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Endocrinology Vol. 142, No. 11 4813-4817
Copyright © 2001 by The Endocrine Society

ARTICLES

The Effect of Tibolone on Fat Mass, Fat-Free Mass, and Total Body Water in Postmenopausal Women

Ingrid B. Meeuwsen, Monique M. Samson, Sijmen A. Duursma and Harald J. Verhaar

Mobility Laboratory, Department of Geriatric Medicine, Utrecht University Medical Center, 3508 GA Utrecht, The Netherlands

Address all correspondence and requests for reprints to: Dr. Ingrid B. A. E. Meeuwsen, Department of Geriatric Medicine, Utrecht University Medical Center, P.O. Box 85500 (Room W01.209), 3508 GA Utrecht, The Netherlands. E-mail: i.meeuwsen{at}azu.nl


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Changes in body composition occur around the menopausal transition. The major characteristics are a decline in fat-free mass and an increase in body fat as a percentage of body weight. These alterations might be affected by age only or by menopause-related changes in hormone concentration. In this study the effects of tibolone, a tissue-specific compound with favorable effects on bone, vagina, and climacteric symptoms, were determined on body composition using bioelectrical impedance analysis. The focus was especially on fat mass, fat-free mass, and total body water in a group of 85 healthy women (mean ± SD age, 54.2 ± 4.7 yr), between 1–15 yr postmenopausal. Participants were randomly assigned to either tibolone (2.5 mg; n = 42) or identically appearing placebo tablets (n = 43) daily for 12 months. All analyses were based on the intent to treat group and last visit. Compared with placebo, tibolone significantly increased fat-free mass by 0.85 kg (P = 0.003) and total body water by 0.78 liter (P = 0.001). No significant difference was observed on the fat mass parameter (P = 0.16). From these results it can be concluded that tibolone may counteract the postmenopausal changes in body composition.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
BODY WEIGHT INCREASES with age in both men and women. Whether the rate of weight gain is influenced by the occurrence of the menopause is not clear. Although many women report that they gained weight at or near the time of their menopause, the amplitude and even the reality of the menopause-related gain in weight remain controversial (1). Body composition also changes with age; fat mass increases, whereas decreases in bone, lean body mass, and body protein and a relative expansion of extracellular fluid have been observed (2). As a result, an increase in body fat as a percentage of body weight occurs. Additionally, redistribution of body fat, with a relative increase in the proportion of abdominal fat (android distribution) is observed (3, 4).

Factors involved in the menopause-related alterations in body composition, particularly the decrease in lean mass, are assumed to be E and/or progesterone deficiency, changes in muscle and/or adipose tissue metabolism, modification of eating behavior, modification of life style, environmental factors, genetic predisposition, and reduction in energy expenditure (5). According to Gallagher et al. (6), three factors may contribute to the gradual fall in energy expenditure with age and menopause: loss of luteal phase, effect of aging on fat-free mass, and perhaps a specific effect of the menopause on resting metabolic rate. The reduction in fat-free mass may be responsible for a decrease in energy expenditure favoring weight gain if the caloric intake is not reduced.

Besides the above-mentioned E and or progesterone deficiency, other hormones such as cortisol, ACTH, GH, and androgens might be involved in the menopausal changes in body composition (7). Both overall and upper body adiposity have been associated with increased free T levels and lower SHBG concentrations in premenopausal and postmenopausal women (8). As E may partly be responsible for the gynoid distribution of body fat, the redistribution of body fat around menopause might be prevented by hormone replacement therapy (HRT). Several studies have demonstrated prevention of the shifting of body fat to a more central location by the use of HRT (9, 10, 11). A common perception among women going through menopause is that HRT causes weight gain (12). Fear of weight gain is one of the factors contributing to poor compliance with HRT regimens. However, available evidence, obtained from systematic Cochrane review, suggests that HRT does not cause weight gain (13), although it might cause rehydration. This rehydration can promote an increase in body weight, but is also associated with an improvement in the water-holding capacity of the skin (14). The lack of agreement among these studies may be partially caused by the difference in HRT regimens and dosages used. Conclusions from a single study need to be confirmed to assure that it can be extrapolated into general practice.

Tibolone is a tissue-specific compound that displays estrogenic, progestogenic, and mild androgenic activities after oral administration (15, 16). Tibolone (2.5 mg) has been extensively used by postmenopausal women in Europe for the treatment of climacteric symptoms and prevention of osteoporosis. To our knowledge there is only one study available of the effects of tibolone on body composition (17).

The present study was designed to examine the effects of tibolone (2.5 mg) compared with placebo on body weight and body composition in postmenopausal women over a 1-yr period. Measurements were performed by bioelectrical impedance analysis (BIA), and the parameters used were fat mass (FM), fat-free mass (FFM), total body water (TBW), extracellular water (ECW), intracellular water (ICW), body cell mass (BCM), and the phase angle expressing the arc tangent of the ratio between reactance and resistance.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Participants
Eighty-five healthy women (mean ± SD age, 54.2 ± 4.7 yr), who where at least 1 yr and at maximum 15 yr after natural menopause were enrolled in a randomized, double blind, placebo-controlled, single center trial during the accession period of August 1997 and July 1999. The study protocol was approved by the medical ethical board of the Utrecht University Medical Center.

Participants were recruited by local paper advertisements. Information about the study was given in verbal and written form to all potential subjects. At screening and after giving written informed consent, subjects underwent the following examinations: medical history, physical and gynecological examination, and mammography if one had not been performed during the previous 12 months. Women who met any of the following criteria were not included in the study: presence or history of sex hormone-dependent malignancies; the use of HRT or other steroid medication or muscle growth affecting drugs during the last 6 months before the start of the study; hypertension (>170 mm Hg systolic, >105 mm Hg diastolic); active liver disease or a history of this condition with failing of liver function tests to return to normal; presence or history of endometrial hyperplasia with or without atypia; undiagnosed vaginal bleeding; presence or history of cardiovascular, cerebrovascular, or thromboembolic disorders; consumption of more than four alcoholic drinks per d; porphyria; hemoglobinopathy; use of sex hormones, anabolics, corticosteroids, insulin, anticoagulants, or enzyme-inducing drugs; participation in a clinical trial during the last 3 months; body mass index (BMI) below 18 kg/m2 or above 29 kg/m2; or unwilling to fill out a diary card for 12 months. Concomitant medication that could interfere with the study drugs or influence muscle strength as well as anticoagulants and enzyme-inducing drugs were not allowed during the study period.

Intervention
Eligible participants were randomly assigned to 2.5 mg tibolone or identically appearing placebo pills (NV Organon, Oss, The Netherlands) daily for 12 months; pills were taken orally in the morning. Randomization was performed at a 1:1 ratio by the Department of Dispensing Services and Control of NV Organon.

Compliance with treatment was monitored by means of a diary card and by counting the remaining tablets at each visit. Special effort was made to keep the participants motivated, with check-up calls after 1 and 9 months.

Anthropometry
Body composition assessments were performed at baseline and after 3, 6, and 12 months of treatment. Body weight was measured to the nearest 0.1 kg (Seca Alpha 770, Vogel & Halke GmbH and Co., Hamburg, Germany) and height to the nearest millimeter using a wall-mounted stadiometer (18). BMI was calculated as kilograms per m2. All measurements were performed by the same investigator (I. B. Meeuwsen).

BIA
Bioelectrical impedance measurement is an indirect method and is based on the two-compartment model. In the two-compartment model the body is divided into two distinct compartments: body fat and FFM. The electrical impedance (Z) of the body is measured by introducing a small alternating current and measuring the potential difference that results. Impedance has two components or vectors, termed resistance (R) and reactance (Xc). Resistance is the ability of an object to transmit an electrical current. In the body, highly conductive lean tissues contain large amounts of water and conducting electrolytes, and therefore represent a low resistance electrical pathway. Fat and bone, on the other hand, are poor conductors. Reactance is the voltage stored by a condenser for a brief period of time. In the human body, reactance is a measure of the volume of cell membrane capacitance and an indirect measure of the intracellular volume or body cell mass. Whereas body fat, TBW, and ECW offer resistance to electrical current, only cell membranes offer capacitive reactance. Reactance is not affected by the quantity of body fat. Generally, high reactance values from a BIA measurement indicate better health and cell membrane integrity (19).

BCM is defined as the intracellular mass of the body, which contains the majority of the body’s potassium (98–99%). All oxygen consumption, CO2 production, glucose oxidation, protein synthesis, and other metabolic work takes place within the BCM. The BCM represents the metabolic active component of the body (20). The phase angle (arc tangent of the ratio of Xc/R) electrically describes how voltage and current lead or lag each other in any circuit of resistors and capacitors. A phase angle of 45° would reflect a circuit (or body) with an equal amount of capacitive reactance and resistance. With 0° the circuit is only resistive (as in a system with no cell membranes) and with 90° the circuit is only capacitive (all membranes with no fluid) (21).

The reproducibility in measuring TBW and lean body mass will approximate the 0.99 test-retest correlation (19, 22, 23). BIA can be used to track change, both long term (days, months) and short term (minutes, hours). The sensitivity of BIA (TBW, FFM, and BCM) has been proven to be accurate in long-term studies. (19, 20). These studies had significant correlations to dual x-ray absorptiometry and total body isotope counting (K40).

Body composition assessments
Bioelectric impedance measurements were taken on the right side of the body using a tetrapolar BIA 101 impedance analyzer (RJL Systems, Detroit, MI). Resistance (R) and reactance (Xc) were measured, recorded in ohms, during application of an alternating electric current of 800 µA and 50 kHz. All measurements were taken with the participant supine, the arms relaxed at the sides but not touching the body, and thighs separated. After cleaning all skin contact areas with alcohol, aluminum foil spot electrodes were placed on the dorsal surfaces of the hands and feet at the distal metacarpals and metatarsals, respectively, and also between the distal prominences of the radius and the ulna and between the medial and lateral malleoli at the ankle.

Statistical analysis
Data from the intent to treat group were used to assess efficacy. For all parameters, descriptive statistics were calculated by treatment group and by assessment for the original measurements for changes from baseline and for percent changes from baseline. The last visit was used for the treatment group comparison. Each of the parameters was analyzed by means of an analysis of covariance model. This model incorporated treatment group as a factor and baseline as a covariant. Results are expressed as estimates of the treatment differences with 95% confidence intervals and two-sided P values. P < 0.05 was considered the cut-off point to establish statistical significance in all analyses. Scatter plots of the values found at last visit vs. the baseline values were used to assess the adequacy of the analysis of covariance. The assumption of a normally distributed parameter was checked graphically by making a normal probability plot of the residuals. All analyses were performed using SAS version 6.12 for PC (WinNT version 4.0, SAS Institute, Inc., Cary, NC).


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Compliance
Eighty-five women were randomized and started treatment. Eighty-one women contributed to the analysis (tibolone, n = 39; placebo, n = 42). This group was classified as the intent to treat group. Nine subjects (tibolone, n = 4; placebo, n = 5) reported hysterectomy in their medical history. In total, five subjects (5.9%) discontinued the trial (tibolone, n = 3; placebo, n = 2). Most discontinuations were within the first months after enrolment in the study (four of five). Reasons for dropout were malaise (tibolone, n = 2), clinically significant abnormal mammography (placebo, n = 1), poor compliance (tibolone, n = 1), and personal problems unrelated to study (placebo, n = 1). This last subject discontinued from the trial in month 7 and was therefore included in the intent to treat analysis. Overall compliance with treatment was 98–99%. The demographic and clinical characteristics of each group at baseline are presented in Table 1Go. At baseline, no statistically significant group differences were seen for any characteristic (all P > 0.05).


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  		Table 1. Baseline characteristics of postmenopausal women treated with tibolone (n = 39) or placebo (n = 42) for 1 yr (intent to treat group)

 
Efficacy analyses
For the treatment group comparison, the last visit was taken for analysis. The parameters were analyzed separately, and no adjustment for multiple testing was made. All analyses indicated no interaction between treatment and baseline effects, and the assumption of normality was not violated when the corresponding plots were taken into account. No serious outliers were found in the residual plots. No violation of the parallel regression concept was found; all test probabilities were far from significance.

In Table 2Go an overview is presented with the mean values for the tibolone and placebo groups corrected for baseline differences (least squared means). The difference has been calculated as well as the probability (P), testing for equivalence of the mean values. Additionally 95% confidence intervals are presented in this table. It can be concluded from Table 2Go that the BIA parameters were significantly different at the 5% level between the treatment groups, for FFM, TBW, ECW, ICW, reactance (Xc), and resistance (R). The other parameters, body weight, FM, phase angle, and BCM, did not appear to be significantly different. Compared with placebo, the estimated treatment effect in the tibolone group is 0.85 kg for FFM, 0.78 liter for TBW, 0.49 liter for ECW, and 0.32 liter for ICW. Finally, the estimated treatment effects of tibolone compared with placebo for reactance and resistance were -2.8 and -20 ohm, respectively.


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  		Table 2. Results of the efficacy analyses (intent to treat group) on the BIA parameters at last visit in postmenopausal women treated with tibolone (n = 39) or placebo (n = 42)

 
Changes from baseline
For each parameter descriptive statistics were calculated by treatment group. In addition, the calculations were performed for the absolute and percent changes from baseline (Table 3Go). The changes from baseline were compared using a t test. Significant changes from baseline were observed in the tibolone group only for the parameters ICW, BCM, and phase angle. On the other hand, in the placebo group significant changes from baseline were observed for all parameters except FFM. Absolute changes from baseline for the major end points, FM, FFM, and TBW, are presented in Fig. 1.


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  		Table 3. Summary statistics and absolute and percent changes from baseline for postmenopausal women treated with tibolone or placebo

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
In this randomized, double blind, placebo-controlled trial we investigated the effect of tibolone on body composition parameters in a group of postmenopausal women over a 1-yr treatment period. The results of this study indicated significant treatment effects at the last visit in the tibolone group compared with the placebo group for the parameters FFM (0.85 kg), TBW (0.78 liter), ECW (0.49 liter), ICW (0.32 liter), reactance (-2.76 ohm), and resistance (-20.03 ohm). No significant differences between tibolone and placebo were observed on body weight, FM, phase angle, or BCM. The increase in TBW during tibolone use might be the result of an increase in BCM, a decrease in FM, or simply water retention. However, the increment in BCM (while body weight remained unchanged) suggested that the increase in TBW resulted at least in part from a gain in lean body mass.

To our knowledge, this is only the second study on the effect of tibolone on body composition in postmenopausal women. The first study was designed to compare the effects of tibolone with those of two different conventional HRT regimens and to no therapy. The focus in that study was on the changes in body weight and body composition during an observation period of 2 yr (17). Total body FM, expressed as a percent change from baseline, increased significantly in controls (3.6 ± 1.5%) and remained unchanged in the tibolone group (-1.6 ± 1.9%). Total lean body mass decreased significantly in controls (-1.7 ± 0.7%) and remained stable in tibolone-treated subjects (+0.4 ± 0.5%). These results are comparable to those observed in our 1-yr intervention study. In our study population, the tibolone-treated group, FFM did not significantly change from baseline (0.8 ± 0.8%), and total FM remained stable (0.2 ± 0.7%). On the other hand, in the placebo group FM increased significantly (3.3 ± 1.3%), whereas FFM remained unchanged (0.7 ± 1.1%).

The effects of the administration of tibolone in these two studies are small. However, they match the results of a longitudinal body composition study in women (mean ± SE age, 70.2 ± 7.8 yr) with a mean ± SD follow-up time of 4.7 ± 2.3 yr. This study was designed to evaluate changes in body composition over time in healthy community-dwelling and independently living elderly adults (6). In a younger group of women participating in the Fels Longitudinal Study (24), measurements were made biennially from 40–66 yr of age. These women gained body weight as they became older, at an annual rate of approximately 0.55 kg/yr. Additionally, a significant age-related increase in BMI was observed as well as an increase in total body fat of approximately 0.41 kg/yr. The women lost FFM at an average rate of about 0.11 kg/yr. Postmenopausal women had significantly higher total body fat and percent body fat values than premenopausal women. Finally, women who had taken E for more than 5 yr had significantly higher FFM than nonusers, but there were no differences in FFM values between women who had taken E for less than 5 yr and nonusers. Overall, it appears that changes in body composition are small and are not often significant in a 1-yr period. Nevertheless, the use of HRT, especially long-term use, may counteract changes in body composition parameters.

It has been suggested that E may influence body composition through several potential mechanisms. E2 might inhibit the action of adipose tissue lipoprotein lipase, the enzyme that hydrolyzes circulating triglycerides, allowing for the uptake of fatty acids into adipocytes (25). Furthermore, data from rodent models indicate that E acts as an anorectic, decreasing voluntary food intake (26), increasing physical activity-related energy expenditure (27), and possibly increasing resting energy expenditure (28). E is not the only hormone to have an altered concentration around the time of menopause. Changes can also be observed, for example, in progesterone, T, GH, and IGF-I levels (29). Replacement therapy with a topically administered gel containing androstanolone in postmenopausal women has been found to reduce total body weight and total body fat (30), and administration of GH and IGF-I to postmenopausal women has been reported to increase FFM and decrease FM (31, 32). From these studies it can be concluded that postmenopausal HRT might prevent the shift from gynoid to android fat distribution. It is unclear, however, whether the commonly observed postmenopausal gain in weight and FM is related entirely to aging or is accelerated by E deficiency (33). The issue of weight gain is important not only because of aesthetic considerations, but also because body FM and its distribution correlate with risks of coronary artery disease (9) and certain cancers (34).

The drug used in our trial, tibolone (2.5 mg), is a tissue-specific compound associated with estrogenic, progestogenic, and androgenic activities after oral administration. Based on the results of endocrinological studies in laboratory animals, tibolone exerts an estrogenic activity about 1/20th that of ethinyl E2, a progestogenic activity 1/8th that of norethisterone, and an androgenic activity 1/50th that of methyltestosterone (35). The administration of tibolone affects GH release and IGF-I plasma levels (36). The increase in plasma GH levels with no change in pituitary maximal response to GHRH supports the hypothesis of a major role of E2 in reducing the inhibitory tone(s) by acting on endogenous GHRH release, rather than a direct effect in changing pituitary sensitivity to GHRH. According to Hopkins (37), serum IGF-I levels in women receiving tibolone remained essentially unchanged, whereas control women demonstrated a significant decrease in IGF-I values. Due to these combined actions it is difficult to determine which mechanism is responsible for the exerted effect.

Besides the varying effects of HRT on body composition, another factor to consider is the method of assessment of body composition (38). BIA is a relatively fast and noninvasive method. It uses estimation equations derived from indirect methods. As a result, prediction of body fat and water content might be impeded by inaccuracies as a result of the method itself and as a consequence of assumptions used in the reference method (23). Nonetheless, BIA has proven to be valid and sensitive to use in intervention studies (39, 40, 41). BIA seems to be preferable to simpler methods, as hydrodensitometry is strongly influenced by changes in bone density and is invasive and time-consuming, and the skinfold method is highly observer-biased (23).

From this study it can be concluded that there is a treatment effect of tibolone on FFM, TBW, ECW, and ICW compared with placebo in a 1-yr intervention period. According to changes from baseline it appeared that the placebo group showed declining values for TBW and ECW and an increment in FM. As these parameters remained unchanged in the tibolone group, it might be concluded that these changes could be prevented by the use of tibolone. Furthermore, as no differences were observed in body weight, our results might indicate a favorable redistribution of body composition parameters in women using tibolone. Tibolone seems to prevent the decline in lean body mass that has been mentioned as a major hallmark of the menopause, but because of the relatively small changes in body composition that occur throughout this 1-yr period, more longitudinal studies around the time of menopause and long-term studies of the effect of HRT are recommended.



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  		Figure 1. Absolute changes from baseline for the primary end points, FM (kilograms), FFM (kilograms), and TBW (liters) in postmenopausal women treated with tibolone (n = 39) or placebo (n = 42) for 1 yr (intent to treat group). Bars indicate the mean ± SEM. *, Significant change from baseline (P < 0.05).

 

   Acknowledgments
 


   Footnotes
 
This work was supported by NV Organon (Oss, The Netherlands). The support included manufacturing and providing of tibolone and placebo tablets, statistical advice, and monitoring of the study according to the Guidelines of Good Clinical Practice.

Abbreviations: BCM, Body cell mass; BIA, bioelectrical impedance analysis; BMI, body mass index; ECW, extracellular water; FFM, fat-free mass; FM, fat mass; HRT, hormone replacement therapy; ICW, intracellular water; TBW, total body water.

Received May 14, 2001.

Accepted for publication July 30, 2001.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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