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

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.

The effects of growth hormone and/or testosterone on whole body protein kinetics and skeletal muscle gene expression in healthy elderly men: a randomized controlled trial.

CONTEXT: Alterations of protein turnover may contribute to the progressive decline of muscle mass with aging. OBJECTIVE: Our objective was to examine the effects of near-physiological recombinant human GH and/or testosterone (T) administration to older men on whole body protein kinetics and muscle gene expression. DESIGN, SETTINGS, AND PARTICIPANTS: A 6-month randomized, double-blind, placebo-controlled trial in 21 healthy elderly men aged 65-75 yr, was performed. Participants were randomized to receive placebo GH and placebo T, rhGH and placebo T (GH), T and placebo GH (T), or rhGH and T (GHT). INTERVENTIONS: The leucine rate of appearance (index of proteolysis), nonoxidative leucine disposal rate (an index of protein synthesis), and leucine oxidation rate were measured with an infusion of l-[1-(13)C] leucine. Muscle biopsies for the measurement of gene expression were performed. Body composition and aerobic capacity (maximal oxygen capacity) were measured. RESULTS: Serum IGF-I levels increased significantly with GH and GHT (P < 0.001) compared with placebo. T increased significantly only in the T group (P = 0.028). Leucine rate of appearance and nonoxidative leucine disposal rate increased with GH (P = 0.015, P = 0.019) and GHT (P = 0.017, P = 0.02), but leucine oxidation did not change significantly in any treatment group. Midthigh muscle mass and maximal oxygen capacity increased (P < 0.04) with GHT only. Expression of muscle function genes did not change significantly, but the within-group comparisons revealed a significant increase of androgen receptor expression in the GHT group (P = 0.001). CONCLUSION: This study showed that 6-month treatment with low-dose GH alone or with T in healthy elderly men produces comparable increments in whole body protein turnover and protein synthesis.

Effects of growth hormone and/or testosterone on very low density lipoprotein apolipoprotein B100 kinetics and plasma lipids in healthy elderly men: a randomised controlled trial.

OBJECTIVE: To assess the effects of low dose recombinant growth hormone (GH), testosterone (T) and combined GH and T, on lipid profiles and very low density lipoprotein apolipoprotein B (VLDL apoB) metabolism. DESIGN AND PATIENTS: Sixty-nine healthy elderly men (65-80 yr) were studied in a six month double-blind, placebo-controlled trial. Participants were randomised to placebo GH and placebo T (P), GH and placebo T (GH), T and placebo GH (T) or GH and T (GHT). MEASUREMENTS: Plasma lipid profiles were assessed before treatment and at 6 months. VLDL apoB absolute secretion rate (ASR) and fractional catabolic rate (FCR) were measured in a subset of 21 men: P (n=5); GH (n=5); T (n=6); GHT (n=5), with an infusion of 1-(13)C leucine. Fat mass (FM) was measured by DEXA and intra-abdominal fat (IAF) by CT scan. RESULTS: IGF-I levels increased in the GH and GHT (P<0.001) groups: testosterone increased in the T (P=0.029) and GHT (P=0.05) groups. There was no change in total cholesterol, LDL-cholesterol, HDL-cholesterol, triglycerides, apolipoprotein A-I, apolipoprotein B or lipoprotein(a) in the GH, GHT or T groups. In the subset of 21 men, IGF-I levels increased similarly with GH and GHT (P<0.01) but T levels increased only with T (P<0.03). FM and IAF decreased significantly only with GHT (P<0.01, P=0.01). Treatment with GH, T or GHT had no effect on VLDL apoB ASR or VLDL FCR. CONCLUSION: Co-administration of GH and T in near physiological doses in healthy elderly men resulted in favourable changes in body composition without altering the plasma lipid profile or VLDL apoB metabolism.

The effects of growth hormone and/or testosterone in healthy elderly men: a randomized controlled trial.

CONTEXT: Declines in GH and testosterone (Te) secretion may contribute to the detrimental aging changes of elderly men. OBJECTIVE: To assess the effects of near-physiological GH with/without Te administration on lean body mass, total body fat, midthigh muscle cross-section area, muscle strength, aerobic capacity, condition-specific quality of life (Age-Related Hormone Deficiency-Dependent Quality of Life questionnaire), and generic health status (36-Item Short-Form Health Survey) of older men. DESIGN, SETTINGS, AND PARTICIPANTS: A 6-month, randomized, double-blind, placebo-controlled trial was performed on 80 healthy, community-dwelling, older men (age, 65-80 yr). INTERVENTIONS: Participants were randomized to receive 1) placebo GH or placebo Te, 2) recombinant human GH (rhGH) and placebo Te (GH), 3) Te and placebo rhGH (Te), or 4) rhGH and Te (GHTe). GH doses were titrated over 8 wk to produce IGF-I levels in the upper half of the age-specific reference range. A fixed dose of Te (5 mg) was given by transdermal patches. RESULTS: Lean body mass increased with GHTe (P = 0.008) and GH (P = 0.004), compared with placebo. Total body fat decreased with GHTe only (P = 0.02). Midthigh muscle (P = 0.006) and aerobic capacity (P < 0.001) increased only after GHTe. Muscle strength changes were variable; one of six measures significantly increased with GHTe. Significant treatment group by time interactions indicated an improved Age-Related Hormone Deficiency-Dependent Quality of Life questionnaire score (P = 0.007) in the GH and GHTe groups. Bodily pain increased with GH alone, as determined by the Short-Form Health Survey (P = 0.003). There were no major adverse effects. CONCLUSION: Coadministration of low dose GH with Te resulted in beneficial changes being observed more often than with either GH or Te alone.

Preliminary development of a new individualised questionnaire measuring quality of life in older men with age-related hormonal decline: the A-RHDQoL.

BACKGROUND: There is increasing interest in hormone replacement therapy to improve health and quality of life (QoL) of older men with age-related decline in hormone levels. This paper reports the preliminary development and evaluation of the psychometric properties of a new individualised questionnaire, the A-RHDQoL, measuring perceived impact of age-related hormonal decline on QoL of older men. A-RHDQoL design was based on the HDQoL for people with growth hormone (GH) deficiency and the ADDQoL (for diabetes). METHODS: Internal consistency reliability and some aspects of validity of the A-RHDQoL were investigated in a cross-sectional survey of 128 older men (age range: 64 - 80 yrs), being screened for inclusion in a trial of GH and testosterone (T) replacement, and who completed the A-RHDQoL once. Respondents rated personally applicable life domains for importance and impact of their hormonal decline. A single overview item measured present QoL. Serum levels of Insulin-like Growth Factor-I and total T were measured. RESULTS: Of the 24 A-RHDQoL domains, 21 were rated as relevant and important for older men. All domains were perceived as negatively impacted by hormonal decline. The most negatively impacted domains were: memory (-4.54 +/- 3.02), energy (-4.44 +/- 2.49), sex life (-4.34 +/- 3.08) and physical stamina (-4.29 +/- 2.41), (maximum range -9 to +9). The shorter 21-domain A-RHDQoL had high internal consistency reliability (Cronbach's alpha coefficient = 0.935, N = 103) and applicable domains could be weighted and summed into an overall Average Weighted Impact score. The questionnaire was acceptable to the majority of respondents and content validity was good. The single overview item measuring present QoL correlated significantly with total T levels [r = 0.26, p <0.01, N = 114]. CONCLUSION: The new 21-item A-RHDQoL is an individualised questionnaire measuring perceived impact of age-related hormonal decline on the QoL of older men. The internal consistency reliability and content validity of the A-RHDQoL are established, but the measure is at an early stage of its development and its sensitivity to change and other psychometric properties need now to be evaluated in clinical trials of hormone replacement in older men.