Testosterone and growth hormone in older men: for better or for worse?

Abstract

Evaluation of: Sattler FR, Castaneda-Sceppa C, Binder EF et al. Testosterone and growth hormone improve body composition and muscle performance in older men. J. Clin. Endocrinol. Metab. 94(6), 1991–2001 (2009).

In men, testosterone and IGF1 levels decline with increasing age, and lower levels of these hormones are associated with poorer health. A recent, randomized clinical trial demonstrates the additive effects of testosterone and growth hormone supplementation to increase lean body mass, reduce fat mass and improve muscle strength in older men. These findings highlight the interaction between these two hormones and provide a model for further evaluation of combined therapy to explore other end points, such as cardiovascular risk.

Keywords::

• body composition
• growth hormone
• male ageing
• muscle performance
• testosterone

Testosterone levels decline as men grow older, with a parallel age-related fall in growth hormone (GH) secretion, resulting in lower circulating levels of IGF1. Both testosterone and GH possess comparable anabolic actions to preserve muscle mass and inhibit the accumulation of fat. Thus, the question arises as to whether reduced levels of both are more deleterious to health and whether supplementation with a combination of hormones might provide synergistic benefit. Sattler et al. report the results of a randomized trial in which the effects of achieving testosterone levels in the low-normal compared with high-normal range, together with incremental levels of GH supplementation are studied [1]. The findings indicate an additive beneficial effect of combined hormonal therapy on parameters of body composition and muscle performance. Further studies are needed to examine whether combined therapy would result in additive benefits for other end points, for example, the risk of cardiovascular disease. An additional consideration would be whether newer oral agents could successfully modulate testosterone and GH levels in aging men, thus avoiding the need for parenteral therapy.

Methods

Sattler et al. recruited community-dwelling men aged 65–90 years with morning serum testosterone levels in the lower half of the adult male range (5.2–19.1 nmol/l) and serum IGF1 levels in the lower tertile for adults (<167 ng/ml) [1]. Other criteria included prostate-specific antigen (PSA) no higher than 4.0 ng/ml, hematocrit no more than 50% and fasting glucose less than 7.0 mmol/l.

From baseline to week 12, participants received a long-acting gonadotropin-releasing hormone agonist (leuprolide acetate 7.5 mg, intramuscularly) to suppress endogenous luteinizing hormone secretion. Men were randomized to treatment with 1% transdermal testosterone gel 5 g (Groups A–C) or 10 g (Groups D–F) each morning. Participants self-administered 0, 3 or 5 µg/kg of recombinant human GH (rhGH) as an evening subcutaneous injection (Groups A/D, B/E and C/F, respectively) with hormonal therapy extending to 16 weeks. Outcome measures were body composition measured by dual-energy x-ray absorptiometry, assessment of leg press, leg extension and flexion, latissimus pull-down and chest press, and peak oxygen consumption (VO₂) and aerobic endurance with cycle ergometry. Testosterone was measured using immunoassays for screening and liquid chromatography–tandem mass spectrometry for study samples. IGF1 and insulin were assayed using immunoassays.

Results

Of 242 men consented and screened, 122 were randomized and 112 completed all study assessments at week 17. At baseline, average BMI was 27.4 kg/m², testosterone was 12.5 nmol/l and IGF1 was 111 ng/dl. The average increase in testosterone was 5.0 nmol/l in men receiving 5 g and 17.7 nmol/l in men receiving 10 g of testerone gel. Treatment with rhGH 3 and 5 µg/kg increased serum IGF1 by 64 ng/dl and 108 ng/dl, respectively. Of note, the higher dose of testosterone alone resulted in increased IGF1 in men who did not receive GH (14 ng/dl in Group D). There was a progressive increase in lean body mass across Groups A–F averaging from 1.0 to 3.0 kg, with statistically significant changes in Groups C–F. Total fat decreased progressively by an average of 0.8–2.3 kg in Groups A–F, with significant changes in Groups C, E and F. For both outcomes, the magnitude of changes was similar in Groups C and D, and greatest in Groups E and F. Maximal voluntary muscle strength improved in Groups D–F by 23–35%. While aerobic endurance did improve in all six groups, there was no clear dose-related trend. Fasting glucose levels increased by 0.17 mmol/l across the entire study population, with no significant change in indices of insulin resistance or total and low-density lipoprotein cholesterol. In the study population as a whole, high-density lipoprotein cholesterol increased by 0.09 mmol/l and fasting triglyceride level decreased by 0.20 mmol/l.

Side effects reported included joint pain or knee swelling (36%), edema (35%), aching or muscle pains (29%), skin rash or bruises (19%), and cough or nasal congestion (15%), which were not related to dose levels of testosterone or rhGH. Breast engorgement or nipple pain (14%) occurred transiently and was more frequent in men receiving 10 versus 5 g of testosterone gel. There were significant increases in blood pressure with each of the six interventions (average 12/8 mmHg), with partial resolution over a further 12 weeks of follow-up. Increases in hematocrit were observed but PSA increased significantly only in Group F (from 1.1 to 1.8 ng/ml). Both hematocrit and PSA values fell towards baseline on repeat testing after discontinuation of treatments. Statistical analysis did not show interactions amongst the treatment interventions, consistent with hormonal therapy exerting independent but complementary effects. However, there were significantly positive additive effects of higher testosterone and GH doses for gain of lean body mass and loss of fat mass, with benefits increasing in magnitude from lower to higher dose combinations.

Expert commentary

This study demonstrates that a higher dose of testosterone in combination with GH exerts greater beneficial effects on body composition in older men, compared with either testosterone alone or a lower dose of testosterone and GH. The results are consistent with previous trials that reported greater beneficial effects on body composition, with the combination of testosterone and GH compared with either hormone alone [2,3]. However, Sattler et al. were also able to stratify the intensity of both testosterone and GH therapy to demonstrate incremental effects of increasing hormone levels from the low-normal to high-normal range. The study confirmed the relatively high frequency for reporting of side effects of therapy and identified an increase in blood pressure as a potential concern. The study was not powered to detect treatment-related changes in metabolic parameters and caution is required in extrapolating outcomes beyond 16 weeks. Of note, the observation that treatment with testosterone alone results in an increase in IGF1 levels in older men supports experimental evidence for testosterone stimulating GH, and hence IGF1, secretion [4]. As testosterone and IGF1 levels decline with increasing age in men, older men are more likely to exhibit lower testosterone or IGF1 levels [5]. Both lower testosterone and lower IGF1 levels are associated with poorer health outcomes in older men (for reviews, see [6–8]). However, there is ongoing debate as to whether reduced circulating testosterone and IGF1 cause ill-health, particularly cardiovascular events, or whether they are markers for pre-existing disease. Therefore, additional randomized, controlled clinical trials are needed to test whether maintaining testosterone and IGF1 levels in ageing men would not only improve measures of body composition, but also preserve health and specifically prevent cardiovascular events. The potential for combined hormone supplementation with both testosterone and GH needs to be further explored in this broader context.

Five-year view

Further investigations of the benefits and risks of testosterone or GH, or combined hormonal supplementation in older men are likely to explore outcomes beyond body composition, such as insulin resistance and cardiovascular risk. Observational data could clarify age-specific thresholds of testosterone or IGF1 that identify men at a higher risk of ill health, and provide an estimate of risk reduction per incremental change in hormone levels. These would allow optimal design of the larger long-term interventional studies needed to determine whether testosterone, GH or combined therapy would reduce the incidence of cardiovascular events in aging men. However, GH therapy in particular is relatively inconvenient, requiring daily subcutaneous injections, and is expensive. The vast majority of older men with lower testosterone or IGF1 levels do not have pituitary or testicular damage that would necessitate treatment with testosterone or GH [5,6]. They may be candidates for newer oral therapies, such as anastrozole, an aromatase inhibitor that increases pituitary luteinizing hormone secretion and hence endogenous testosterone production in men [9], although it is unclear how reduced estradiol levels might impact on any changes in body composition and metabolism. By contrast, treatment with the orally active GH secretagogue capromorelin increases GH and IGF1 secretion in older adults, resulting in increased lean body mass and improved physical performance [10]. Therefore, future trials of testosterone and GH therapy in older men may involve conventional hormone supplementation or newer approaches to optimizing endogenous hormone production.

Key issues

• • Testosterone and IGF1 levels in men decline with increasing age.

• • Sattler et al. evaluated effects of testosterone, growth hormone or combined therapy on measures of body composition and muscle performance in older men.

• • A higher dose of testosterone in combination with growth hormone exerted greater beneficial effects on body composition, compared with either testosterone alone or a lower dose of testosterone and growth hormone.

• • Side effects of therapy were relatively frequent, and included increased blood pressure.

• • These findings highlight the interaction between these two hormones and provide a model for further evaluation of combined therapy to explore other end points such as cardiovascular risk.

Financial & competing interests disclosure

Bu Beng Yeap is the recipient of a Project Grant (513823) from the National Health and Medical Research Council of Australia and has received a speaker’s honorarium from Bayer Healthcare. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.