The 21 men studied were representative of the approximately one third of all men 60 to 80 years old who have plasma IGF-I concentrations of less than 350 U per liter (as compared with a range of 500 to 1500 U per liter in healthy men 20 to 40 years old).4 Our findings cannot be generalized to the approximately two thirds of all men over 60 who have plasma IGF-I concentrations of more than 350 U per liter or to women of a similar age. Furthermore, our entry criteria focused the study on an overtly healthy subgroup of older men.
In the absence of obesity,4 below-normal weight,20 or liver disease,21 a plasma IGF-I concentration of less than 350 U per liter in older men generally signifies that they secrete very little growth hormone.4 To verify this explanation for the low plasma IGF-I concentration in these men, it would be necessary to measure serum growth hormone levels at frequent intervals for 24 hours or to determine the 24-hour urinary excretion of growth hormone. We did not do this, but Ho et al. found that the 24-hour integrated serum growth hormone level was markedly lower in the men over 55 than in men 18 to 33 years old.22 An alternative explanation for a low plasma IGF-I concentration is decreased production of plasma IGF-I binding proteins. Most of the IGF-I plasma is bound to these proteins, but their concentrations vary little in healthy people who eat a normal diet.
In the 12 men in group 1, initially low plasma IGF-I concentrations were raised to the normal range for young adult men by the dose of growth hormone administered, with no evidence of tachyphylaxis or hormone resistance. The dose, approximately 0.03 mg per kilogram three times a week, was based on published estimates of the rate of growth hormone secretion in young men23 and was comparable to or smaller than doses given previously to children with growth hormone deficiency24 , 25 and young adults.10 11 12 13 The plasma IGF-I responses to this dose in these older men were similar in magnitude to those in younger people. That “replacement” rather than pharmacologic doses were being administered was confirmed by the plasma IGF-I measurements, which remained within the range for healthy young adults (500 to 1500 U per liter) throughout the treatment period (Table 3). We conclude that in aging men with low plasma IGF-I concentrations hepatic responsiveness to human growth hormone is not impaired, and the decline in plasma IGF-I concentrations in such men results from growth hormone deficiency rather than growth hormone resistance. The increase in plasma IGF-I levels that occurs when growth hormone is administered to children with growth hormone deficiency reflects not only augmented hepatic production of IGF-I, but also increased production of one of the binding proteins that transport IGF-I.26 The extent to which the production of IGF-I binding protein is increased by the administration of growth hormone has not yet been studied in adults.
At the beginning of our study, adverse reactions to human growth hormone were thought to be unlikely because physiologic doses were being used. Furthermore, similar or larger doses have not caused undesired reactions in children or young adults.10 11 12 13 14 , 25Nevertheless, it remained possible that this dose, when given for six months to older subjects, might cause some manifestation of hypersomatotropism, such as edema, hypertension, diabetes, or cardiomegaly.27 28 29 Although none of these conditions developed, there were small increases in the mean systolic blood pressure and fasting plasma glucose concentration of the group of men who received growth hormone.
The magnitude of the increases in lean body mass and the decreases in adipose-tissue mass (8.8 and -14.2 percent above and below base line, respectively) in the aging men who received human growth hormone for six months was similar to the magnitude of these responses in children8 , 9 and young adults10 11 12 13 treated with similar or lower doses for three to six months, a comparison that provides further evidence that tissue responsiveness to growth hormone and IGF-I is not altered in older men. Until now, the evidence for such a conclusion came only from short-term nitrogen-balance experiments.14, 30 31 32
Salomon et al. reported that the administration of human growth hormone in a dose of 0.49 unit per kilogram per week (0.19 mg per kilogram per week) for six months to adults 20 to 50 years old who had growth hormone deficiency lowered the serum cholesterol concentration significantly.13 Serum cholesterol concentrations did not change in our study, in which the dose of growth hormone was about half as large (0.9 mg per kilogram per week). The divergent results could reflect differences in the subjects’ ages, the degree of growth hormone deficiency, the dose of hormone, or all three.
In rodents, the increase in lean body mass in response to growth hormone is due to increases in the volume of skeletal muscle, skin, liver, kidney, and spleen.1 , 7 In young human subjects, an enlargement of muscle and kidney induced by growth hormone has been documented8 9 10 11 12; other organs have not yet been assessed. The reduction in adipose-tissue mass when children with growth hormone deficiency are treated with human growth hormone is associated with a redistribution of adipose tissue from abdominal to peripheral areas.31 It is not known, however, whether the increase in lean body mass and the decrease in adipose-tissue mass are qualitatively as well as quantitatively similar in old and young human subjects.
Biosynthetic human growth hormone had no detectable effect on the bone density of the radius or proximal femur in the aging men, but it increased the density of the lumbar vertebrae by about 1.6 percent. Although the decrease in bone density with advancing age in men may be due in part to diminished secretion of growth hormone,1 , 33 longer periods of administration of human growth hormone will be required before a final conclusion can be drawn regarding its efficacy in reversing that decrease. A similar interpretation applies to the lack of increase in the mandibular-height ratio.
The findings in this study are consistent with the hypothesis that the decrease in lean body mass, the increase in adipose-tissue mass, and the thinning of the skin that occur in older men are caused in part by reduced activity of the growth hormone—IGF-I axis, and can be restored in part by the administration of human growth hormone.1 , 2 The effects of six months of human growth hormone on lean body mass and adipose-tissue mass were equivalent in magnitude to the changes incurred during 10 to 20 years of aging.1 , 34 , 35Among the questions that remain to be addressed are the following: What will be the benefits and what will be the nature and frequency of any adverse effects when larger numbers of elderly subjects and other doses of human growth hormone are studied? What organs are responsible for the increase in lean body mass, and do their functional capacities change as well? Only when such questions are answered can the possible benefits of human growth hormone in the elderly be explored. Since atrophy of muscle and skin contributes to the frailty of older people, the potential benefits of growth hormone merit continuing attention and investigation.