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BRIEF REPORT |
Julius Center for Health Sciences and Primary Care (M.M., Y.T.v.d.S., D.E.G.) and Department of Geriatrics (M.M.), University Medical Center Utrecht, 3508 GA Utrecht, The Netherlands; and Department of Internal Medicine (A.W.v.d.B., S.W.J.L.), Erasmus University Medical Center Rotterdam, 3000 CA Rotterdam, The Netherlands
Address all correspondence and requests for reprints to: Yvonne T. van der Schouw, Ph.D., Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Room Stratenum 6.131, P.O. Box 85500, 3508 GA Utrecht, The Netherlands. E-mail: y.t.vanderschouw{at}umcutrecht.nl.
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Abstract |
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Objective: The objective of the study was to assess whether hormone replacement with dehydroepiandrosterone (DHEA) and/or atamestane might improve the course of frailty.
Design: This was a double-blind, randomized, controlled trial.
Setting: The study was conducted in the general community.
Participants: Participants included 100 nonhospitalized, nondiseased, independently living men, aged 70 yr and over with low scores on strength tests. Seventeen participants did not complete the trial.
Intervention: Subjects were randomly assigned to one of four intervention arms: atamestane (100 mg/d) and placebo, DHEA (50 mg/d) and placebo, a combination of atamestane (100 mg/d) and DHEA (50 mg/d), or two placebo tablets for 36 wk.
Main Outcome Measures: Physical frailty was measured by means of a specific test battery, including isometric grip strength, leg extensor power, and physical performance.
Results: The randomization was successful, and 83 (83%) men completed the intervention. There were no differences between the treatment arms and placebo group in any of the outcome measurements after intervention.
Conclusions: The results of this double-blind, randomized trial do not support the hypothesis that hormone replacement with DHEA and/or atamestane might improve the course of frailty.
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Introduction |
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Research has suggested that the age-related decline of androgens in men plays a distinct role in the development of several aspects of frailty (1, 3, 4). Therefore, hormone replacement with testosterone and/or dehydroepiandrosterone (DHEA) might improve the course of frailty. Previous studies investigating DHEA effects in elderly men showed contradictory results; some observed changes in body composition and muscle strength (5, 6), whereas others observed no effect of DHEA treatment (7, 8, 9, 10). Studies investigating the effect of testosterone supplementation have shown that muscle mass and strength increased (11, 12, 13), cognitive functions improved (14, 15), and bone mineral density (BMD) increased (11, 13, 16), but sometimes at the expense of an increase in the size of the prostate (13). An alternative strategy to augment endogenous testosterone secretion is the use of an aromatase inhibitor, i.e. atamestane, which in elderly men results in a 30–50% increase in testosterone (17).
We designed a double-blind, placebo-controlled study in 100 elderly men to evaluate the safety and efficacy of DHEA, atamestane, and the combination of both on physical frailty. Furthermore, we evaluated the effect of these interventions on BMD, body composition, general well-being, cognitive function, and atherosclerosis.
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Subjects and Methods |
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Subjects
One hundred elderly men aged 70 yr and above were selected from 400 elderly, nonhospitalized, nondiseased, independently living men in the Rotterdam area who participated in a preceding observational study (4). Those individuals with the lowest scores on isometric grip strength (IGS) (<30 kg) and leg extensor power (LEP) (<100 Nm) were selected and asked to participate in the present study. Two hundred volunteers underwent the screening program for the present trial. Subjects were excluded if they had severe arthropathic deformation of the knee joint, myocardial infarction within the last 6 months, history of stroke or transient ischemic attacks, high systolic/diastolic blood pressure, any active malignant disease with significant impact on the physical condition, history of prostatic cancer, diabetes mellitus treated with insulin, abnormal liver function with clinical significance, history of alcohol or drug abuse within the last 2 yr, and/or participation in another clinical study. Of 200 subjects screened, 100 entered the double-blind, randomized, placebo-controlled, four-arm trial.
Intervention
After completion of the baseline tests, subjects were randomly assigned to one of four intervention arms using a blocking factor. A list of randomization numbers was computer generated by personnel from Schering-AG (Berlin, Germany), who were not involved in the trial. The men were randomized to receive atamestane (100 mg/d) and placebo, DHEA (50 mg/d) and placebo, a combination of atamestane (100 mg/d) and DHEA (50 mg/d), or two placebo tablets. Both placebo tablets had an outer appearance identical with that of either atamestane tablets or DHEA tablets. For each treatment period of 28 d, the volunteer received two glasses with 28 tablets each. Two tablets, one tablet from each glass, were taken on each day of the treatment period without a treatment-free interval during 252 d of treatment (36 wk). Subjects were instructed to take the drugs during breakfast. Schering AG provided the tablets. To endure compliance, volunteers were required to return empty glasses and the remaining trial medication at each clinical visit. A pill count that indicated an overall compliance of less than 80% was registered as noncompliance.
Study flow
In total, men visited the outpatient clinic seven times. End points were assessed at baseline and dependent on the end point one to four times in 36 wk. Visit 7 was the final visit after completion of the posttreatment observation period, scheduled approximately 24 wk after the last tablet intake.
Hormone measurements
Blood samples were collected in the morning after an overnight fast. Serum concentrations of total testosterone (nanomoles per liter), SHBG (nanomoles per liter), estradiol (picomoles per liter), DHEA (nanomoles per liter), DHEA sulfate (DHEAS; micromoles per liter), IGF binding protein (IGFBP)-1 (micrograms per liter), and IGFBP-3 (milligrams per liter) were measured by RIA using commercial kits (Diagnostic Systems Laboratories, Inc., Webster, TX). Total IGF-I (micrograms per liter) was measured by an IGFBP-blocked RIA (Medgenix Diagnostics, Brussels, Belgium).
Primary outcome variables
Physical frailty was measured by means of a specific test battery, as described previously (4), by one member of the research team, including IGS, LEP, and physical performance (PP). IGS was measured using an adjustable handheld dynamometer (JAMAR, Horsham, PA) at the nondominant hand. LEP was measured as described previously (4), using the MicroFET dynamometer (Hoggan Health Industries, West Jordan, UT). PP includes measurements of standing balance, walking speed, and ability to rise from a chair.
Secondary outcome variables
Activities of daily living (ADL) were assessed using a modified version of the Stanford Health Assessment Questionnaire. Folstein’s minimental state examination (MMSE) was used as a global test for cognitive function. To determine carotid artery intima-media thickness (IMT) as a quantitative measure of generalized atherosclerosis, ultrasonography of both the left and right common carotid artery and the bifurcation was performed with a 7.5-MHz linear array transducer (Ultramark IV; ATL, Ramsey, NJ), as described previously (18). BMD was measured at the femoral neck, trochanter, and the Ward’s triangle using dual-energy x-ray absorptiometry (QDR-1000 densitometer; Hologic, Bedford, MA). In addition, lean body and fat mass and total BMD were measured. Height and weight were measured and body mass index (BMI) was calculated.
Data analyses
Data were analyzed according to an intention-to-treat analysis. For the participants who did not complete the trial, we used the last measurement of the outcome variables and carried this forward to the final (36th wk) visit. The individual differences between baseline and the 36th wk of the treatment period of the primary and secondary outcome variables were calculated. Linear regression analyses were used to assess the differences in change of outcome measurements of the three treatment groups, compared with the placebo group. Furthermore, we performed multivariate analysis of covariance for repeated measures for the variables with more than two repeated measures. In addition, we did a per protocol analysis, including only participants who had completed the whole treatment protocol. With at least 25 men in each of the four groups, a difference of 12 Nm of LEP and 3.3 kg of IGS could be detected at a 5% level of significance with 90% power. All analyses were carried out using SPSS 12.0 for Windows statistical package (SPSS Inc., Chicago., IL).
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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), with no material differences among the four intervention groups at baseline. No differences were found for baseline characteristics between the dropouts (n = 17) and the participants who completed the trial (n = 83).
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At baseline hormone levels were similar for the four intervention groups (Table 1
). Mean endogenous DHEA and DHEAS increased in the DHEA and DHEA/atamestane group (Table 2). Total testosterone levels increased in all three treatment groups (Table 2). IGF-I levels increased in the DHEA/atamestane group [beta = 9.3, 95% confidence interval (CI) 1.3, 17.3] but not in the other intervention groups. No changes were observed for IGFBP-1 and IGFBP-3 in all treatment groups (Table 2). No differences were observed for posttreatment hormone levels (after 60 wk) among the four groups.
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No differences in change of IGS and PP score were observed for the three treatment groups, compared with the placebo group (Table 2). Compared with the placebo group, LEP declined in all intervention groups. However, this relative decline was due to a significant increase in LEP in the placebo group after 36 wk (beta = 6.35, 95% CI –0.06, 12.76) (Table 2). No significant longitudinal association was found between treatment group and any of the frailty measurements (data not shown).
Secondary outcome variables
No differences in change of ADL, MMSE, and IMT were observed for the three treatment groups, compared with placebo (Table 2). Concerning BMD, in the atamestane group, trochanter BMD had increased with 0.04 g/cm2 (95% CI 0.00, 0.08). For the other localizations, no differences in changes in BMD between placebo and intervention were observed (Table 2). The placebo group showed a statistically significant decrease in BMI after 36 wk (beta = –0.62 kg/m2, 95% CI –0.99, –0.25). Compared with the placebo group, increased BMI was observed in both the atamestane and DHEA groups; mean differences (95% CI) were 0.36 (–0.08, 0.80) and 0.81 (0.37, 1.25) kg/m2, respectively (Table 2).
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Discussion |
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To interpret these findings, some strengths and limitations of the study need to be addressed. The study was randomized and double blind, and the dropout remained within reasonable limits. No differences in baseline characteristics were observed between the dropouts and the remainder of the study group.
The fact that baseline serum testosterone levels were within the normal range, with a lower limit of 11 nmol/liter (19), could be an explanation for not finding an effect. This is in line with results presented by O’Donnell et al. (20), who demonstrated that men whose testosterone and DHEA levels are high are likely to receive little benefit in PP from increased levels of either hormone. Furthermore, the study population might have been too small to detect differences between the intervention groups. Moreover, the trial period of 36 wk might be too short to find differences between the treatment groups. However, Morales et al. (5, 6) did find significant effects on physical and psychological well-being after a shorter treatment period. Another possible explanation of the found results could be that the men were not frail enough. One of the inclusion criteria was that these men should live independently and should be capable of visiting the study center without assistance, which probably already caused the exclusion of really frail old men.
To our knowledge no trials have been performed to assess the effect of atamestane on physical frailty. Atamestane is an aromatase inhibitor, which increases testosterone levels and decreases estradiol levels (17). In our study estradiol levels only marginally decreased; however, it could be suggested that the counterregulatory decrease in estrogens may counterbalance any positive effect on physical frailty of the increase in androgens.
In conclusion, the results of this trial do not support the hypothesis that supplementation of DHEA, atamestane, or the combination in elderly men has an effect on frailty. It could be suggested that a longer treatment period and/or higher dose is needed to find an effect on physical frailty, muscle strength, and functional performance.
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Footnotes |
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Abbreviations: ADL, Activities of daily living; BMD, bone mineral density; BMI, body mass index; CI, confidence interval; DHEA, dehydroepiandrosterone; DHEAS, DHEA sulfate; IGFBP, IGF binding protein; IGS, isometric grip strength; IMT, intima-media thickness; LEP, leg extensor power; MMSE, minimental state examination; PP, physical performance.
Received November 7, 2005.
Accepted June 19, 2006.
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References |
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