Chiistos S. Mantozoros, MD. DSc, and Alan C. Moses, MD

Growth hormone and insulin-like growth factor 1 (IGF-1) are important anabolic hormones. They enhance intestinal absorption of calcium and phosphate and may play a direct role in DNA synthesis in bone, proliferation of osteoblasts, and accumulation of procollagen messenger RNA. Although the actions of growth hormone were thought to be caused by circulating IGF-1 alone, recent evidence suggests that growth hormone and other hormones stimulate local production of IGF-1, which acts in a paracrine-autocrine fashion in some tissues.

Secretions of growth hormone substantially declines with age and results in concentrations of IGF-1 that are approximately 50% lower in elderly men than in younger men, and are associated with clinical manifestations of the insulin resistance syndrome.

Since the introduction of recombinant human growth hormone, impressive data have accrued on its ability to promote linear growth in children with growth hormone deficiency or advanced renal failure. The embracing of recombinant human growth hormone as a therapeutic tool in pediatric endocrinology has been accompanied by a search for further indications for its use. Although parenteral injection of recombinant human growth hormone by athletes and body builders is acknowledged as abuse, recent studies have explored its use (and that of IGF-1) as medically appropriate therapy in adults with acquired growth hormone deficiency, in older adults with physiologic deficiency of growth hormone, in patients in severely catabolic states (such as those who have had trauma, burns, or extensive surgery) and in persons with AIDS-associated wasting. What is the rationale for these treatments, and how strongly do the data support replacement therapy with recombinant human growth hormone in these situations?

Earlier studies have shown that short-term recombinant human growth hormone therapy increases lean body mass and muscle mass and reduces fat mass in young athletes, malnourished patients, patients who have had surgery, patients with renal failure, patients with burns, and adults with childhood-onset growth hormone deficiency. Preliminary studies of elderly persons and patients with AIDS-associated cachexia show that short-term therapy with high doses of recombinant human growth hormone (0.1 mg/kg of body weight per day) increases oxidation of fat and improves nitrogen balance, protein synthesis, and body mass. In the longest study to date, recombinant human growth hormone increased lean body mass by 8.8% and decreased adipose tissue mass by 14.4%. Moreover, short-term therapy with low doses of recombinant human IGF-1 (4 µg/kg·hr–1 intravenously for 12 hours a day for 10 days) produced transient nitrogen retention in patients with cachexia associated with human immunodeficiency virus (HIV) infection, although no clear anabolic effect was seen.

In this issue, Waters and colleagues  report the results of their recent 12-week randomized clinical trial of recombinant human growth hormone (1.4 mg/d), recombinant human IGF-1 (5 mg twice daily), or both in patients with HIV-associated wasting. Therapy resulted in modest weight gain, an increase in lean body mass, and an increase in muscle strength but inconsistent improvements in quality of life. The study concluded that such therapy was not warranted until further evidence of efficacy (including improved survival) becomes available. Moreover, two recent studies showed that recombinant human growth hormone (0.68 mg/d) plus recombinant human IGF-1 (10 mg/d) could not produce sustained anabolic responses in HIV-infected patients.

Growth hormone replacement improves muscle volume, strength, and exercise capacity in young adults with hypopituitarism, but no changes in strength or functional ability have been seen in healthy older men receiving an average dosage of 1.8 mg/d. Thus, in patients with AIDS-associated cachexia and elderly persons with growth hormone deficiency, it is still unclear whether changes in body composition include increases in muscle mass or correlate with clinically important improvements in strength, physical mobility, ability to exercise, metabolic values, cardiovascular function, or quality of life.

Bone formation and resorption appear to increase during treatment with recombinant human growth hormone. In a 30-month study  of replacement therapy in adults with childhood-onset growth hormone deficiency, bone turnover markers peaked at 6 months and bone density continued to increase. Treatment of older men for 6 months increased bone mineral density in the lumbar vertebrae by 1.6% but did not increase bone mineral density in the radius or proximal femur, a result similar to that seen in nonelderly, growth hormone-deficient adults. The effect of growth hormone treatment on risk for fractures in elderly persons remains unknown.

In a study reported in this issue, Schambelan and colleagues investigated 178 patients with HIV-associated wasting. Patients who received recombinant human growth hormone at an average dose of 6 mg/d (4.3-fold more than the dose used by Waters and colleagues) for 12 weeks had a sustained increase in body weight and lean body mass, a decrease in fat, and an increase in treadmill work output. Quality of life, days of disability, and use of medical resources were the same in patients who did and those who did not receive growth hormone. No adverse effects on immune function or changes in mortality rate were seen, but the study was not designed (and probably lacked the power) to detect differences in these outcome measures.

The increase in lean body mass may represent water retention, increased protein synthesis, both, or neither. Accuracy of measurement of body mass may be altered by rapid hydration of water-depleted intracellular compartments in patients with chronic malnutrition Rapid weight gain in patients treated with exogenous recombinant human growth hormone suggests that fluid retention has the potential to skew measurements of lean body mass. In addition, although only 22% of the increase in exercise capacity (workload multiplied by body weight) induced by growth hormone could be attributed to increased weight, the marginal statistical significance might still reflect the increase in weight. Improved exercise capacity and body weight were not associated with better quality of life or less-frequent use of medical resources.

An advisory committee of the Food and Drug Administration (FDA) recently examined these and other data and heard testimony about treatment with recombinant human growth hormone for AIDS-associated wasting. Although the data reported by Schambelan and colleagues showed a weight gain of 1.6 kg after treatment, a second study by the same investigators did not duplicate these results, thereby failing to meet a condition of FDA approval. Nonetheless, the FDA approved this treatment of AIDS-associated wasting under the auspices of an expanded access program.

Also in this issue, Baum and colleagues address the effects of 18 months of low-dose recombinant human growth hormone replacement therapy (initial average dose, 0.6 mg/d [10% of the dose used by Schambelan and colleagues], adjusted to normalize IGF-1 levels) on bone mineral density, body mass, and body composition in patients with adult-onset growth hormone deficiency. Therapy increased lean body mass by 2.5 kg, decreased fat mass by 3.6%, stimulated bone turnover, and increased bone mineral density by 2.4% to 5.1%. Left ventricular mass, left ventricular performance, and exercise capacity did not change with therapy.

Baum and colleagues' study provides further support for the use of dose hormone replacement therapy in growth hormone-deficient adults. It also shows that adjusting therapy according to the circulating level of IGF-1 can avoid significant side effects that have been seen in other studies, probably without decreasing the benefits.

In conclusion, despite the excitement and promise of treatment with recombinant human growth hormone for HIV-associated wasting and for growth hormone deficiency in adults, many questions remain unanswered—a frustrating situation for those desperately in need of help. Although some recent data are inconclusive, we are making progress. The studies on AIDS-associated wasting in this issue should provide a strong impetus for additional studies to define precisely who will and will not benefit from administration of recombinant human growth hormone or recombinant IGF-1.