of soft tissue and bone (total body bone mineral [TBBM]). The soft tissues are composed of fat mass (FM) and lean tissue mass (LTM). Lean body mass (LBM) is the sum of the LTM and TBBM. The percentage of total body fat was calculated as the FM divided by the sum of FM, LTM, and TBBM. These components were measured initially by dual photon (“jGd) absorptiometry (DPA)‘” and after 2 years by dual energy X-ray absorptiometry (DEXA).” The precision errors (coefficient of variation percentage [CV%]) of the DPA measurements of the LTM, FM, and TBBM are 2.1% (0.9 kg), 7.6% (1.1 kg), and 2.4%‘. respectively. The accuracy errors are of the same magnitude.“’ The precision errors (CV%) of the DEXA measurements are for LTM, FM, and TBBM: 3.1% (1.4 kg); 6.4% (1.1 kg); and 1.2% (0.03 kg).” The abdominal fat percentage (AF%) including both subcutaneous and intra-abdominal fat (the present technique cannot separate these compartments) was initially measured with DPA in an area 15 cm broad between the upper edge of the second lumbar vertebra and the lower edge of the fourth lumbar vertebra.‘j and after 2 years with DEXA. The precision errors (CV%) of the AF% measurements with DPA and DEXA were 9% and 7%, respectively.” In our laboratory. the DEXA scanner (not available at the beginning of the present study) replaced the DPA scanner to improve precision and because it was a more convenient measurement procedure.“,” The DPA results are presented both as raw values and as values corrected according to an earlier established regression between DPA and DEXA.‘” Blood samples for serum lipids and lipoproteins were taken before randomization and every 3 months for 2 years during the
The subjects were selected by means of a questionnaire
Metabol/sm, Vol40,
No 12 (December), 1991: pp 1323-1326
From the Depariment of Clinical Chemistry, University of Copenhagen, Glostrup Hospital, Glostrup, Denmark. Supported by a grant from Statens Sundhed.widenskabeiige Forskningsrd, Copenhagen, Denmark. Address reprint requests to Dr Jens Haarbo, Department qf Clinical Chemistry, University of Copenhagen, Glostncp Hospital. Denmark. Copyright 0 1991 by W B. Saunders Company 0026-049519114012-0017$03.OOlO
1323
HAARBO ET AL
1324
estrogen-progestogen period. High-density lipoprotein (HDL)cholesterol was separated from chylomicrons, and low-density lipoprotein (LDL)-cholesterol, very low-density lipoprotein (VLDL)-cholesterol by a phosphotungstate-MgCI, precipitation technique.14 Serum total cholesterol, triglycerides, and HDLcholesterol were determined enzymatically by Chem I (Technicon Instruments, Tarrytown, NY). LDL-cholesterol was then estimated as described by Friedewald et al.”
Statistics Student’s t test for paired and unpaired data and one-way ANOVA were used to compare the groups. The relation between the change in AF% and the mean change in serum lipids and lipoproteins during the 2 years of the study (calculated as the mean difference between the initial value [NO%] and the following eight measurements) was investigated by calculation of parametric correlation coefficients. These analyses were performed with the Statistical Analysis System (SAS). RESULTS
Table 1 shows the clinical data of the three groups as well as serum lipids and lipoproteins. The groups were well matched. Table 2 gives the parameters for body composition (FM, LBM, TBBM, AF%) for the three groups. No significant differences between the groups were observed. The two hormone replacement groups were thereafter pooled to improve the statistical power of the study. No significant differences in these parameters (Tables 1 and 2) were seen when the combined hormone group was compared with the placebo group. The AF% remained virtually unchanged in the estrogenprogestogen group, whereas it increased significantly (5.5%) in the placebo group (P < .OS), an increase that was also significantly different from the result in the estrogen-progestogen group (P < .05) (Fig 1). The total body fat percentage tended to increase in the placebo group (1.3% corresponding to about 1 kg), whereas it was unchanged in the estrogen-progestogen group (Fig 1). LBM tended to decrease in the placebo group (0.64 kg rt 0.4 [mean +- SEMI) and remained unchanged in the estrogenprogestogen group (-0.01 kg 2 0.3). The differences in total body fat percentage and LBM did not, however, reach statistical significance. In addition, the estrogen-progestogen group had unchanged TBBM values, whereas in the placebo group it decreased significantly (4.5%) (Fig 2). This difference was highly statistically significant (P < .OOl).
Table 2. Body Composition Was Measured Initially With DPA and After 2 Years With DEXA (Mean f 1 SD) EZV/LNG
E,VICPA
Placebo
17.5 + 6.9
FM (kg) DPA
18.4 ? 6.2
21.1 + 8.6
DPA (corrected)
20.4 2 6.5
23.3 2 9.4
19.5 + 7.5
DEXA
20.9 2 6.8
23.5 2 7.4
20.4 2 6.5
LBM (kg) DPA
45.4 2 3.1
45.5 + 5.2
46.6 ? 3.6
DPA (corrected)
43.3 2 3.3
43.5 f 5.6
44.7 2 3.9
DEXA
43.9 & 4.1
43.3 + 4.8
44.0 f 3.8
TggM (g) DPA
3,240 + 334
3,215 2 429
3,323 f 374
DPA (corrected)
3,757 * 293
3,735 * 377
3,830 + 328
DEXA
3,807 2 423
3,723 + 549
3,658 2 458
AF % DPA
28.3 t 11.3
32.7 +- 13.6
25.5 ? 10.0
DPA (corrected)
31.5 2 12.4
36.4 r 14.9
28.5 2 11.0
DEXA
33.2 5 8.8
36.4 & 9.3
34.2 2 9.1
-
NOTE. The DPA results are also given after transformation to DEXA equivalents
(DPA [corrected])
according
to an earlier established
regression equation. There were no statistically significant differences between groups in any of the body composition
parameters
in the
Table.
The estrogen-progestogen therapy reduced the serum concentrations of total cholesterol (8.5%) and LDLcholesterol (13%) as compared with the placebo group (P < .OOl), whereas HDL-cholesterol and triglycerides did not change differently during the a-year study period. The change in AF% was not statistically significantly related to the mean change in serum lipids or lipoproteins (P > .05) (r values: serum total cholesterol, .15; serum triglycerides, .Ol; serum LDL-cholesterol, .22; serum HDL-cholesterol, -.07). DISCUSSION
The present randomized placebo-controlled study suggests that hormone replacement therapy prevents the increase in abdominal fat that occurs after menopause. This finding may be of considerable importance, as the abdominal distribution of fat is an important independent predictor of cardiovascular disease.’ The beneficial effect of estrogen on atherogenesis may therefore partly be explained by the prevention of abdominal fat.
Table 1. Initial Clinical Findings, Serum Lipids, and Lipoproteins (Mean + SD) E,V/LNG (n = 19)
E,V/CPA (n = 19)
Placebo (n = 24)
22.4 2 9.9
20.9 z 8.4
17.6 r 8.6
Height (cm)
163.2 + 5.0
164.3 + 5.6
163.4 + 5.5
Weight (kg)
65.1 + 9.2
67.1 ?z 11.5
64.5 2 8.1
8MI (kg/m’)
24.4 + 3.2
24.8 + 3.7
24.2 f 3.6
Total cholesterol (mmol/L)
6.7 ? 1.3
6.1 ? 0.7
6.0 r 1.2
Triglycerides (mmol/L)
1.1 + 0.5
1.0 t 0.5
1.0 f 0.5
HDL-cholesterol (mmol/L)
1.8 f 0.5
1.7 f 0.4
1.9 & 0.3
LDL-cholesterol (mmol/L)
4.5 + 1.4
4.0 2 0.8
3.7 -+ 1.1
Menopausal age (mo)
Fig 1. Change in AF% and total body fat percentage (FAT%) in the estrogen-progestogen group (0) and placebo group (0). lP < .05.
1325
HORMONE THERAPY AND BODY COMPOSITION
ATBBM
(g)
t
50
does,
ever,
increase
contribute
to highlighting
the rather
large
study.
The howin
AF%. Our data demonstrated a 4.5% loss from TBBM during the 2 early postmenopausal years. This change, which is in agreement with earlier data,“.” could be prevented by treatment with a combination of estrogen and progestogen. Such treatment regimens have already proved effective in the prevention of postmenopausal osteoporosis in the total skeleton and in any local region of the skeleton.“-” It has been noted that the results obtained with DPA and DEXA are not identical and in longitudinal studies the data must be converted when data are initially obtained with DPA and thereafter with DEXA.” Wahner et al” and Kelly et al” found slopes of 0.97 and 0.84, respectively, in regressions of spinal bone mineral density measured by DPA (Lunar DP3) versus DEXA (Hologic QDR). In a previous study of healthy subjects WC found the following regression relationships: FM,,,, = 1.09 FM,,,,, + 0.28: = 0.88 LBM,,,,, = 1.07 . LBM,,,,% - 5.34; TBBM,,,, TBBM,,, + 913.” Obviously, if DEXA and DPA results arc to be compared, one of the sets of data should be corrected according to regressions such as those given above. We chose to correct our data into DEXA equivalents. The results should be interpreted with caution, as any data convertion by means of regression equations introduces an error. However, such an error may disguise a true relation, and so the P values of the present study would probably have been even smaller had DEXA been available at the beginning of the study. The nonsignificant relation between the change in AF% and the cumulated change in serum lipids and lipoproteins is consistent with previous findings, which indicate that abdominal fat is related to serum lipids and also has an independent effect on cardiovascular disease.‘.’ Furthermore, the estrogen-mediated antiatherogcnic effect is only partly explained by the effect on serum lipids and lipoproteins.‘.’ The abdominal fat as measured by the present technique cannot be separated into subcutaneous and various intra-abdominal fat depots. However, previous studies suggest that intra-abdominal fat is the significant predictor of cardiovascular disease. Furthermore, an underlying disturbance in the metabolism of sex steroids. glucocorticoids, lipoproteins, or insulin may explain some of the relations between intra-abdominal fat and cardiovascular disease.LU~l’ In conclusion, the present study suggests that combined estrogen-progestogen therapy prevents abdominal fat and bone loss after menopause, and may maintain the premenopausal relation between FM and LBM. the (regional)
_I
-5:: “r-,,i*
- 100
level of statistical significance in the present small change in the total body fat percentage
\
1
”
-200 I
0 Fig 2. Change in TBBM in the estrogen-progestogen placebo group (0). ***P < ,001.
1 2 years group (0) and
The estrogenic effect on the distribution of body fat may partly be explained by effects on lipoprotein lipase activity, lipolytic responsiveness, and sensitivity of femoral and abdominal adipocytes.‘b.‘7 It has thus been demonstrated that premenopausal women, in contrast to postmenopausal women, have higher lipolytic activity in the abdominal adipose tissue and higher activity of lipoprotein lipase in the femoral adipose tissue.‘6.‘7 In addition, postmenopausal estrogen therapy has been shown to increase the activity of lipoprotein lipase in the femorogluteal region, which could bring about accumulation of triglycerides.16 Estrogen depletion, for instance, during menopause may therefore influence these mechanisms. This could lead to a relative increase in abdominal fat, which, as well as being an independent cardiovascular risk factor in itself, is also associated with diabetes mellitus, an atherogenic lipid and lipoprotein profile, and hypertension.6.‘X.‘9 All of these are associated with an increased risk for cardiovascular disease. Qur data suggest that postmenopausal estrogen-progestogen therapy may prevent the increase in total body FM and the decrease in LBM seen in the placebo group, although these differences were not statistically significant. These findings are consistent with those of previous studies, which have indicated that hormone replacement therapy prevents the increase in total body FM, as well as the decrease in skin collagen.*“~” These menopause-related changes in body composition seem to be relatively small (about 1 kg over 2 years) and would not therefore reach the
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