basal growth hormone concentration increased following a weight loss focused dietary intervention in...

Introduction

altered blood concentrations of sex and anabolic hormonesare associated with many aging-related chronic diseases,including among others, reductions in skeletal muscle mass andstrength (1). reduced anabolic stimulus from reduced levels ofgrowth hormone (GH) and testosterone may lead to a reductionin skeletal and muscle mass, and an increase in abdominalvisceral fat (2). as a consequence, sarcopenic obesity mayensue, resulting in impairments in physical function, mobilitydisability, and exercise capacity (3). this is consistent withfindings that individuals with GH deficiency have impairmentsin physical function and increased disability (4). evidencesuggests that normal aging lowers blood concentrations ofgrowth and sex steroid hormones and binding proteins (5-8).Obesity, in addition to aging, has profound effects on themetabolism and concentrations of hormones. For example,testosterone and DHea concentrations are lower in obese vs.nonobese men with significant inverse relationships betweenhormones and visceral fat levels (9). Finally, impairments inphysical function and performance (10) are more prevalent inolder adults, consistent with reports that one-third of olderadults report having some level of disability or difficulties inphysical function (11).

lifestyle modifications to increase physical activity and dietrestriction to lower body weight are frequently the first line oftherapy to reduce risk of chronic diseases. However, the effectof these behavior changes on circulating concentrations of sexand anabolic hormones is not definitely known, especially inolder individuals that do not have frank hormone deficiencies.cross-sectional and longitudinal trials in younger cohortsindicate that weight loss and exercise training improvehormonal profiles. rapid and sustained weight loss in youngerobese individuals increase levels of total testosterone, freetestosterone, sex-hormone binding globulin (sHBG) and GH(12, 13). Growth hormone concentrations increase followingresistance and endurance exercise in women and men, althoughthis effect was found to be diminished in older men (14, 15).

there have only been a very limited number of studies thathave examined the effect of weight loss and exercise programsin older obese adults in a randomized clinical trial design.these have been limited in that they are only for a shortduration or only in those without frank hormonal deficiency.therefore, the primary aim of this study was to examine theeffects of randomization to an 18-month intervention of dietaryfocused weight loss, exercise training interventions, theircombination, or a control group on hormone levels in olderoverweight and obese men and women. cross-sectional

BASAL GROWTH HORMONE CONCENTRATION INCREASED FOLLOWING A WEIGHT LOSS FOCUSED DIETARY INTERVENTION

IN OLDER OVERWEIGHT AND OBESE WOMEN G.D. Miller1, B.J. Nicklas2, c.c. Davis3, c. leGault3, s.P. Messier1

1. Department of Health and exercise science, Wake Forest university, Winston-salem Nc 27109; 2. Department of internal Medicine; 3. Department of Public Health sciences, WakeForest university school of Medicine, Winston-salem, Nc 27157. send correspondence to: Gary D. Miller, PhD, Box 7868 reynolda station, Department Health and exercise science,

Wake Forest university, Winston-salem, Nc 27109-7868, [email protected], 336-758-1901; 336-758-4680 (fax)

Abstract: Objectives: Growth and sex steroid hormones decrease with aging and obesity. the effect of dietaryweight loss and exercise training lifestyle interventions was examined on hormones as well as determining theirrelationships with physical function in older obese and overweight adults. Design: individuals were randomizedinto one of four 18 month interventions: Healthy lifestyle (Hl), exercise, Diet, and exercise-Diet. Setting:clinical research setting with facility based exercise and nutrition education and behavior classrooms.Participants: Older (≥60 yrs) overweight and obese (BMi≥28 kg/m2) adults with knee osteoarthritis (n=309) wererecruited for the study. Intervention: Weight loss goal for Diet groups was ≥5%. exercise groups trained (mostlywalking and resistance training) 3 days/week for 60 min/session. Measurements: Body weight, growth hormone(GH), corticosterone, sex-hormone binding globulin (sHBG), testosterone, and dehydroepiandrosterone (DHea)were measured at baseline, 6, and 18 months. Physical function was determined through performance task (6-min walking distance) and self-reported questionnaires (Western Ontario McMaster university Osteoarthritisindex-WOMac) at similar time points. Results: Diet, exercise, and exercise-Diet groups lost 4.9%, 3.5%, and6.2% of their weight at 18 months, respectively. there was a significant diet treatment effect on GH levels inwomen as higher concentrations of this hormone were apparent following dietary weight loss intervention(p=0.01). No other hormones were affected by either diet or exercise treatments in men or women. a significantinverse correlation between baseline 6-minute walking distance and sHBG (r=-0.33) was found in men.Conclusion: the increase in basal GH levels from the diet treatment in women suggests that this lifestylebehavior intervention may mitigate the age- and obesity-related decreases in growth hormone levels, to helppreserve muscle mass, strength, and physical function in older adults.

Key words: Hormones, older adults, dietary induced weight loss, exercise training, physical function.

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The Journal of Nutrition, Health & Aging©Volume 16, Number 2, 2012

JNHA: GERIATRIC SCIENCE

Received June 14, 2010Accepted for publication December 1, 2010

analysis at baseline was also performed to further support therelationship between hormone concentrations with body massindex (BMi) and physical function.

Methods

Study Populationstudy participants were enrolled in the arthritis, Diet, and

activity Promotion trial (aDaPt). complete details of thisstudy design and primary outcome measures are publishedelsewhere (16, 17). irB approval was acquired and informedconsent was obtained from participants. aDaPt compared theeffects of an 18 month dietary weight-loss intervention (Diet),an exercise intervention (exercise), a combined exercise-dietary weight loss intervention (exercise-Diet) and a healthylifestyle control group (Hl), on self-reported disability andphysical function in older, overweight and obese, sedentaryadults with knee osteoarthritis (Oa). community dwellingolder adults (n=316; ≥ 60 years of age) with symptomatic kneeOa were recruited. Blood was obtained from 309 of theparticipants for this analysis. additional inclusion criteriaincluded BMi ≥ 28.0 kg·m-2, sedentary lifestyle, and self-reported difficulty in performing at least one of the followingactivities attributed to knee pain: lift and carrying groceries,walking one-quarter mile, getting in and out of a chair, or goingup and down stairs.

InterventionsBoth Diet and exercise-Diet groups were prescribed similar

dietary weight loss intervention strategies. the weight lossgoal for these two groups was a mean loss ≥ 5% of initial bodyweight. Details of the intervention are described elsewhere(16). Participants were individually counseled on reducingenergy intake by ~250-500 calories per day to achieve thedesired weight loss. they met in group and individual sessionsthroughout the study in a 3:1 ratio. Primary strategies includedcognitive behavioral based treatment with emphasis onreducing portion sizes and fat intake.

the exercise program was conducted three days per week for60 minutes per session and was similar for the exercise andexercise-Diet groups. the exercise program consisted of awarm-up phase (5 minutes), an aerobic phase (15 minutes), astrength phase (20 minutes), a second aerobic phase (15minutes), and a cool-down phase (5 minutes). the primarymode of aerobic training consisted of walking. the exerciseintensity for the aerobic exercise was 50-85% of the heart ratereserve using the symptom limited maximum heart rateobtained from a graded exercise test (GXt). lower bodystrength training was also employed.

Participants randomized to the Hl group met monthly for 1hour during the first 3 months of the trial. topics for thesesessions included osteoarthritis, obesity, and exercise. inaddition, phone contacts were performed on a monthly (formonths 4-6) and bimonthly (months 7-18) basis.

MeasurementsDescriptions and time course of all measurements obtained

in aDaPt are reported by Miller and coworkers(16). atbaseline, 6 months and 18 months testing visits, participantsreported in the morning after a 12-hour fast to the Generalclinical research center (Gcrc) of Wake Forest universityMedical center for blood draws via the antecubital vein andbody weight and height.

serum was used for the measurement of the hormones andbinding protein (corticosterone, GH, DHea, testosterone, andsHBG). all hormones were measured using an automatedimmunoanalyzer (iMMulite®, Diagnostics Productscorporation, los angeles, ca). sensitivities and ranges,respectively, for the hormones and binding protein, werecorticosterone, 5.52 nmol/l and 27.6-1380.0; GH 0.01 μg/land 0-40; testosterone 0.35 nmol/l and 0.7-55.5; DHea 69.4nmol/l and 104.1-3470.0; and sHBG 0.02 nmol/l and 0-180nmol/l. all samples were measured in duplicate and theaverage of the two values was used for data analyses.

self-reported physical function, pain, and stiffness weremeasured using the 24 item Western Ontario and McMasteruniversity Osteoarthritis index (WOMac) (18). theWOMac has been validated, and is recommended by theOsteoarthritis research society as the measure of choice (18).Participants respond to specific questions rating their pain,stiffness, and difficulty to perform specific tasks on a 1 (none)to 5 (extreme). Physical performance was determined using the6-minute walk distance. Participants were instructed to walk asfar as possible in a 6-minute time period on an establishedcourse. they were not allowed to carry a watch and were notprovided with feedback during the trial.

Statistical Analysissimple statistics such as means, standard errors, and percent

distributions were computed on baseline descriptive measures,overall and by study group. Means and standard errors werecalculated by gender and group for baseline hormone measures.Group differences at baseline were assessed using an aNOvaanalysis for continuous measures and chi-square testing forcategorical measures. a repeated measures analysis wasperformed using mixed modeling to look at the differencesbetween the study groups and the change in hormones over thelength of the study. additional covariates in the modelsincluded race, age, and baseline measures of hormones andBMi. since there were differences between males and femaleson some outcome measures, analyses were done stratified ongender. a second analysis for examining main effects of dietand exercise interventions on hormone levels was performed.Mixed model based least square means and standard errors ateach visit were computed by gender and group. log-transformations were used on hormone outcomes presentingskewed distributions. lastly, we looked at baselinerelationships by gender between hormones and BMi andfunction measures using spearman correlation. significancewas determined using a 0.05 level. all analyses were conducted

HORMONES, WEIGHT LOSS AND EXERCISE IN ELDERLY


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using sas version 9.1 (cary, Nc).

Results

Baseline characteristics across each of the four arms of thestudy are presented in table 1. there were no significantdifferences among the groups at baseline for age, gender, race,body weight, or BMi. the mean age for participants at the startof the study was 68.6 (0.4) years with 72% women and 76%white. Baseline BMi was 34.3 (0.3) kg/m2 with an averagebody weight of 93.9 (1.0) kg across all groups.

Table 1Baseline characteristics by groups

Mean (SD) Overall Healthy Diet Exercise Diet - P value Lifestyle Exercise

Number N = 309 N = 76 N = 80 N = 79 N = 74age (yrs) 68.6 (0.4) 68.7 (0.7) 67.9 (0.6) 69.0 (0.7) 68.7 (0.8) 0.62Gender (% 72.2 67.1 71.3 76.0 74.3 0.63females)race (%)White 75.7 79.0 71.3 74.7 78.4 0.85Black 22.3 19.8 27.5 22.8 18.9Other 2.0 1.2 1.2 2.5 2.7

Body Weight 93.9 (1.0) 95.8 (2.2) 95.2 (1.7) 92.1 (1.7) 92.2 (2.1) 0.39(kg)Body Mass 34.3 (0.3) 34.3 (0.6) 34.5 (0.6) 34.2 (0.6) 34.2 (0.7) 0.98index (kg·m-2)

values are presented as Means ± seM unless indicated; N's represent the maximumnumber of participants within each grouping

at 6 months, the exercise-Diet group had lost 6.3% (3.1) oftheir initial body weight, and maintained that level at 18months (6.2% (3.1)). the Diet only group also showedsignificant weight loss at 6 months (3.9% (2.6)) and at 18months (4.9%, (2.7)). although the exercise group did notshow weight loss at 6 months (0.7% (2.8)), by 18 months theyhad lost 3.5% (2.7) of their initial weight. the Healthylifestyle controls also lost 1.1% (3.4) and 1.6% (3.4) at 6 and18 months, respectively.

Baseline levels of GH, testosterone, and sHBG weresignificantly different among men and women; testosteronewas higher in men, and GH and sHBG were higher in women.thus, hormone results are presented and analyzed separatelybased on gender. at baseline there were no differences amongtreatment groups in circulating levels of hormones or bindingproteins for men or women (P values not shown for baselinecomparisons). comparisons across time and interventionsshowed no differences in hormones or binding protein levelsbetween treatment groups or data collection periods in men.However, in women, there were 2 notable significant effects.there was an increase in cortisol concentrations at 18 monthscompared to 6 months (p=0.01) (table 2). additionally, andthe most marked finding from this study, was a treatment effecton GH (table 2) (p=0.01). specifically, both Diet relatedtreatment groups demonstrated higher levels of GH comparedto the non-Diet treated groups (exercise and Hl) (all p<0.05).

there was no other treatment effect on hormones for diet orexercise interventions.

Table 2serum hormone and binding protein levels at baseline, 6-

months and 18-months by gender for each intervention group

Healthy Diet Exercise Diet - P-value for P-value for Lifestyle Exercise Comparing Comparing

Groups AcrossAcross Time

Follow-Up

Men (N) 25 23 19 19cortisol (nmol/l)

Baseline 289.7±24.8 278.7±30.3 248.3±22.1 253.8±19.3 .88 .376-Months 229.0±22.1 267.6±22.1 240.0±24.8 251.1±27.618-Months 278.7±22.1 220.7±22.1 278.7±24.8 273.1±27.6

DHea (nmol/l)Baseline 279.0±34.0 263.4±37.5 250.5±28.1 266.8±27.1 .64 .266-Months 289.1±29.8 231.8±30.2 228.3±30.2 245.3±35.718-Months 282.8±30.5 255.0±28.8 284.2±33.0 251.2±34.4

Growth Hormone μg/lBaseline 3.4±1.2 2.4±0.9 2.4±1.0 6.9±3.0 .57 .336-Months 3.5±2.8 2.6±3.0 7.4±2.5 11.1±3.318-Months 5.8±2.8 3.4±3.5 3.3±2.7 3.0±4.0

testosterone (nmol/l)Baseline 9.9±0.8 9.4±1.0 9.5±1.0 10.6±1.1 .77 .766-Months 9.2±0.8 10.4±0.8 10.1±0.9 10.2±0.918-Months 9.7±0.8 9.6±0.8 9.3±0.9 10.7±1.0

sHBG nmol/lBaseline 35.7 ± 2.3 35.0 ± 3.1 35.2 ± 3.6 39.1 ± 3.6 .89 .696-Months 35.9 ± 4.2 39.6 ± 4.1 38.9 ± 4.4 40.0 ± 4.918-Months 42.3 ± 3.9 39.4 ± 3.7 35.1 ± 4.6 41.5 ± 4.7

Women (N) 51 57 60 55cortisol (nmol/l)

Baseline 264.9±13.8 278.7±16.6 251.1±13.8 289.7±13.8 .60 .016-Months 231.8±13.8 242.8±13.8 237.3±13.8 245.6±16.618-Months 251.1±16.6 286.9±16.6 251.1±13.8 262.1±16.6

DHea (nmol/l)Baseline 232.5±25.7 231.8±19.4 210.3±20.1 206.1±17.4 .66 .606-Months 214.8±15.6 217.2±14.6 229.0±20.5 222.1±18.718-Months 197.8±17.4 242.6±16.7 228.3±17.7 231.4±20.1

Growth Hormone (μg/ml)Baseline 10.3±2.5 9.5±2.4 9.0±1.8 7.7±1.1 .01 .116-Months 7.7±2.4 15.3±2.3 3.0±2.5 12.8±2.518-Months 5±2.7 2.7±10.3 4.8±2.6 11.9±2.7

testosterone (nmol/l)Baseline 1.7±0.2 1.8±0.2 1.7±0.2 1.7±0.1 .26 .406-Months 1.7±0.3 1.8±0.2 1.3±0.2 1.7±0.318-Months 1.8±0.3 2.0±0.2 1.4±0.3 1.8±0.3

sHBG (nmol/l)Baseline 60.4 ± 6.2 64.2 ± 5.4 57.6± 5.1 76.8 ± 6.7 .70 .556-Months 66.7 ± 3.9 70.5 ± 3.8 65.2 ± 4.1 74.1 ± 4.818-Months 69.6 ± 4.3 71.1 ± 4.3 65.4 ± 4.2 61.8 ± 4.8

DHea, dehydroepiandosterone; sHBG, sex hormone binding globulin; values arepresented as Means ± seM.

Physical function measures at baseline, separated by genderare shown in table 3. this is for the 6 minute walk distance aswell as the self-reported WOMac questionnaire. Furthermore,correlations were performed between baseline measures offunction and hormones for men and women (tables 4). asignificant negative correlation was apparent between plasmalevels of sHBG and distance walked (r=-0.33) in men, suchthat those with higher levels of sHBG walked less distance.No other significant associations between hormones andfunction were observed, although there was a trend for anassociation between testosterone and WOMac stiffness in men(r=-0.21; p=0.08) and testosterone and WOMac function inwomen (r=-0.18; p=0.09).



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Table 3Physical function measures at baseline

Men Women

Distance Walked (m) 1516.14 ± 24.53 1317.57 ± 17.44WOMac Function (units) 1.27 ± 0.07 1.50 ± 0.05WOMac Pain (units) 1.26 ± 0.07 1.45 ± 0.05WOMac stiffness (units) 1.66 ± 0.08 1.94 ± 0.05

values are means ± seM

Table 4associations of functional measures with hormones andbinding protein at baseline for men (a) and women (B)

A. Distance WOMAC WOMAC WOMACMen Walked Function Stiffness Pain

cortisol r = 0.09 -0.01 -0.09 0.07p = 0.45 0.95 0.45 0.54

n = 70 72 72 72DHea -0.07 -0.14 -0.14 -0.08

0.63 0.30 0.28 0.5557 59 59 59

Growth Hormone -0.03 -0.16 -0.03 -0.180.85 0.26 0.82 0.21

50 51 51 51sHBG -0.33 0.06 0.01 0.16

0.01 0.61 0.92 0.1770 72 72 72

testosterone 0.04 -0.18 -0.21 0.040.74 0.13 0.08 0.73

70 72 72 72

B. Distance WOMAC WOMAC WOMACWomen Walked Function Stiffness Pain

cortisol r = -0.11 0.01 0.06 0.03p = 0.14 0.85 0.46 0.68

n=168 188 188 188DHea 0.13 0.09 0.11 -0.04

0.22 0.37 0.28 0.6889 102 102 102

Growth Hormone -0.13 -0.02 0.003 -0.020.11 0.78 0.97 0.80151 169 169 169

sHBG -0.05 -0.11 0.01 -0.080.51 0.16 0.93 0.31158 177 177 177

testosterone -0.08 -0.18 -0.05 -0.150.45 0.09 0.65 0.14

81 92 92 92

Discussion

this study examined the effects of lifestyle behavior basedinterventions incorporating dietary induced weight loss andexercise training on growth and sex hormones and bindingprotein levels in older overweight and obese men and women.in addition, cross-sectional analysis was performed to assessthe relationships between hormone concentrations and physicalfunction measures at baseline. Previous research has shownthat aging, weight status, and physical activity alter hormoneconcentrations, which may contribute to diabetes, skeletalmuscle loss, and visceral fat accumulation, among otherconditions(19-21). since initial treatment of these comorbidities

involves lifestyle modifications of diet and exercise, it was ofinterest to determine if interventions that target dietary andphysical activity behaviors improve hormones and bindingprotein profiles. Our findings are noteworthy in that theyprovide randomized controlled trial evidence that the maineffect of an 18-month dietary induced weight loss interventionincreased systemic concentrations of GH in older overweightand obese women compared to women randomized to the non-Diet intervention groups. the potential impact of thesefindings is to lessen the reductions or even improve changesassociated with aging, obesity, and reductions in hormones, thatlead to decreases in muscle mass and strength and detriments inphysical function. Whereas some clinicians continue to behesitant in prescribing weight loss for their obese older adults,these data provide further evidence for improvements in healthindices accompanying weight loss in this population.

Previous evidence demonstrates a robust relationshipbetween decreases in GH and changes in body composition andphysical function that occur with aging(1, 22). However,attempts to restore GH levels through exogenous administrationof the peptide to older adults are presently debated due toequivocal findings (23). supplementation of GH in pathologicdeficiency states has been shown to be effective in certainanimal and human models in restoring muscle mass, withgreater effects occurring when incorporating exercise with thesupplement (24, 25). However, in non-GH deficient models,the findings are controversial with some showingimprovements in protein synthesis (26) and muscle mass (27,28), whereas others showed no effect of supplementation onmuscle mass, strength, or performance (29). additionally,supplementation of GH produces significant side effects,including edema, gynecomastia, disturbances in glucosehomeostasis, and joint pain (30, 31). Because of these untowardactions, demonstrating increases in GH levels throughbehavioral interventions is significant. in earlier work, weshowed that both exercise and diet interventions in this cohortproduced improvements in physical function in men andwomen combined; however, no measures of strength or bodycomposition were performed in this study (17). thus, probablemechanisms for physical function changes in women in the dietintervention groups may be related to the GH improvements.this is an area of future research.

the underlying reason for the gender effect from the diettreatment with GH is not known. in nonpathological states,women and men show decreases in circulating daytime andnighttime concentrations of GH with age (32, 33); growthhormone secretion is pulsatile with maximal secretionoccurring in the night. However, latta et al., showed nodifferences in 24-hour GH secretion in healthy older men andwomen, but did show that men had greater nighttime secretionof GH compared to women (34). Only basal GH concentrationswere obtained in our study, which limits the interpretation ofthe findings and may explain our lack of a finding ofintervention changes in GH in males. Determining 24 hour

sampling would provide a more complete picture of the effectof the intervention on the hormone, including capturing peaklevels; the largest secretion occurs at the onset of the sleep andrepresents the majority of the daily output. an additionallimitation for this study is the lack of measurement of othercomponents of the GH axis, including insulin-like growthfactor 1 (iGF-1). recent work has shown that iGF-1 is lower inwomen vs. men, decreases with age and higher levels of BMi,and is lower in individuals with increasing number of metabolicsyndrome factors (35). Furthermore, higher iGF-1 levels havebeen associated with better physical function measures in olderobese adults (36). in light of this earlier work and our currentfindings, this is a potentially critical area of research to pursue.

the lack of change from the interventions for sHBG andtestosterone is in contrast to an earlier cross-sectional studywhich showed exercise trained older men had higher sHBGand testosterone levels than age-matched sedentary men (37).selected studies have investigated hormone changes followingexercise training programs, although they are limited by beingcross-sectional in design, their study length, type of exerciseperformed, or age of cohort. results from a heavy resistancetraining program showed significant improvements in strengthin older men and women after 6 months of training (38), butsimilar to our findings, no changes in the hormone profilewhich included testosterone, DHea, GH, cortisol, or sHBG,were found from the intervention.

Obesity has been shown to reduce steroid hormones andbinding proteins; reductions in testosterone and sHBG wereshown in men who became obese during a follow-up agingstudy (39). in support of this earlier work, others found thatboth testosterone and sHBG were negatively correlated withmeasures of body fat (6). the impact that weight loss mayhave on these hormone levels is limited and the few publishedstudies have focused on a younger cohort with mean ages of30-45 years (12) compared to over 65 years in the currentanalysis. For example, testosterone and sHBG increased withrapid and sustained weight loss in men with metabolicsyndrome abdominal obesity and placed on a very low caloriediet for 9 weeks followed by a 12 month maintenance period(12).

Because obesity is a risk factor for osteoarthritis of the knee(40), and this joint disease is the leading cause of functionalimpairment (41), it was of interest to examine the relationshipsof the anabolic and sex hormones with physical functionmeasures in this obese and overweight older adult cohort. Wehypothesized that individuals with lower levels at baseline ofhormones would have worse function. this was supportedfrom results showing that sHBG is inversely related to distancewalked (r=-0.33), indicating that higher levels of sHBG areassociated with a shorter walking distance. sHBG binds toestrogen and testosterone, thereby reducing the active, freeform of the hormone. this was the only significant relationshipobserved between the hormones and functional measures atbaseline. Previous work by O’Donnell and colleagues showed

that in older men (55-85 years), low levels of testosterone andDHea were related to poor physical performance(42). theyfurther suggested that increasing hormone levels above athreshold does not confer additional benefit. this may explainour lack of associations as the current concentrations of thehormones at baseline may have been higher than this threshold,thereby eliminating significant associations with functionalmeasures.

in summary, aging and obesity have been shown to affectlevels of circulating growth and sex anabolic hormones. Ourresults demonstrate an 18 month dietary-induced weight lossintervention increases basal levels of growth hormone inwomen. the clinical impact of this is not known as there islack of a consensus on the impact of raising baselineconcentrations of this hormone in older adults, although itwould suggest a potential improvement, or a lessening indetriments in muscle mass and strength present with aging.Furthermore, exercise training had no impact on hormonelevels in men or women. the lack of association betweenfunction measures and hormones at baseline may be a reflectionof hormones being above a threshold.

Funding and Support: this project was funded by the claude D. Pepper Olderamericans (Grant 5P60aG10484-00) and the General clinical research center (GrantM01-rr07122).

Disclosure Statement: the authors have nothing to disclose.

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