Human Growth Hormone and Aging

Normal Changes in the Growth Hormone Axis with Aging
The rate of GH secretion from the anterior pituitary is highest around puberty, and declines progressively thereafter. This age-related decline in GH secretion involves a number of changes in the GH axis, including decreased serum levels of insulin-like growth factor-1 (IGF-1) and decreased secretion of growth hormone-releasing hormone from the hypothalamus. The cause of the normal age-related decrease in GH secretion is not well understood, but is thought to result, in part, from increased secretion of somatostatin, the GH-inhibiting hormone.

Normal aging is accompanied by a number of catabolic effects, including a decrease in lean mass, increase in fat mass, and decrease in bone density. Associated with these physiologic changes is a clinical picture often referred to as the somatopause: frailty, muscle atrophy, relative obesity, increased frequency of fractures and disordered sleep. These clinical signs of aging are, without doubt, the manifestation of a very complex set of changes which involve, at least in part, the GH-axis. Naturally, this has spurred considerable interest in administering supplemental GH as a "treatment" for aging in humans, and the availability of recombinant human GH has made such studies feasible.

In contrast to the view that GH deficiency contributes to the aging phenomenon, there is information suggesting that normal or high levels of GH may accelerate aging. Mice with genetic dwarfism due to deficiency in GH, prolactin and thyroid-stimulating hormone live considerably longer than normal mice, and the increased levels of GH seen with acromegaly in humans are associated with reduced life expectancy. Both of these findings are likely due to metabolic effects of GH.

GH Replacement Therapy in GH-deficient Adults for anti-aging
Adult-onset GH deficiency in humans is almost always due to pituitary disease, usually from a tumor or theraputic efforts to treat a tumor. Such patients have increased risk of death from cardiovascular disease, and, relative to age-matched controls, show increased fat mass, reduced muscle mass and strength, lower bone density, and higher serum lipid concentrations. Additionally, they suffer from reduced vigor, sexual dysfunction and emotional problems.

More than a dozen clinical trials have sought to evaluate GH replacement in patients with adult-onset deficiency. The goal has usually been to normalize serum IGF-1 concentrations by daily injections of GH. In essentially all cases, several months of GH replacement therapy led to increased lean mass and decreased adiposity (especially in visceral fat). The effects of GH treatment on bone density and hyperlipidemia has been inconsistent or minor, as have been the effects on strength and mental abilities. Common side effects observed in these trials included edema and joint/muscle pain, which appeared related to dose of GH. Since the first of these trials was conducted in 1988, long term risks are not yet known.

GH Therapy in the Elderly 
Long before Ponce de Leon went in search of the legendary fountain of youth, people sought treatments to prevent or reverse the effects of aging. In 1990, considerable excitement was generated from a report by Rudman and colleagues which described wonderful effects of GH treatment in a small group of elderly men. These volunteers, who ranged in age from 61 to 81 years, showed increased lean body and bone mass, decreased fat mass and, perhaps most dramatically, restoration of skin thickness to that typical of a 50-year-old.

The study cited above and a handful of others have provided an initial understanding of the benefits, limitations and risks of sustained (6 to 12 month) GH supplementation in elderly men and women. A consistent finding in these investigations was a high incidence of adverse side effects - edema, fluid retention and carpal tunnel syndrome - which necessitated reductions in GH dose of cessation of treatment. GH treatment consistently induced an increase in serum IGF-1, a decrease in fat mass and increase in lean mass.

The effects on fat and lean masses may be viewed as positive effects, but, at the end of the day, it has to be asked whether GH treatment improved functioning in the elderly. In the studies in which function was objectively assessed, GH treatment did not improve cognitive function, and, despite the effects on lean body mass, was not any more effective than exercise alone in promoting strength. Long-term GH therapy in elderly postmenopausal women lead to significant increases in bone mineral density, but these increases were less than what is routinely achieved with estrogen replacement. While it must be acknowledged that a relatively small number of elderly patients have been treated for prolonged periods with GH, the controlled trials conducted thus far do not support is efficacy in aleviating age-related deficits in cognitive or somatic function.

Another indication of potentially serious side effects of GH therapy in adults, including the elderly, has been provided by controlled clinical trials that assessed the utility of human GH treatment in critical illness, where endogenous GH secretion is typically suppressed. GH therapy was anticipated to attenuate the catabolic effects of illness and thereby decrease duration of hospitalization. The results of several clinical trials involving hundreds of patients, demonstrated a significant increase in mortality associated with high doses of GH. Additionally, those patients treated with GH that survived had longer periods of intensive care and hospitalization than those receiving placebos.

 References and Reviews

Borst SE and Lowenthal DT: Role of IGF-1 in muscular atrophy of aging. Endocrine 7:61-63, 1997. 
Cummings DE and Merriam GR: Growth hormone therapy in adults. Annu Rev Med 54:513-533, 2003. 
Holloway L, Butterfield G, Hintz RL, et al.: Effect of recombinant human growth hormone on metabolic indices, body composition, and bone turnover in healthy elderly women. J Clin Endocrinol Metab 79:470-479, 1994.
Marcus R and Hoffman AR: Growth hormone as therapy for older men and women. Annu Rev Pharmacol Toxicol 38:45-61, 1998.
Papadakis MA, Grady D, Black D, et al.: Growth hormone replacement in healthy older men improves body composition but not functional ability. Ann Int Med 124:708-716, 1996.
Rudman D, Feller AG, Nagraj HS, et al.: Effects of human growth hormone in men over 60 years old. New Eng J Med 323:1-6, 1990.
Taaffe DR, Pruitt L, Reim J, et al.: Effects of recombinant human growth hormone on the muscle strength response to resistance exercise in elderly men. J Clin Endocrinol Metab 79:1361-1366, 1994.
Takala J, Ruokonen E, Webster NR, et al.: Increased mortality associated with growth hormone treatment in critically ill adults. New Eng J Med 341:785-792, 1999.
Vance ML and Mauras N: Drug therapy: Growth hormone therapy in adults and children. New Eng J Med 341:1206-1216, 1999.