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Endocrine Care |
Nutrition, Metabolism, and Exercise Laboratory, Donald W. Reynolds Center on Aging (C.P.L., S.A.F., W.J.E.), Department of Radiology (D.M.L.), The University of Arkansas for Medical Sciences and the Geriatric Research, Education and Clinical Center, Central Arkansas Veterans Healthcare System (C.P.L., D.H.S., S.A.F., W.J.E.), Little Rock, Arkansas 72205
Address all correspondence and requests for reprints to: William J. Evans, Ph.D., Nutrition, Metabolism, and Exercise Laboratory, Donald W. Reynolds Department of Geriatrics, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205. E-mail: . EvansWilliamJ{at}uams.edu
Abstract
Megestrol acetate (MA) (Bristol-Myers Squibb Co., Princeton, NJ) increases weight gain in AIDS and cancer patients and in age-related cachexia; however, the weight gain is predominately fat. We determined if adding resistance exercise and/or testosterone (T) replacement to MA administration would result in a more favorable body composition change than MA alone. Thirty older men (aged 67.0 ± 5.8) completed this 12-wk study. All subjects received MA and were randomly assigned to one of the following groups: placebo (P) injections, resistance training (RT) and P (RT + P), weekly injections of T (100 mg/wk) or, RT and T (RT + T). The mean increase in body weight for all groups combined was 3.8 kg (P < 0.0001), but this increase was not different between groups. There was a significant interaction for the change in thigh muscle cross-sectional area (P = 0.0006). Thigh muscle cross-sectional area was significantly reduced from baseline by 5.20 [1.62] cm2 (P = 0.05) in P which was not prevented in T [-4.44 (1.66) cm2 from baseline; P = 0.04]. RT prevented this decline [+0.61 (1.41) cm2 from baseline]. Muscle cross-sectional area increased 4.51 (1.69) cm2 from baseline in RT + T (P = 0.002 vs. P and P = 0.002 vs. T). Despite significant weight gain, MA appears to have an antianabolic effect on muscle size even when combined with T replacement. Resistance exercise attenuated this reduction in muscle mass and when combined with T had an anabolic effect on muscle mass.
IN MANY INDIVIDUALS, aging is associated with decreased food consumption and anorexia (1, 2, 3), resulting in low body weight. Low body weight is related to increased mortality in the elderly (4, 5). Another manifestation of aging is sarcopenia, the age-related loss of skeletal muscle mass. Interventions to increase body weight and in particular skeletal muscle mass in the underweight elderly may increase functional ability and quality of life (6).
The synthetic progestin, megestrol acetate (MA) (Bristol-Myers Squibb Co., Princeton, NJ), is currently used clinically to treat a reduction in appetite and weight loss in AIDS and cancer patients and in the underweight elderly. MA has been shown to be effective in inducing increases in appetite and gains in body weight in AIDS and cancer patients (7, 8, 9, 10, 11, 12) and in the underweight elderly (13, 14). However, the composition of the weight gain with MA in AIDS and cancer patients has been shown to be predominantly (8) or entirely (7) fat. This may be due to the reduction in circulating testosterone (T) associated with MA ingestion (15, 16, 17, 18). Although nonfavorable body composition changes with MA ingestion have been shown to occur in AIDS and cancer patients (7, 8), its use is prevalent in geriatric patients because low body weight is associated with increased mortality in the elderly (4, 5) and MA has been shown to increase body weight in this population (13). Despite the fact that a net loss of skeletal muscle mass is a primary manifestation of cachectic conditions, no studies have directly evaluated the effect of MA on changes in skeletal muscle mass.
In the present investigation, we attempted to increase the accretion of fat-free mass/skeletal muscle mass and reduce the accretion of fat mass with MA administration by combining MA with T replacement and/or resistance training (RT). Specifically, we examined the independent and combined effects of T replacement and/or RT on circulating hormones, body composition, and muscle strength in underweight elderly men. One possible reason for the predominant fat storage resulting from MA is its effect on circulating T. We tested the hypothesis that the composition of the weight gain would be affected by using anabolic stimulae of T and progressive resistance exercise training.
Materials and Methods
Experimental subjects
This study was approved by the Human Research Advisory Committee at the University of Arkansas for Medical Sciences. All subjects gave written consent before their participation in this study. Men with a body mass index of 25 kg/m2 or less and between the ages of 60 and 85 were recruited for the study. Subjects were medically stable, generally healthy (all medical problems were under control and medication dosage was stable) and weight stable for the previous 2 months. After completing a preliminary medical history form and signing screening and study consents, subjects had the following routine tests performed: 1) a 12-lead EKG; 2) a screening blood draw to assess routine clinical measures; and 3) a health history and physical. Subjects were excluded for the following reasons: metastatic disease, exertional angina, and any condition that prevented RT (severe osteoarthritis, for example). The descriptive statistics for the study participants (mean ± SD) are presented in Table 1
. One subject was eliminated from data analyses as he was deemed noncompliant. This conclusion was reached via three criteria: 1) This subject despite being in the RT + P group had no fall in serum T; 2) This subject had no decrease in cortisol; and 3) When asked if he had been compliant throughout the study, the subject replied that he had not.
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MA has consistently been shown to stimulate appetite and weight gain. The purpose of this study was to affect the composition of this weight gain. Four groups were studied in this investigation. All subjects received MA. Group P received P (saline injection) for 12 wk, group RT + P received weekly P injections and RT for 12 wk, group T received T replacement for 12 wk, and group RT + T received T replacement and RT for 12 wk.
Interventions
MA ingestion. For all groups, oral daily ingestion of MA (800 mg/d) was initiated at the beginning of the study and continued for the duration of the study. Subjects were asked to ingest the MA with breakfast.
RT. For the groups receiving MA and RT (RT + P) and MA, T, and RT (RT + T), Keiser pneumatic RT machines (Keiser Sports Health Equipment, Fresno, CA) were used to train the subjects. Two upper body exercises (chest press and arm pull) and three lower body exercises (leg press, leg extension, and leg curl) were performed 3 d per week (Monday, Wednesday, and Friday). Training was performed at 80% of one repetition maximum (1 RM) for three sets with the first two sets consisting of eight repetitions and the final set being performed to the point where a full repetition could not be completed. The RT was progressive. When 12 repetitions could be completed on the third set, the resistance for all three sets was moved up 5–10% for the next workout. The 1 RM was determined two times before the initiation of training, after 6 wk of training and after 12 wk of training. The 1 RM from the second testing session, before the initiation of the training regimen, was considered to be the baseline value as it has been shown by Frontera et al. (19) that significant increases in strength occur from the first testing session to the second testing session.
T administration
T was delivered in a double-blind P controlled fashion. For groups that received T, T and RT (RT + T), a once weekly im injection of T enanthate (100 mg) was administered starting the first day of training and was administered on the same day of the week for another 11 wk. For groups P and RT + P the same volume of isotonic saline was injected once weekly to keep the subjects blinded from the intervention.
Measurements
Measurements were made before the interventions (PRE), after 6 wk of the interventions (MID), and after 12 wk of the interventions (POST).
Whole body plethysmography
Body weight was measured to 0.01 kg on a calibrated scale, and body density was determined by whole body air displacement plethysmography using the Bod Pod system (Life Measurement Instruments, Concord, CA). Fat mass, and fat-free mass were calculated from body density using the formula of Siri (20): %body fat = 4.950/Db-4.50.
Computed tomography (CT)
CT scans of the dominant thigh were obtained at its greatest circumference. A GEI Scanner was used operating at 120 kV and 200 mA. A 10.0-mm slice was obtained and the scanning time was 1 sec. Before the scan, subjects maintained a supine position for at least 60 min to minimize fluid shifts that can influence thigh cross-sectional area (21).
From the CT image, the cross-sectional areas of fat, muscle, and occupied by the quadriceps femoris muscle group and the knee flexors taken together were obtained using the Slicomatic program (Tomovision, Montréal, Canada). The range of Hounsfield units used to assess the quantity of fat were -250 to -40 and for muscle were -30 to 150.
Hormone measures
Venous blood was sampled from an antecubital vein at 0700 h after subjects awoke. All blood samples were obtained while the subject was had been in the supine position for at least 15 min.
Blood samples were obtained Thursday morning after a Wednesday morning injection for the Mid time point and Thursday morning 8 d after the final injection for the Post time point. Serum total T (nmol/liter) and sex hormone binding globulin (SHBG; nmol/liter were measured using commercially available RIA kit (Alpco Diagnostics, Windham, NH). Free T (nmol/liter) was calculated from total T and SHBG concentrations according to the law of mass action as described by Sodergard et al. (22). Association constants of SHBG and albumin for T of 1 x 109 L/mol and 3 x 104 L/mol, respectively, were used for all samples. For reference, the mean total serum T concentration for young adult men is 18.7 ± 3.7 nmol/liter (23) with a range of 12.1–27.7 nmol/liter (24).
Statistical analyses
A three-way ANOVA (hormone status x RT status x time) with repeated measures on the time variable was used on serum total T and serum-free T. The change from preintervention to post intervention was calculated for all other variables on each group and a two-way ANOVA was performed with hormone status (T or P) and training status (RT or no-RT) being the independent variables. When a significant difference was observed, the Newman-Keuls posthoc test was performed to determine the location of the differences between pairs of means. All data with exception of the descriptive statistics are mean ± SE. Data were considered significantly different at P 
0.05.
Results
Body weight
No significant difference (P = 0.39 training effect; P = 0.13 hormone status; P = 0.16 interaction) was observed between the groups for the change in body weight (Table 2). The mean increase in body weight for all groups combined was 3.8 ± 0.8 kg (P < 0.0001).
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A significant interaction was observed for total serum T (P < 0.001; Fig. 1) and serum-free T (P < 0.001; Fig. 2), which were significantly and substantially lower for P and RT + P groups than the T and RT + T groups at both MID and POST testing. No other differences were observed.
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RT increased muscle strength (P < 0.0001) with no additional effect of hormone status (P = 0.20; Fig. 3). In addition, no significant hormone by training status interaction was observed (P = 0.81).
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There was a significant strength training effect on whole body fat-free mass (P = 0.03; Table 1
) no hormone effect (P = 0.22) or hormone by training interaction was observed (P = 0.80).
A significant interaction effect (P = 0.0006; Fig. 4) was observed for thigh muscle cross-sectional area, which was reduced from baseline by 5.20 (1.62) cm2 (P = 0.05) as a result of MA ingestion alone (P). RT with MA (RT + P) attenuated this decline [+0.61 (1.41) cm2 from baseline], but T administration had no effect [-4.44 (1.66) cm2 from baseline; P = 0.04]. RT and T administration (RT + T) with MA increased thigh muscle cross-sectional area 4.51 (1.69) cm2 (P = 0.002 vs. P and P = 0.002 vs. T) from baseline.
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) for the change in thigh fat cross-sectional area with individuals on P exhibiting a 75% greater increase than individuals on T.
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As expected, MA resulted in significant weight gain. However, the major finding of this investigation was that MA induced a significant loss of skeletal muscle mass despite significant weight gain. This loss of skeletal muscle mass was independent of circulating T as the reduction of muscle mass was similar in those individuals who received T compared with those that received P. RT attenuated this loss of muscle mass and combining T replacement with RT led to a significant increase in muscle mass. The combination of T replacement with MA therapy reduced the amount of fat mass gained as measured by whole body measurements and CT of the thigh, when compared with P.
It has been known for some time that MA therapy results in a large reduction in circulating T concentrations (15, 16, 17, 18, 25). In the present study, the T concentration was reduced to castrate levels. A significant interaction was observed for serum total T (Fig. 1), which was substantially lower for P and RT + P groups than T and RT + T groups at both MID and POST testing. We also observed a drastic reduction in free T concentrations to castrate levels in the present investigation (Fig. 2).
Whole body muscle strength increased by approximately 20% in the RT group and approximately 18% in the RT + T group (Fig. 4). Thus, the addition of T to strength training and MA ingestion did not have any effect on muscle strength in this investigation. Furthermore, the administration of T with MA ingestion and without RT resulted in no greater strength improvement than MA alone.
A significant strength training effect was observed on whole body fat-free mass, but no hormone effect or hormone by training interaction was observed. However, when thigh skeletal muscle cross-sectional area was assessed to be significant, a significant hormone by training interaction was observed. The P group experienced a 5.2 cm2 reduction in thigh muscle cross-sectional area despite substantial weight gain (5.1 kg). There are at least three operable mechanisms for this finding. First, MA reduced circulating T levels down to castrate concentrations. It has been shown previously, in young men, that a reduction in circulating T concentrations down to castrate levels, results in a loss in fat-free mass and a reduction in muscle strength (26). However, the reduction in T does not appear to be the operative mechanism in our investigation as T replacement did not attenuate the loss in skeletal muscle mass. Thus, T alone was ineffective in reducing the muscle loss associated with MA. Androgen binding to the AR has been shown to be required for muscle hypertrophy to occur (27). Inoue et al. (27) reported that electrical stimulation induced hypertrophy was attenuated by the administration of an AR antagonist. In addition, it has been shown the MA can bind to ARs and block the binding of T (28). Thus, a potential mechanism for the reduction in muscle mass that we observed in the P group may have been due to reduced T binding to the AR as a result of competition for this receptor by MA. This may result in a reduction in protein synthesis relative to protein degradation and a net loss of muscle mass.
An additional explanation for the reduction in muscle mass with MA therapy is the possibility of a direct effect of progesterone on net protein balance. Engelson et al. (29) has shown that in castrated rats, that MA administration reduced the carcass protein content, relative to castrated rats that did not receive MA. In this castrated condition, there would be little T for MA to block at the AR, and this would suggest a direct effect of progesterone in causing net negative protein balance. Supporting this contention, recently, Toth et al. (30), reported that progesterone administration in ovariectomized rats reduced the rate of skeletal muscle protein synthesis relative to control ovariectomized rats. Thus, based on the data of Engelson et al. (29) and Toth et al. (30), there is likely a direct effect of MA specifically, and more generally, progesterone, on protein synthesis and/or protein breakdown. Both the P group and the T group had a 4–5 cm2 reduction in muscle cross-sectional area with no differences between these groups. These data suggest that even when circulating T is elevated, as it was in the groups receiving T in our investigation, if high levels of progesterone are present, there is a reduction in skeletal muscle mass.
In contrast to the use of T with MA, when individuals ingesting MA resistance trained, there was an attenuation in the loss of muscle mass (P vs. RT + P). Furthermore, when T was combined with RT (RT + T), there was an increase in muscle cross-sectional area of 4.5 cm2. A possible, although speculative, explanation for the effect of RT in attenuating the loss in muscle mass associated with MA, is an increase in ARs. It has been shown that, in rats, three electrical stimulation sets (one set = 2 sec at 10 V and 100Hz) every 2 d increased the AR concentration by approximately 25% by d 3 (31). In addition, in humans, an acute bout of either concentric or eccentric RT resulted in an increase in AR mRNA (32). Thus RT (RT + P) may have increased the number of ARs and increased the probability that T would bind to the AR relative to progesterone. Further, the addition of T to RT may have increased the probability that T would bind to the AR relative to MA. This may explain the observed increase in muscle size when MA was combined with RT and T (RT + T).
We examined two measures of body fat. Whole body plethysmography was used to represent whole body fat mass, and thigh fat mass as assessed by CT was used to represent peripheral fat mass. A significant hormone effect was observed for whole body fat mass (P = 0.03) and thigh fat mass (P = 0.02). The P group had a 71.4% greater increase in whole body fat mass, and a 75% greater increase in thigh fat mass. It appears, therefore, that T reduced the accumulation of fat mass. The significantly smaller increase in whole body fat mass and thigh fat mass for the individuals on T may have resulted from the previously observed effects of T on reducing the incorporation of triglyceride into fat stores (33) by inhibiting lipoprotein lipase and increasing lipolysis (34). The fact that fat mass increased significantly less in those individuals who received T suggests that T administration can lessen the effects MA on body fat gain.
MA has been used to treat geriatric cachexia (13, 14). Clearly, MA therapy will stimulate weight gain in the elderly (13, 14). However, additional problems associated with aging are sarcopenia, and physical frailty. The data from our investigation demonstrated that MA ingestion (800 mg/d) alone will accelerate sarcopenia independent of its effects on circulating T levels. To put these data in practical perspective, Frontera et al. (35), reported a loss of 12.5% of muscle CSA in elderly subjects over 12 yr. If we assume a linear rate of muscle loss, the 4.57% reduction in muscle mass observed in the group ingesting MA alone corresponds to aging by 4.4 yr. This is a substantial amount of muscle mass loss induced by only 3 months of MA ingestion. Resistance exercise alone but not T replacement alone attenuated the loss of muscle mass associated with MA ingestion, and therefore we suggest that elderly individuals who are interested in gaining weight using MA should also undertake progressive RT. The combination of T replacement, resistance exercise, and MA ingestion appears to be efficacious in gaining muscle mass. In addition, T replacement reduced fat gain that was associated with MA administration.
MA is a powerful appetite stimulant. In patients where anorexia causes involuntary weight loss, MA can maintain or increase body weight. Whether a loss in muscle mass in these patients results in increased morbidity and/or mortality cannot be determined by the present experiment. However, the data from this investigation suggest that MA administration is contraindicated in conditions that result in muscle atrophy.
Acknowledgments
We thank the employees of the General Clinical Research Center and Arlene Sullivan, Advanced Practice Nurse, for their excellent technical assistance with this project. In addition, we thank James Fluckey, Ph.D., for his assistance with the RIAs and Stephen Winters, M.D., for providing the computer program for calculation of free T.
Footnotes
This study was supported by a grant from Bristol-Myers Squibb Co., by General Clinical Research Center Grant M01-RR-12488, RO1-AG-15385 (to W.J.E.), and by F32-AG-05873 (to C.P.L.) from the NIH.
Abbreviations: CT, Computed tomography; MA, megestrol acetate; MID, measurements made after 6 wk of interventions; P, placebo; POST, measurements made after 12 wk of the interventions; PRE, measurements made before the interventions; RM, repetition maximum; RT, resistance training.
Received November 5, 2001.
Accepted February 12, 2002.
References
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