Supplemental testosterone produced significant gains in total and appendicularn mass, muscle strength, and aerobic endurance with significant reductions in whole-body and trunk fat. Outcomes appeared to be further enhanced with GH supplementation. (J Clin Endocrinol Metab 94: 1991–2001, 2009)

 

Context: Impairments in the pituitary-gonadal axis with aging are associated with loss of muscle mass and function and accumulation of upper body fat.

 

Objectives: We tested the hypothesis that physiological supplementation with testosterone and GH together improves body composition and muscle performance in older men.

 

Design, Setting, and Participants: One hundred twenty-two community-dwelling men.

 

 Main Outcome Measures: Body composition by dual-energy x-ray absorptiometry, muscle performance, and safety tests were conducted.

 

Alterations in body composition, physical function, and substrate metabolism occur with advancing age.

 

Loss of skeletal muscle mass (sarcopenia) contributes to declines in muscle strength and function along with diminished quality of life .

 

In the Baltimore Longitudinal Aging Study, quadriceps strength decreased about 30% between 50 –70 yr of age .

 

In the Copenhagen Heart Study, leg strength in 80-yr-olds was 20 – 30% lower than in 70-yr-olds .

 

Substantial losses in strength may result in difficulty rising from a chair, climbing stairs, generating gait speed, and maintaining balance (7), eventually resulting in frailty.  

 

These changes contribute to loss of independence, social isolation, depression, and inactivity, thereby increasing the risk for disability, osteoporosis, and bone fractures.

 

Advancing age is also associated with upper body obesity and insulin resistance, both risk factors for accelerated atherogenesis .

 

Coincident with these age-related deteriorations in clinical status, endogenous production of anabolic hormones declines .

 

Approximately 25–30% of men over 60 yr of age have hypogonadal testosterone levels (10) that may be associated with sarcopenia, muscle weakness, and upper body obesity

 

Restoring testosterone to youthful levels has increased synthesis of myofibrillar proteins (13), total body cell mass (14), muscle strength (13, 15), and reduced trunk and visceral fat; blood pressure; lipids; and improved insulin sensitivity

 

 It is unclear whether these benefits translate to enhanced functional performance (18). Declines in GH and IGF-I may also contribute to these age-related comorbidities in persons with normal testosterone levels .

 

After puberty, 24-h GH production decreases progressively by about 14% per decade and up to 70% by the eighth decade of life.

 

Similarly, circulating levels of IGF-I, a mediator of several but not all anabolic effects of GH, decline through the eighth to ninth decades with levels below the 2.5 percentile in 85–90% of older men  along with losses of lean tissue and increases in adiposity.

 

In obese adults, GH supplementation may reduce abdominal fat (25–28). Better understanding of the relative contributions of the testosterone and GH/IGF-I axes to sarcopenia, impaired muscle performance, and obesity could have therapeutic implications .

 

Only two single-site studies investigated the effects of administering these hormones in combination but both used supraphysiological doses of recombinant human (rh) GH and failed to demonstrate substantive improvements in muscle performance.

 

Our hypothesis was that endogenous testosterone and GH are important independent but complementary regulators of skeletal muscle mass and function, central obesity, and substrate metabolism throughout life into advanced age.

 

To test this hypothesis, we conducted a multicenter study in older, community-dwelling men with levels of testosterone and IGF-I typical of their age to determine the effects of augmenting testosterone with a transdermal gel on muscle mass, physical performance, and adiposity and whether these effects could be augmented by increasing GH-IGF-I status with physiological doses of recombinant human GH.

 

By wk 17, maximal voluntary strength of the major muscle groups of the upper and lower body increased significantly by 23  27% up to 35  31% in the three highest dose groups .

 

However, paired muscle strength data were obtained for only 95 subjects. Intermittent musculoskeletal symptoms (e.g. flare of unilateral knee osteoarthritis) prevented some participants from performing all five strength tests, and other subjects showed different levels of motivation during testing sessions, despite coaching efforts to achieve maximal performance.

 

These factors or insufficient sample size per treatment cell may have limited our ability to demonstrate statistical interactions or dose effects of the two hormones on muscle strength.

 

Nevertheless, increases in muscle strength validated that the increases in lean tissue demonstrated by DEXA were due to accretion of myofibrillar protein and not just hydration effects.

 

Furthermore, the increases in voluntary strength were of a similar magnitude to the losses reported in longitudinal studies of aging through the eighth to ninth decades of life, suggesting that the treatment effects were physiologically relevant.

 

There were also sizable improvements in aerobic endurance for all six groups that ranged from 51  77 to 160  200 sec at wk 17.

 

Collectively, the global improvements in skeletal muscle strength and aerobic endurance were more substantial than previously reported in studies of testosterone, rhGH, or combination of the two hormones during treatment in older men, which showed minimal if any benefits .

 

These improvements in muscle performance for our subjects with relatively intact functional status will be important if such effects can be translated to allow more functionally impaired individuals with sarcopenia or frailty to perform physical tasks and activities of daily living with less effort.

 

Adverse events occurring during therapy were generally modest and included the small but reversible increases in hematocrit (2.0  3.2%) and PSA (0.2  0.8 ng/dl) at wk 16, both typical of testosterone therapy (60).

 

However, the increases in systolic and diastolic blood pressure of 12  14 and 8  8 mm Hg, respectively, across the six groups that persisted, albeit at lower levels for up to 3 month after study therapies had been discontinued, were not anticipated.

 

Previous testosterone and GH treatment studies generally showed no effect or decreases in blood pressure , although GH has been reported to increase blood pressure.

 

It is possible that increases in blood pressure, which also occurred without rhGH, were related to expansion of intravascular volume  as reflected by the 35% occurrence of new lower extremity edema or due to an unexpected high frequency of certain polymorphisms of the androgen receptor CAG repeat.

 

Regardless, this important outcome must be investigated further in future studies of these anabolic hormone therapies. There were no worrisome metabolic changes and some improvements. Fasting blood glucose increased by about 3 mg/dl, but mean levels remained well below the threshold for impaired fasting glucose  in all groups.

 

Similarly, insulin resistance as assessed by the HOMA-IR and QUICKI indices, worsened minimally across the study population but did not reach significance in any of the six groups.

 

 

 

Total and LDL cholesterol were unchanged but HDL cholesterol improved by 3.5  6.7 mg/d and fasting triglycerides decreased by 18  57 mg/dl for the entire study cohort.

 

We do not know whether more prolonged therapy would further reduce upper body fat or enhance physical activity and thereby improve metabolic parameters associated with cardiovascular disease risks or adversely affect these metabolic parameters.

 

In conclusion, combined administration of physiological doses of testosterone and rhGH resulted in substantial gains in lean mass, voluntary muscle strength, and aerobic endurance along with reductions in total and trunk fat that were of greater magnitude than treatment with testosterone alone.

 

An Institute of Medicine Expert Panel has recommended conducting focused short-term efficacy trials of testosterone in older persons with symptomatic impairments before embarking on larger, long-term safety trials (64).

 

In this context, our preliminary findings provide the basis to carefully evaluate the health benefits and safety of strategies that augment both androgen and GH/IGF-I status in future controlled studies before using these agents together in clinical practice to treat complications of aging.

 

Future efficacy trials to evaluate such strategies should be conducted in older persons with functional limitations, especially those with sarcopenia or frailty.

 

 

 

 

 

 

 

 

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