Hormone replacement therapy and physical function in healthy older men. Time to talk hormones?

Abstract

Improving physical function and mobility in a continuously expanding elderly population emerges as a high priority of medicine today. Muscle mass, strength/power, and maximal exercise capacity are major determinants of physical function, and all decline with aging. This contributes to the incidence of frailty and disability observed in older men. Furthermore, it facilitates the accumulation of body fat and development of insulin resistance. Muscle adaptation to exercise is strongly influenced by anabolic endocrine hormones and local load-sensitive autocrine/paracrine growth factors. GH, IGF-I, and testosterone (T) are directly involved in muscle adaptation to exercise because they promote muscle protein synthesis, whereas T and locally expressed IGF-I have been reported to activate muscle stem cells. Although exercise programs improve physical function, in the long-term most older men fail to comply. The GH/IGF-I axis and T levels decline markedly with aging, whereas accumulating evidence supports their indispensable role in maintaining physical function integrity. Several studies have reported that the administration of T improves lean body mass and maximal voluntary strength in healthy older men. On the other hand, most studies have shown that administration of GH alone failed to improve muscle strength despite amelioration of the detrimental somatic changes of aging. Both GH and T are anabolic agents that promote muscle protein synthesis and hypertrophy but work through separate mechanisms, and the combined administration of GH and T, albeit in only a few studies, has resulted in greater efficacy than either hormone alone. Although it is clear that this combined approach is effective, this review concludes that further studies are needed to assess the long-term efficacy and safety of combined hormone replacement therapy in older men before the medical rationale of prescribing hormone replacement therapy for combating the sarcopenia of aging can be established.

Figure 1.

Aging-related detrimental changes in body systems that lead to physical function decline, with both anabolic hormone milieu and aerobic exercise capacity playing a key role. Solid lines represent well-established findings of aging, and dashed lines represent additional proposed mechanisms that may also contribute to frailty. RMR, Resting metabolic rate; AEE, activity energy expenditure.

Figure 2.

The relationship between the 24-h integrated GH concentration (IC-GH; y-axis) and age (x-axis) of 89 male and 84 female normal subjects. [Redrawn from Z. Zadik et al.: The influence of age on the 24-hour integrated concentration of growth hormone in normal individuals. J Clin Endocrinol Metab 60:513–516, 1985 (40), with permission. © The Endocrine Society.]

Figure 3.

Serum GH profiles from a young woman, a young man, an older woman, and an older man sampled every 20 min for 24 h. Pulses were categorized as large (L) or small (S) depending on whether the rise was greater or less than three times the threshold criterion for a pulse. [Reproduced from K. Y. Ho et al.: Effects of sex and age on the 24-hour profile of growth hormone secretion in man: importance of endogenous estradiol concentrations. J Clin Endocrinol Metab 64:51–58, 1987 (100), with permission. © The Endocrine Society.]

Figure 4.

Mean (±se) change from baseline in fat and lean mass of the arms, legs, and trunk, as determined by DEXA, of 108 men over 65 yr of age who were treated with either T or placebo (54 men each). The decrease in fat mass in the arms (P < 0.02) and legs (P < 0.001) and the increase in lean mass of the trunk (P < 0.001) in the T-treated subjects were significantly different from those in the placebo-treated subjects at 36 months. Other changes were not significantly different between the two groups. [Reproduced from P. J. Snyder et al.: Effect of testosterone treatment on body composition and muscle strength in men over 65 years of age. J Clin Endocrinol Metab 84:2647–2653, 1999 (21). © The Endocrine Society.]

Figure 5.

The effects of placebo (P), GH, testosterone (T), and GH plus T (GHT) on appendicular fat mass (top) and appendicular lean mass (bottom). Columns show results at baseline and 6 months. [Reproduced from M. G. Giannoulis et al.: The effects of growth hormone and/or testosterone in healthy elderly men: a randomized controlled trial. J Clin Endocrinol Metab 91:477–484, 2006 (48), with permission. © The Endocrine Society; and http://encore.ulrls.lon.ac.uk/iii/encore/record/C_Rb3127431∼S1?lang=eng.

Figure 6.

DEXA-derived changes (mean ± se) in LBM and fat mass for each treatment group (T transdermal gel 5 g, groups A–C; 10 g, groups D–F; rhGH 0 μg/kg · d, groups A and D; 3 μg/kg · d, groups B and E; and 5 μg/kg · d, groups C and F) from baseline to wk 17. A, Increases in total LBM (solid bars) and appendicular lean mass (hatched bars). Changes across groups are significant for linear trend for total lean mass (P = 0.0002) and appendicular lean mass (P = 0.0002). B, Decreases in total BF mass (solid bars) and trunk fat (hatched bars). Changes across groups are significant for linear trend for total fat mass (P = 0.0004) and trunk fat (P = 0.0003). *, Bonferonni adjusted within group changes (P < 0.008). Pairs of treatment groups with different letters (e.g., a vs. b) are significantly different by one-way analysis of covariance with pairwise comparison (Tukey adjusted; P < 0.05). [Reproduced from F. R. Sattler et al.: Testosterone and growth hormone improve body composition and muscle performance in older men. J Clin Endocrinol Metab 94:1991–2001, 2009 (602), with permission. © The Endocrine Society.]

Figure 7.

The effects of placebo (Pl), GH, testosterone (Te), and combined GH and testosterone (GHTe) on LBM (A), fat mass (B), percentage change from 0 to 6 months in the midthigh CSA (C), and VO₂max (D). In A, B, and D, solid shading is baseline, and gray columns represent 6-month values. *, P < 0.02; **, P < 0.01; ***, P < 0.001. [Reproduced from M. G. Giannoulis et al.: The effects of growth hormone and/or testosterone in healthy elderly men: a randomized controlled trial. J Clin Endocrinol Metab 91:477–484, 2006 (48), with permission. © The Endocrine Society.]