Systematic Review: The Safety and Efficacy of Growth Hormone in the Healthy Elderly

Context Human growth hormone (GH) is widely sold and used as an antiaging agent. Contributions The researchers reviewed all clinical trials of GH to determine if it is safe and effective in the healthy elderly. They found that GH had no important effects on body composition but led to frequent adverse effects, most notably soft tissue edema and arthralgias. Cautions Clinical trials of GH have been small, and they may not have been able to detect important differences. Implications Published data about GH use in the elderly is limited, but available evidence suggests that risks far outweigh benefits when it is used as an antiaging treatment in healthy older adults. The Editors Since the 1990 publication of an article by Rudman and colleagues (1) suggesting that a short course of recombinant human growth hormone (GH) therapy could reverse decades of age-related changes in body composition in otherwise healthy elderly men, the use of GH as an antiaging therapy has increased rapidly in the United States and worldwide (2). Interest in Rudman and colleagues' results has remained high (3), spawning several popular books in the lay press (47). Use of GH as an antiaging therapy ranks as 1 of the most popular health-related Internet searches (8). Although the exact number of people who use GH as an antiaging therapy is unknown, Perls and colleagues (2) reported that 20000 to 30000 people used GH in the United States as an antiaging therapy in 2004 (9), a more than 10-fold increase since the mid-1990s (10, 11). Annual sales of GH worldwide exceed $1.5 billion (2), one third of which may be for off-label use (12). Proponents of GH for its antiaging properties claimed that more than 100000 people received GH without a prescription in 2002 (2, 11). The rationale for using GH as an antiaging therapy, referred to by some as the sweet syringe of youth (10), lies in the age-related decline in activity of the hypothalamic growth hormoneinsulin-like growth factor axis, a phenomenon referred to as the somatopause (1319). Some signs and symptoms of GH deficiency (that is, GH deficiency due to hypothalamic or pituitary defects), such as increased adiposity and decreased lean body mass, are similar to changes that occur with aging, suggesting that GH replacement therapy may ameliorate age-related changes. Although GH therapy improves body composition (20), bone density (20, 21), and cholesterol levels (22) and may decrease death (23) in people who are GH-deficient, its safety, efficacy, and role in the healthy elderly is highly controversial (24). Whereas proponents of GH have recommended its use for treating the somatopause (18, 19, 25, 26), others, including the American Association of Clinical Endocrinologists (27), have warned that such therapy is not warranted. High levels of insulin-like growth factor-1 (IGF-1), which are regulated by GH levels, may be associated with serious adverse events (12), including prostate cancer (28). Furthermore, the distribution of GH for use as an antiaging therapy in the United States is illegal (2). We performed a systematic review and meta-analysis of randomized, controlled trials to determine the safety and efficacy of GH therapy in the healthy elderly. We aimed to evaluate the effects of GH on body composition, exercise capacity, bone density, serum lipid levels, and glucose metabolism. In addition, we sought to synthesize the evidence on adverse events associated with GH use in the healthy elderly. Methods Literature Searches An author and a professional librarian developed search strategies to identify potentially relevant studies. We searched MEDLINE and EMBASE databases for English-language studies published through 21 November 2005 using keywords including growth hormone; aging; and randomized, controlled clinical trials (Appendix Table 1). We searched bibliographies of retrieved articles for additional studies. Appendix Table 1. Search Strategy Study Selection We sought 2 types of randomized, controlled trials: those that compared injectable GH therapy with no GH therapy and those that compared injectable GH therapy plus lifestyle interventions (that is, exercise with or without a dietary intervention) with lifestyle interventions alone. We included studies that: 1) evaluated at least 10 participants; 2) included participants who received GH therapy for 2 weeks or more; 3) enrolled only community-dwelling participants; 4) assessed participants with a mean body mass index of 35 kg/m2 or less and a mean age of 50 years or more; and 5) provided data on at least 1 clinical outcome of interest. We excluded studies that: 1) focused solely on evaluating GH-releasing factor, other GH secretagogues, or IGF-1; 2) explicitly included patients with diabetes mellitus, cardiac disease, thyroid disease, osteoporosis, or cancer; or 3) evaluated GH as a treatment for a specific illness (for example, adult GH deficiency, the HIV wasting syndrome, renal failure, or critical illness). Data Abstraction An author reviewed the titles and abstracts of articles identified through our search and retrieved potentially relevant studies. Two physicians with postdoctoral training in health services research, endocrinology, or both reviewed each retrieved study and abstracted data independently onto pretested abstraction forms. We resolved abstraction differences by repeated review. If a study did not present data necessary for analysis, mentioned results but did not present data, or presented data graphically, we requested additional data from study authors. If several studies presented findings from the same cohort, we used these data only once in our analysis. Abstracted Data We abstracted 4 types of data from each study: 1) study quality (for example, quality of randomization, blinding, outcomes, and statistical analyses) (29, 30); 2) study sample characteristics (for example, age, sex, weight, medical conditions, and baseline IGF-1 levels); 3) study interventions (for example, dosage, frequency, and length of GH therapy); and 4) clinical outcomes. We included studies that provided data on at least 1 of the following 6 clinical outcomes of interest: 1) body composition (for example, weight, lean body or fat-free mass, or fat mass); 2) strength or functional capacity (for example, handgrip strength or maximal rate of oxygen consumption); 3) bone dynamics (for example, femoral neck or lumbar spine bone mineral density or bone mineral content); 4) cardiovascular risk factors (for example, heart rate, total, low-density lipoprotein, and high-density lipoprotein cholesterol levels or triglyceride levels); 5) insulin resistance markers (for example, fasting glucose and insulin levels and 2-hour glucose post75-gram oral glucose tolerance test results); 5) quality-of-life or depression scales; or 6) adverse events. Because the terms lean body mass and fat-free mass are typically used interchangeably in scientific literature, we combined data on fat-free mass and lean body mass into the single category of lean body mass. Quantitative Data Synthesis To describe key study characteristics, we computed mean values weighted by the number of participants in each trial. To evaluate the effects of GH on the outcomes of interest, we computed a change score for each clinical outcome for participants in the treatment and control groups as the value of the outcome at the end of the trial minus the value of the outcome at the start of the trial. We then used these change scores to calculate 2 study effect sizes: the Hedges' adjusted g, which is an estimate of the standardized mean difference (31), and the weighted mean difference (32). We calculated both study effect sizes because the Hedges' adjusted g, although an unbiased estimate, lacks units; whereas the results of the weighted mean difference are in the same units as the clinical outcome of interest, facilitating clinical interpretation. Our results from either method did not substantially differ, and we present effect sizes calculated by using only the weighted mean difference. If studies reported standard errors, we converted them to standard deviations. For studies that did not report the variance of an outcome at the end of the trial minus that at the start of the trial, we calculated the variance as the sum of the variances at the start and end of the trial minus twice the covariance. Calculation of the covariance between the end of the trial and the start of the trial requires the correlations from individual patient data. Because these correlations were unavailable, we computed the correlation of the reported means, which ranged from 0.61 to 0.99, and used values over this interval to estimate the covariance for each outcome. We chose a correlation of 0.80 as our baseline value, although the pooled effect sizes did not substantially change when we varied the correlation over the range of 0.61 to 0.99. We combined studies by using the DerSimonian and Laird inverse variance weighted method (random-effects model) and the MantelHaenszel method (fixed-effects model) (31, 32). We present the results from only the random-effects model because of statistical heterogeneity in some clinical outcomes. For body composition measures, we calculated separate summary effect sizes for the following: 1) studies of groups receiving GH versus studies of groups not receiving GH; 2) studies of GH plus lifestyle interventions versus studies of lifestyle interventions alone; 3) studies in which researchers administered GH for less than 26 weeks versus studies in which they administered GH for 26 weeks or more; and 4) study populations in which researchers evaluated only men versus studies evaluating only women. Because few studies have reported outcomes other than body composition measures, we calculated a single effect size for other clinical outcomes. We evaluated the effects of study heterogeneity on our summary results. We sought sources of heterogeneity affecting body composition outcomes t