Does Growth Hormone Therapy in Conjunction With Resistance Exercise Increase Muscle Force Production and Muscle Mass in Men and Women Aged 60 Years or Older?

Advancing age is associated with a reduction in skeletal muscle protein and muscle force production, a syndrome referred to as sarcopenia. This process occurs during normal aging, but it is accelerated by physical inactivity and degenerative or other disease conditions.[1] Decreased muscle mass and force production are associated with an increased risk of falling[2] and, therefore, an increased risk for hip fracture.[3] Reduced muscle force production with aging can also result in physical disability and frailty[1] and in a loss of independent function,[4] and it contributes to escalating health care costs.[5] Our understanding of the mechanisms responsible for sarcopenia is limited. The most obvious intervention is exercise, but the feasibility and effectiveness of exercise in this population are still under investigation. Pharmacological and nutritional interventions for sarcopenia have been proposed,[6-8] but preliminary evidence is not encouraging.[6-15] Efficacious interventions for elderly people need to enhance both muscle protein mass and force production.

The biological consequences of advancing age and the progressive decline in physical activity with age contribute to sarcopenia. Exercise, especially resistance exercise training, has the potential to improve overall fitness and quality of life. The physiological and functional benefits of increased muscle activity, even into the ninth decade of life, have been reported.[16] Thus, human skeletal muscle protein maintains the ability to respond to, and adapt favorably to, exercise-induced increases in contractile activity throughout the life span. The ability to adapt with advancing age, however, may be somewhat limited by other biological processes. For example, circulating concentrations and the pulsatile release patterns of several hormones that regulate metabolism are reduced with advancing age.[7-9,12,17-21] By virtue of their anabolic actions on body proteins, low serum growth hormone (GH),[8,9,12,17-19] testosterone,[7,15,20] dehydroepiandrosterone (DHEA),[22] and perhaps estrogen[23] along with reduced insulin action,[24,25] have been implicated as mediators of the muscle protein wasting that typifies aging. This update will consider the effect of recombinant human growth hormone (rhGH) replacement therapy alone, and in conjunction with resistance exercises, on muscle force production in elderly men and women (aged 60 years and older). For the purpose of this review, we consider muscle force production to be the maximum voluntary contractile force output (MVC) measured (1) on an isokinetic dynamometer at a fixed angular velocity (range=0 [degrees] -240 [degrees]/s) or (2) as the 1-repetition maximum (1-RM) determined on an isotonic weight-lifting device (eg, Body Masters,(*) Universal,([dagger]) Cybex,([double dagger]) Nautilus([sections])). Where appropriate, we will indicate the mode of testing and the muscle group involved.

Effects of Growth Hormone on Body Composition and Muscle Performance

After an age of about 30 years, GH secretion by the pituitary gland tends to decline.[8,10,12,17-20,22] Consequently, low endogenous GH levels occur with advancing age, and this is temporally associated with the decline in lean body mass and muscle force. The association between declining GH concentrations and lean body mass has led to the hypothesis that the restoration of circulating GH concentrations will reverse the muscle wasting associated with advancing age. In the early 1980s, recombinant deoxyribonucleic acid (DNA) technology was applied to large-scale synthesis of human growth hormone (rhGH). That rhGH replacement therapy has the potential to increase lean body mass and skeletal muscle force is evident from administration of rhGH to GH-deficient adults and children.[26,27] When adults with GH deficiency acquired in childhood or adulthood were treated with rhGH in a double-blind, placebo-controlled, crossover trial, increments in thigh muscle volume, quadriceps femoris muscle isometric force, and maximum exercise capacity (maximum output [in kilojoules] on a cycle ergometer) were observed.[26] These findings, however, must be considered in light of the fact that these patients were also given supplemental doses of several other hormones (eg, thyroxine, testosterone, estrogen, progesterone, glucocorticoids) that may have acted synergistically with GH and promoted recovery of lean body mass, muscle protein, and performance. Complex alterations in circulating hormone concentrations and in the factors (eg, binding proteins, receptor population/affinity) that modulate hormone actions occur with advancing age. Thus, it would appear to be unlikely that a single hormonal "magic bullet" that would reverse the adverse consequences of aging could be identified and administered.

In the Table, we have summarized most of the recent scientific literature with respect to aging, rhGH administration, and changes in body composition and muscle force production. It is evident from the Table that a wide variety of dosages have been administered, study length has been variable, increments in lean body mass were often noted, but side effects from administration were prevalent. In only 4 of the 9 studies cited[9-11,14,18,24,28-30] were changes in muscle production determined.

[TABULAR DATA NOT REPRODUCIBLE IN ASCII]

Early studies[9,28] demonstrated that short-term (7-21 days) administration of high doses (30-120 [micro]g/kg/d) of rhGH promoted whole-body nitrogen retention in elderly individuals. Quite striking were the findings of Kaiser et al,[9] who reported that daily rhGH administration (100 [micro]g/kg) for 21 days improved whole-body nitrogen retention, increased body weight, and stimulated appetite in men and women aged 60 years and older who were malnourished. The results from these initial short-term studies suggested that long-term rhGH administration might stimulate whole-body protein anabolism enough to reverse the loss in lean body mass and muscle mass associated with advancing age.

Recombinant human growth hormone replacement therapy was originally proclaimed by some researchers[18] to represent the "fountain of youth" after the results of a placebo-controlled crossover trial showed an increase in lean body mass (8.8%) and a decrease in fat mass (14.4%) in 61- to 81-year-old men given approximately 30 [micro]g of rhGH per kilogram of body weight 3 times per week for 6 months. Subsequent reports have been less positive. Papadakis et al[10] treated 26 men with rhGH (30 [micro]g/kg, 3 times/wk) for 6 months in a randomized, double-blind, placebo-controlled trial. The rhGH treatment increased lean body mass and decreased fat mass. However, knee flexion and extension muscle force, determined as the MVC on an isokinetic dynamometer (at 120 [degrees]/s), were not improved by rhGH administration. Papadakis et al[10] also reported that side effects attributed to GH administration occurred frequently (eg, edema, arthralgias, myalgias).

These results are very similar to those we recently obtained in 60- to 74-year-old men and women.[24] Eight men and 2 women were randomly assigned to receive rhGH (12 [micro]g/kg/d) for 4 months, and 6 men and 1 woman received placebo injections. Again, lean body mass increased more in the rhGH-treated group, but no improvement in muscle force was observed in the rhGH-treated group. In our study, knee extensor and flexor muscle MVC were measured on an isokinetic dynamometer (60 [degrees]/s), isometrically at a knee joint angle of 135 degrees of extension, and by 1-RM lifts performed on leg press and bench press machines.

In terms of improvement in muscle force, there is one report that differs from our findings. Welle et al[11] reported that maximum voluntary muscle force measured with an isokinetic dynamometer was improved by 14% (versus placebo) in 5 men receiving 30 [micro]g of rhGH per kilogram of body weight 3 times per week for 3 months. The rhGH administration also increased lean body mass and whole-body muscle mass (determined from 24-hour urinary creatinine excretion). The rate of mixed skeletal muscle protein synthesis, however, was not increased after rhGH administration. The 14% increase in muscle force (above placebo) appears to have been derived by averaging the percentage of improvement in the MVC of the right and left knee extensors and flexors, measured at 3 angular velocities: 60 [degrees], 120 [degrees], and 240 [degrees]/s. Most of the improvement in knee extensor force was limited to measurements made at an angular velocity of 240 [degrees]/s. At this time, it is unclear why rhGH administration would improve muscle force at only a single fast angular velocity.

Almost unequivocally, rhGH administration has been reported to increase lean body mass in men and women aged 60 years or older. Maximum muscle force production (MVC, 1-RM) and functional ability, however, have not been improved in parallel with the increments in lean mass. It appears doubtful, therefore, that the increments in lean body mass are occurring in the skeletal muscle, specifically the skeletal muscle contractile proteins. Two frequently reported side effects of rhGH administration in young and elderly adults are fluid retention and joint swelling, particularly in the hand and wrist. Yarasheski et al[12] have determined that total body water content increases with rhGH administration and that it increases out of proportion to what is expected on the basis of increments in lean body mass. Increments in total body water alter the tissue hydration coefficient and confound measurements of body composition made using underwater weighing, bioelectrical impedance analysis, and dual-energy x-ray absorptiometry. These measurement techniques cannot distinguish water from lean tissue, an increase in total body water volume may be misinterpreted as an increase in lean protein mass. It is likely, therefore, that a large portion of the reported gain in lean body mass associated with rhGH administration in elderly individuals is simply fluid retention. The fluid (water) retention appears to be mediated by GH effects on the renin-angiotensin-aldosterone hormone axis because a blockade with the angiotensin-converting enzyme inhibitor, captopril, or the K+sparing diuretic, spironolactone, abolished the rhGH-induced increase in extracellular water.[31]

In addition to swelling and fluid retention, rhGH administration has been associated with other side effects, most notably an increased incidence of carpal tunnel compression, myalgia, arthralgia, and some instances of gynecomastia and Bell palsy.[10,13.9,29] These side effects limit the usefulness of rhGH replacement therapy for elderly people. Another transient side effect of rhGH therapy is elevated blood glucose and insulin concentrations. The diabetogenic effects of GH are especially important in elderly individuals because oral carbohydrate tolerance deteriorates with advancing age.[25,32] In our previous study,[24] administration of 12 to 24 [micro] g of rhGH per kilogram of body weight per day for 16 weeks to 62- to 72-year-old men and women reduced the body's sensitivity to insulin in comparison with a placebo-treated control group (Fig. 1). Furthermore, 16 weeks of resistance exercise training improved insulin sensitivity in older men. Administering daily injections of rhGH to older men doing the same resistance exercise program, however, abolished the improvement in insulin sensitivity.[25] These diabetogenic effects of rhGH administration may limit its use in the elderly population.

rhGH Administration and Resistance Exercise Training

Yarasheski et al[12] administered rhGH to 62- to 75-year-old men enrolled in a 16-week resistance exercise program. The resistance training program was progressive in nature and consisted of moderate- to high-intensity (75%-90% of 1-RM force), low-repetition (4-10 repetitions) weight-lifting exercises (4 sets of each exercise per session, 4 sessions per week). The weight training program involved all major muscle groups, alternated daily between upper-body exercises (biceps curl, shoulder press, deltoid lift, bench press, latissimus pullover, arm cross) and lower-body exercises (leg press, knee flexion, knee extension) and was performed on Nautilus weight training equipment.

Yarasheski et al[12] hypothesized that rhGH administration (12-24 [micro]g/kg/d) would further stimulate the muscle protein anabolic and force improvements associated with a weight-lifting exercise program. Thigh muscle cross-sectional area, however, determined using proton-magnetic resonance imaging and maximum voluntary muscle force in the upper and lower extremities (1-RM measured on the Nautilus strength training equipment), was not increased more by resistance exercise combined with rhGH administration than by resistance exercise without rhGH supplementation. In addition, the fractional rate of vastus lateralis muscle protein synthesis was not further stimulated by rhGH administration (Fig. 2). Lean body mass increased more in the rhGH group, but this additional lean tissue was attributed to an increase in total body water content. The lack of an rhGH effect on body composition, muscle force, and the rate of skeletal muscle protein synthesis in these exercising older men treated with rhGH were very similar to the results obtained by Yarasheski and colleagues[19,33] in exercising young men treated with rhGH. These observations strongly suggest that there is no added benefit to muscle protein accumulation when weight training exercise is supplemented with rhGH administration. Still, it is important to note that weight-lifting exercise training without rhGH therapy resulted in substantial increases in muscle force in elderly men.[12]

Taafe et al[14] have reported similar findings. They initiated rhGH administration in 65- to 82-year-old men after 14 weeks of heavy-resistance exercise training to investigate whether GH would increase muscle force gains during a time in the exercise training program when gains in force had leveled off. While continuing resistance training for an additional 10 weeks, supplementation with rhGH did not further augment the favorable response to resistance exercise training. Thus, Taafe et al concluded that the reduced GH concentration associated with advancing age is not responsible for the leveling off of force gains in elderly men participating in a prolonged resistance exercise program. The resistance training program used by Taafe et al was similar to our program described above. Briefly, 3 sessions per week were completed, and each session consisted of a circuit of 10 exercises involving upper- and lower-body muscle groups. Three sets of 8 repetitions for each exercise were performed, and the intensity was equivalent to 75% of 1-RM. To ensure that the training program was progressive, 1-RM tests were conducted every 2 weeks and the training weight was adjusted accordingly.

Other Considerations

The manner in which circulating GH concentration is increased in GH replacement studies may be important. For example, when a single, subcutaneous injection of GH is given, circulating GH concentrations are elevated for approximately 10 hours.[19] Normally, throughout a 24-hour period, GH is released from the pituitary gland in pulses (particularly during sleep) in response to somatostatin and growth hormone-releasing hormone (GHRH) signals released from the hypothalamus. One pharmacological approach that might avoid the problems associated with a large, single, nonphysiologic injection of GH is to administer GHRH or an analogue of GHRH. A single injection of GHRH, at night, has been shown to elevate circulating GH concentrations for about 4 hours.[34] Nightly injections of GHRH (2 mg) for 6 weeks in elderly men, however, had no effect on body composition or glucose tolerance, although it improved 2 out of 6 measurements of muscle force (I-RM).[34] Unfortunately, no placebo control group was studied; thus, it is difficult to conclude that the more physiologic increments in endogenous GH concentration induced by nightly GHRH administration increased maximum voluntary muscle force production in elderly people with muscle wasting.

In addition to GHRH, several peptide and nonpeptide GH secretagogues have recently been synthesized. These novel compounds act through a unique hypothalamic pathway that increases pituitary GH release into the circulation in synergy with endogenous GHRH.[35] One of these compounds (Merck 677) increases serum GH concentration by increasing the 24-hour pulsatility and amplitude of GH secretion.[35] When administered to elderly individuals, these compounds have the potential to augment the endogenous GH secretory pattern, so it is more similar to that of younger adults. It remains to be determined whether a more physiologic GH-replacement paradigm improves muscle protein mass and force and reduces the side effects associated with rhGH replacement therapy in elderly people.

Acute exercise is a potent stimulus for endogenous GH release. In particular, a single session of intense weight training exercise provokes an acute increase in circulating GH in both younger and older adults. The exercise-induced GH release is attenuated in elderly people.[36] Whether exercise training is important for restoring GH release in elderly people and whether this contributes to the improvements in maximum voluntary muscle force and body composition achieved through weight training have only recently been studied. Both Nicklas et al[37] and Pyka et al[38] have reported that a prolonged progressive resistance exercise program (similar to that described above) does not increase baseline circulating GH concentrations in elderly people. In addition, a prolonged weight training program did not affect the GH secretory response to an acute session of exercise. These findings raise an interesting point. That is, older men and women make improvements (similar to young people) in muscle force and lean body mass in response to weight training exercise despite no increase in the baseline concentrations or endogenous secretory patterns of GH. Thus, the stimulation of endogenous GH release during exercise and the contribution of exogenous GH administration to the increase in muscle protein anabolism and maximum voluntary muscle force that occurs in elderly individuals during weight-lifting exercise training are probably minimal.

Summary

Improved muscle protein mass and increments in maximum voluntary muscle force have rarely been observed in men and women aged 60 years and older who were treated with rhGH. Although rhGH administration has been reported to increase lean body mass in older men and women, it is doubtful that this increase is localized to skeletal muscle contractile proteins. When rhGH administration was combined with 16 weeks of resistance exercises, increases in muscle mass, muscle protein synthesis, and muscle force were not greater in the rhGH-treated group than in a weight training group that received placebo injections. Side effects of rhGH treatment in elderly people are prevalent, not trivial, and further limit its usefulness as an effective anabolic agent for promoting muscle protein accretion in men and women.[10,13] In particular, the induction of insulin resistance and carpal tunnel compression reduces the efficacy of rhGH replacement therapy in elderly individuals. The evidence for a GH-induced increase in human skeletal muscle protein and maximum voluntary muscle force is weak. The optimum dose and GH-replacement paradigm (GHRH, GH-secretagogues) have not been identified. Whether rhGH therapy improves muscle protein mass and force in individuals with severe cachexia associated with major trauma, burns, surgery, or muscular dystrophy is controversial and under investigation.

(*) Body Masters Sport Industry Inc, 700 E Texas Ave, PO Box 259, Rayne, LA 70578.

([dagger]) Universal Gym Equipment Inc, 818 Dows Rd SE, Cedar Rapids, IA 52403.

([double dagger]) Cybex, Div of Lumex Inc, 2100 Smithtown Ave, Ronkonkoma, NY 11779.

([sections]) Nautilus International Inc, 709 Powerhouse Rd, Independence, VA 24348.

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This work was supported by NIH grants AG13629, DK49393, RR00954, and RR00036 and by a grant to Dr Zachwieja from the American Federation of Aging Research.

JJ Zachwieja, PhD, is Assistant Professor and Chief, Exercise and Nutrition Program, Pennington Biomedical Research Center, Baton Rouge, La.

KE Yarasheski, PhD, is Assistant Professor in Medicine, Washington University Medical Center, Division of Metabolism, Endocrinology, and Diabetes, Claude Pepper Older Americans Independence Center, Campus Box 8127, St Louis, MO 63110 (USA) ([e-mail]). Address all correspondence to Dr Yarasheski.