Growth hormone: fountain of youth or death hormone?

Abstract

Both growth hormone and its target hormone, insulin growth factor-I (IGF-1), decline with age.1 This decline with age has been attributed both to a decrease in the secretions of growth hormone releasing hormone and its activity, as well as to an increase in somatostatin from the hypothalamus. Studies in both animals and humans with L-arginine, which is thought to inhibit somatostatin secretion, have demonstrated a vigorous growth hormone response in older persons.2-4 In addition, somatostatin antisera increased growth hormone to a greater extent in older than in younger rodents.5 In this issue of JAGS, Mulligan et al.6 demonstrate that somatostatin inhibits growth hormone secretion in both young and older persons. This demonstrates that the pituitary response to somatostatin remains intact with aging in humans. The enthusiasm for studying growth hormone in older persons increased exponentially approximately a decade ago when Rudman,7 in the pages of JAGS, suggested that a growth hormone “menopause” occurred with aging. He pointed out that many of the physiological changes of aging were similar to the changes associated with growth hormone deficiency. In his original study, he demonstrated some positive effects of growth hormone therapy given to men for 6 months.8 Unfortunately, when the therapy was continued for 12 months, side effects such as carpal tunnel syndrome, gynecomastia, and arthralgias limited the ability of most persons to tolerate growth hormone therapy.9 A number of subsequent studies have demonstrated that in older men and women growth hormone increased muscle mass but not strength.10-15 Exercise was more efficacious than was growth hormone at increasing muscle strength, and growth hormone did not enhance the effects of exercise.15 Other effects of growth hormone included an increase in resting energy expenditure and a decrease in body fat. However, in all of these studies, side effects such as carpal tunnel syndrome, edema, arthralgias, myalgias, and gynecomastia limited the use of growth hormone in many older individuals. Growth hormone has been used to reverse catabolism in some older persons with malnutrition.16, 17 A recent report has described a malnourished man in his 80s who had a marked decrease in growth hormone receptors.18 This decline in growth hormone receptors with malnutrition may be a key to why pharmacological doses of growth hormone may be useful in the treatment of severe malnutrition in older persons. Because malnutrition is a major health problem of older individuals,19 further studies on whether growth hormone can decrease hospital stay or mortality and improve functional status in malnourished older persons are justified. Some have thought that the large number of side-effects associated with growth hormone administration in older persons is a result of the pharmacological nature of the treatment. This has led to an enthusiastic effort to find a mechanism to produce physiological increases in circulating growth hormone levels. Oral growth hormone secretagogues have now been developed. Thorner et al.20 demonstrated that MK-771 can produce a physiological increase in growth hormone. Long-term studies on whether this compound can increase strength without producing unacceptable side effects are not yet published. Several years ago, Denckla21 suggested that the pituitary produced a “death hormone.” Could growth hormone administration to older persons result in a shortened life span? The Snell dwarf mutant mouse, which lacks growth hormone, lives longer than its nonmutant controls that produce growth hormone normally.22 Growth hormone administration to older rodents does not increase life span.23 A study in Paris found that males with higher basal growth hormone levels were more likely to die than were those with lower growth hormone levels.24 These studies do not champion the use of growth hormone as a hormonal “fountain of youth.” See also p 1422 It is possible that increasing tissue IGF-1 may prove more effective at increasing frailty. Baumgartner et al.25 showed that appendicular skeletal mass was best predicted by IGF-1, free testosterone, and physical activity in older men, and by IGF-1 and physical activity in women. Testosterone increases tissue IGF-1 levels26 and has been shown to increase muscle strength in older men27, 28 and muscle mass in women.29 Testosterone, although not side-effect free, seems to have a better safety track record than does growth hormone in older persons.30 At present, the case for growth hormone replacement in healthy older persons is certainly “not proven.” Growth hormone may well have a place in the management of severely ill, malnourished older individuals. The “effect” of oral growth hormone secretagogues that produce physiological levels of growth hormone remains to be determined. It is possible that the decline in growth hormone and IGF-1 represents a protective mechanism that results in prolongation of life span. Further longitudinal epidemiological studies determining whether the decline in growth hormone and IGF-1 with aging has positive or negative effects on health status and life span are needed.