the ageing process is accompanied by an increased prevalence of the signs and symptoms of physical fragility , including sarcopenia , a decrease in exercise tolerance , osteopenia , an increase in visceral adiposity and a worsening of quality of life . adults with growth hormone deficiency ( ghd ) exhibit similar clinical signs , but it is possible to treat them with gh to ameliorate these signs and symptoms . the gh secretion declines gradually with age , whereby studies demonstrate a progressive reduction of 14% secretion per decade of life beginning in the second decade [ 2 , 3 ] . these findings suggest a possible association between ghd and the ageing process [ 4 , 5 ] . the association between the physiological alterations of the ageing process and the reduction of gh secretion is called somatopause . gh replacement is well known to improve body composition , leading to a decrease in total body fat and an increase in lean body mass . however , gh replacement has only shown an effect on muscle strength in gh - deficient adults subjected to long - term gh therapy . few studies have evaluated the effect of gh replacement on muscle strength in elderly people engaged in a program of exercise training [ 2 , 710 ] . specific training that aims to increase muscle strength can potentiate the anabolic effect of gh , which leads to a greater impact on body composition in comparison to gh replacement alone [ 11 , 12 ] . these subjects showed increased exercise capacity with improvements in oxygen uptake and ventilatory threshold after gh therapy . this improvement was most likely due to some combination of increased muscle strength , improved body composition , and improved thermoregulation . gh has been speculated to improve physical capacity in subjects without ghd through stimulation of collagen synthesis in the tendon and skeletal muscle , which leads to better exercise training and increased muscle strength . administration of supraphysiological doses of gh to athletes increases fatty acid availability , reduces oxidative protein loss , particularly during exercise , and increases lean body mass . our purpose was to evaluate the effect of gh therapy on muscle strength in healthy , nonsedentary men over 50 years old . healthy and nonsedentary men ageing 5070 years were recruited by newspaper advertisements with information that patients were needed for a study of hormonal evaluation . exclusion criteria were pituitary disease , gh use in the last 12 months , severe acute disease , hepatic and/or renal chronic disease , uncontrolled systemic arterial hypertension , diabetes mellitus , psychiatric disorders , history of cancer , nontreated hypogonadism , and the presence of any other disease that could interfere with the somatotrophic axis . all patients practiced some kind of exercise ( minimum of three times per week , aerobic and resistance exercise ) to be eligible to be included in the study . twenty - nine subjects were screened for a project about somatotrophic profile in healthy men over 50 years old ( which includes this paper ) and have resulted in other published studies [ 15 , 16 ] . after that , fourteen from the 29 initial patients agreed to participate in this part of the project that included the evaluation of muscle strength in gh x placebo replacement ; those subjects who gave up had personal problems , such as work compromises and address change . all patients signed the informed written consent approved by the ethics committee of the clementino fraga filho hospital / ufrj . at baseline , subjects were submitted to evaluation of gh secretion , testosterone level , body composition , and muscle strength . absence of pituitary disease and normal testosterone levels were necessary for the inclusion in the study . gh secretion was evaluated through insulin tolerance test ( itt ) or glucagon stimulation test ( gst ) and igf - i levels . the itt was performed by intravenous injection of regular insulin at a dose of 0.10.15  iu / kg . blood samples were drawn every 30 minutes from baseline until 120 minutes for the determination of glucose and gh levels . all patients had hypoglycemia ( glucose nadir lower than 40  mg / dl ) during the test . severe ghd was considered when gh peak was lower than 3  g / dl , and it was an exclusion criterion . g / l and the intra - assay coefficient of variation ( cv ) was 5.3% at 1.7  g / l . serum igf - i concentrations were determined by an immunoradiometric assay ( kit dsl-5600 ) , with acid - ethanol extraction . the minimal detection limit was 0.80  ng / ml and the intra - assay was 3.4% at 9.38  ng / ml and 3.7% at 255.8  ng / ml . all subjects had gh peak at gst higher than 3 g / l and had igf - i levels normal according to their age ; that is , none of them had severe ghd ( table 1 ) . subjects were then randomised according to their arrival to the medical evaluation : one patient to each group ( gh and placebo groups ) , sequentially . the gh group received an initial dose of 0.5  ui / day ( 0.2  mg / day ) , with readjustments to 1.0  ui / day ( 0.4  mg / day ) and 1.5  ui / day ( 0.6  mg / day ) after 1 and 2 months of treatment , respectively . these gh dosages were based on the dose used for adults of the same age with ghd at the time of this research . subjects were reevaluated after 6 months of gh therapy or placebo according to the parameters above . pfizer laboratory also provided the placebo . during treatment , every month the patients should take their used gh flask to the medical consult in order to realize a counting flask for control of the correct use of gh . body mass index was calculated using quetelet 's formula ( weight / height ) and the percentage of body fat was calculated using the adipometer on seven cutaneous folds ( tricipital , subscapular , suprailiac , pectoral , axillary , abdominal , and thigh ) according to the pollock and jackson protocol . abdominal circumference was measured using a nonelastic tape at the greatest diameter between the last ribs and the iliac crests . muscle strength was evaluated for the maximum strength based on the concept of maximum repetition ( 1  mr ) ( i.e. , the maximum load that can be performed using the correct technique for an exercise ) . the exercises evaluated were bench press and leg press using a righetto machine ( so paulo , brazil ) , which are dynamic exercises . the bench press focuses on the strengthening of the pectoralis major muscle as well as other muscles including anterior deltoids , serratus anterior , coracobrachialis , scapulae fixers , trapezzi , and the triceps . the bench press was performed according to the following technique : ( a ) initial position : dorsal decubitus , elbows in extension with hands sustaining the barbell , knees and hips semiflexed , and feet on the equipment base ; ( b ) exercise development : elbows flexion , to form a 90 degree angle with the arm and forearm , followed by complete extension of the elbows and horizontal flexion of the shoulders , returning to the initial position . the leg press works the following muscles groups : quadriceps , hamstring , gluteus maximus , and calves ( partially ) . the leg press was performed according to the following technique : ( a ) initial position : hips and knees flexed at a 90 degree angle , feet on the platform , and inferior members slightly separated and lined up within the limits of the iliac crests ; ( b ) exercise development : complete extension of the knees then returning to the initial position . before the use of the equipment , subjects could familiarise themselves with the exercises and the equipment without the load . to determine the load associated with 10  mr , each subject initially performed 10 repetitions of each exercise with a submaximum load , which was considered a load that was possible to mobilise . then , the loads were progressively increased and , with a maximum of 3 trials , the load of 10  mr was reached . if the 10  mr load was not reached after 3 attempts , the subject was asked to come to the laboratory for another opportunity . to reduce the error margin , the following strategies were adopted : ( a ) standardised instructions were given before the test to make the subjects aware of the data collection routine ; ( b ) subjects were instructed on the execution technique of the exercises ; ( c ) the examiner was attentive to the correct position of the patients ' joints at the time of measurement to avoid small variations in joint positioning that could put action on other muscles and lead to erroneous interpretations of the obtained scores ; and ( d ) verbal stimuli were given during the exercise to maintain a high level of motivation . during the 10  mr test , a 25 minute interval was provided between the attempts of each exercise . after the load was obtained for a determined exercise , intervals comparisons between the groups and timepoints were performed using two - way anova for repetitive measures , followed by fischer post - hoc evaluation if necessary . the differences between the baseline and the last measure ( delta ) were compared by student 's t - test for independent variables . thirteen subjects completed the study ( 6 subjects in the placebo group and 7 subjects in the gh group ) . one subject in the placebo group dropped out of the study because of the development of arthralgia . subjects of both groups were similar in age , weight , height , and bmi at baseline ; they were overweight according to bmi ( between 2530  kg / m ) , except one subject who was obese ( bmi 38.5  kg / m)table 1 . all subjects of both groups were nonsedentary ; that is , they performed planned physical activity for more than 150 minutes per week . after 6 months of therapy , the evaluation of the gh and placebo groups did not show evidence of significant differences in weight , bmi , waist , and the sum of the cutaneous folds ( triceps , biceps , subscapular , and iliac folds ) . furthermore , there were no differences on the delta ( 6 months  baseline ) for these parameters between the groups ( table 2 ) . muscle strength in the upper body part , as evaluated by supine horizontal rising , did not increase after 6 months in both groups . muscle strength in the lower body part , as measured by the leg press , showed a statistically significant increase in the gh group when compared to placebo ( table 2 ) . the effects of ageing cause undesirable changes in body composition , a reduction of bone mineral density and muscle strength ( with greater falling risk ) , and worsening exercise capacity , which is associated with a decrease in gh and igf - i levels . however , gh replacement to minimise the adverse effects of ageing must be based on cost - benefit and risk - benefit analysis . furthermore , randomised studies demonstrated that the effectiveness of gh replacement is modest , either on its own or in combination with sex steroids or exercises [ 2 , 4 , 7 ] . our study evaluated muscle strength in men over 50 years of age after 6 months of gh therapy , and we observed a statistically significant increase in leg press responsive muscles ( quadriceps being the mainly muscle evaluated ) when compared to placebo . there was no evidence of alterations in body composition in either group ( gh therapy or placebo ) . the gh group had a bmi and body fat percentage ( represented by the sum of the cutaneous folds ) slightly greater than the placebo group but without statistical significance . therefore , our results differed from those found in the literature , in which an improvement in body composition and no difference on muscle strength during gh replacement are described [ 7 , 9 ] . the effects of gh therapy on body composition ( increased lean body mass and decreased fat mass ) are very well reported [ 1 , 1924 ] , but the effects on muscle strength are unclear , which was one of the objectives of our study . it has already been reported that recombinant human gh administered for 6 months to healthy older men decreases the percentage of body fat and increases lean body mass and igf - i levels to values observed in young adult males . a recent study using a low - dose sustained - release recombinant human gh administered during 26 weeks to subjects with the so - called somatopause showed improvements in body composition and quality of life . many studies in ghd adults demonstrated the normalisation of muscle strength after 10 years of gh replacement [ 6 , 26 , 27 ] but did not show an increase in muscle strength with the use of gh for short periods of time . however , a study of 18 elderly men submitted to progressive weight training for 14 weeks and then randomised to receive either gh or placebo during a further 10 weeks of strength training showed that gh had no effect on muscle strength at any time , but lean body mass increased and fat mass decreased in the gh group . frail older people subjected to gh treatment with or without a structured resistance exercise program had a significantly increase in muscle strength in both gh / exercise as well as the exercise alone groups , but there was a significant increase in the proportion of type 2 fibers at the end of the study in the combined gh / exercise treated subjects . there are few studies in the elderly that combine gh replacement and specific training for muscle strength [ 7 , 8 ] . this type of training could potentiate the anabolic effects of gh , which would cause a greater impact on body composition than gh replacement alone as well as greater impact on muscle strength . gh has been speculated to improve physical capacity in subjects without ghd through its stimulation of collagen synthesis in the tendon and skeletal muscle . furthermore , gh appears to be more important for the reinforcement of the tissue matrix than for muscle cell hypertrophy . thus , the gh use could attenuate or prevent muscle fibre injuries , causing a lower frequency of training disruption and leading to greater training in athletes or nonathletes with the use of gh , which leads to a muscle fibre hypertrophy and consequently an increase in strength . this could explain the increase in leg press responsive muscles in the gh group of the present study . although no participants of our study were athletes or performed supervised physical training before and during the gh x placebo use , none of the subjects were considered sedentary and all practiced some type of exercise ( minimum of three times per week150 minutes per week , aerobic and resistance exercises ) . we can postulate that this group , even without supervised training , had fewer injuries and consequently performed more exercises to increase muscle strength . moreover , the majority of subjects realized walk and running as exercise , which prioritizes the lower body part muscles . another point that corroborates the gain of muscle strength in this group is the documented evidence that adults with ghd have lower fatigue sensation when subjected to gh replacement , which increases the adherence to exercise and leads to cardiopulmonary benefits . although there are conflicting results regarding adults without ghd , it could be another fact that increased the disposition to exercise and consequently to an increase in lower body part strength in subjects in the gh group . the median age of the subjects in our study was lower than the studies cited above . although our objective did not include evaluation of the gonadic axis , subjects were required to have normal serum levels of testosterone to be included in the study . thus , we can attribute the observed amelioration of strength in leg press responsive muscles to the gh therapy , independent of gonadic function . another point is that the majority of the studies were performed for periods less than 6 months , and this could be an explanation for the different results obtained in our study . another consideration is the gh dosage used in our study ; we used a fixed dosage with increases in the first and second months , independent of the patient 's weight . the final gh dosage ( 0.6  mg / day ) was the median dosage used for adults ( men with an average age of 50 years ) with ghd at the time that our study began . however , at the present data , gh dosages are lower in ghd adult replacement ( initial dose of 0.10.3  mg / day ) . we can not discard a pharmacologic effect of this higher gh dosage on muscle strength . although anthropometry is an important method of nutritional evaluation in subjects over 50 years of age , one limitation of our study is that we did not use a more precise method of body composition evaluation . fat tissue redistribution is more prominent in women , and reduction in body water content is more common in men . in addition , the lack of references for anthropometric measures in the brazilian population   can reduce the precision of such evaluations . the use of dual energy x - ray absorptiometry ( dexa ) would improve evaluation of modifications in body composition , mainly lean mass . even still , the results could still be vulnerable to error because dexa is not able to estimate body water accumulation caused by gh therapy . the bmi was demonstrated to be well correlated with anthropometric indicators of nonvisceral fat ( tricipital and subscapular folds ) and abdominal fat ( abdominal circumference ) , in addition to being in direct relation with total body fat mass [ 33 , 34 ] . the fact that we did not find a change in weight in the study group despite an improvement of strength in leg press responsive muscles might suggest that there was an increase in muscle mass and a decrease in fat mass . our study differs from the literature in the following parameters : ( 1 ) age ( our population was younger ) ; ( 2 ) exercise training ( subjects in our study were not considered sedentary and did some type of exercise but not a specific training ) ; ( 3 ) gh dose ( similar to the dose used for ghd adult men at the time of the study ) ; and ( 4 ) longer duration of gh use ( 6 months ) . our study demonstrated an increase in leg press responsive muscles in men over 50 years old after gh therapy , which is important for reducing falls and fractures in aged populations . this finding must be considered and tested in frail older populations , whose physical incapacity is caused primarily by proximal muscle weakness . considering that ageing is related to loss of strength in lower body part and a worsening quality of life , our results can be taken into account for future studies with higher numbers of subjects . however , we must emphasise that gh therapy has been absolutely contraindicated for aesthetic or antiageing reasons until now .