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Copyright, 1990, by the Massachusetts Medical Society EFFECTS OF HUMAN GROWTH HORMONE IN MEN OVER 60 YEARS OLD
DANIEL RUDMAN, M.D., AXEL G. FELLER, M.D., HOSKOTE S. NAGRAJ, M.D., GREGORY A. GERGANS, M.D., PARDEE Y. LALITHA, M.D., ALLEN F. GOLDBERG, D.D.S., ROBERT A. SCHLENKER, PH.D., LESTER COHN, M.D., INGE W. RUDMAN, B.S., AND DALE E. MATTSON, PH.D.
Abstract
In group 1, the mean plasma IGF-I level rose growth hormone–insulin-like growth factor I (IGF-I) axis into the youthful range of 500 to 1500 U per liter during with advancing age may contribute to the decrease in lean treatment, whereas in group 2 it remained below 350 U per body mass and the increase in mass of adipose tissue that liter. The administration of human growth hormone for six months in group 1 was accompanied by an 8.8 percent increase in lean body mass, a 14.4 percent decrease in healthy men from 61 to 81 years old who had plasma adipose-tissue mass, and a 1.6 percent increase in aver- IGF-I concentrations of less than 350 U per liter during age lumbar vertebral bone density (P<0.05 in each in- a six-month base-line period and a six-month treatment stance). Skin thickness increased 7.1 percent (P = 0.07).
period that followed. During the treatment period, 12 men There was no significant change in the bone density of the (group 1) received approximately 0.03 mg of biosynthetic radius or proximal femur. In group 2 there was no signifi- human growth hormone per kilogram of body weight sub- cant change in lean body mass, the mass of adipose tis- cutaneously three times a week, and 9 men (group 2) re- sue, skin thickness, or bone density during treatment.
ceived no treatment. Plasma IGF-I levels were measured monthly. At the end of each period we measured lean mone is responsible in part for the decrease of lean body body mass, the mass of adipose tissue, skin thickness mass, the expansion of adipose-tissue mass, and the thin- (epidermis plus dermis), and bone density at nine skeletal ning of the skin that occur in old age. (N Engl J Med 1990; I N middle and late adulthood all people experience measure the 24-hour secretion of the substance direct- a series of progressive alterations in body composi- ly. Growth hormone secretion can be measured indi- tion.1 The lean body mass shrinks and the mass of rectly, however, by measuring the plasma concentration adipose tissue expands. The contraction in lean body of insulin-like growth factor I (IGF-I, also known as so- mass reflects atrophic processes in skeletal muscle, liv- matomedin C), which is produced and released by the liver and perhaps other tissues in response to growth These structural changes have been considered un- hormone.5 There is little diurnal variation in the plas- avoidable results of aging.1 It has recently been pro- ma IGF-I concentration, and measurements of it are posed, however, that reduced availability of growth hor- therefore a convenient indicator of growth hormone se- mone in late adulthood may contribute to such cretion.5 Plasma IGF-I concentrations decline with ad- changes.1,2 This proposal is based on two lines of evi- vancing age in healthy adults.1,4,6 Less than 5 percent dence. First, after about the age of 30, the secretion of of the healthy men 20 to 40 years old have plasma growth hormone by the pituitary gland tends to de- IGF-I values of less than 350 U per liter, but the values cline.1,3,4 Since growth hormone is secreted in pulses, are below this figure in 30 percent of the healthy men mostly during the early hours of sleep, it is difficult to over 60.4 Likewise, the nocturnal pulses of growth hor-mone secretion become smaller or disappear with ad-vanced age. If the plasma concentration of IGF-I falls From the Department of Medicine, Medical College of Wisconsin, Milwaukee (D.R., I.W.R.); the Medical Service, Veterans Affairs Medical Center, Milwaukee below 350 U per liter in older adults, no spontaneous (D.R.); the Department of Medicine, Chicago Medical School, North Chicago circulating pulses of growth hormone can be detected (A.G.F., H.S.N., G.A.G., P.Y.L., L.C.); the Medicine (A.G.F., H.S.N., P.Y.L.), Nu- by currently available radioimmunoassay methods.4 clear Medicine (G.A.G.), and Dental (A.F.G.) Services, Veterans Affairs MedicalCenter, North Chicago; the Argonne National Laboratory, Argonne, Ill. (R.A.S.); The concomitant decline in plasma concentrations of and the Epidemiology–Biometry Program, University of Illinois School of Public both hormones supports the view that the decrease in IGF-I results from diminished growth hormone secre- Supported by grants from the Department of Veterans Affairs and Eli Lilly and Co., and by a grant (1D31 PE95008-02) from the Public Health Service.
tion.4,6 Second, diminished secretion of growth hor- Downloaded from www.nejm.org on December 01, 2003.
Copyright 1990 Massachusetts Medical Society. All rights reserved.
mone is accompanied not only by a fall in the plasma Table 1. Schedule of Tests during the Base-Line IGF-I concentration, but also by atrophy of the lean body mass and expansion of the mass of adipose tis-sue.1 These alterations in body composition caused by growth hormone deficiency can be reversed by re- placement doses of the hormone, as experiments in rodents,7 children,8,9 and adults 20 to 50 years old10-13 have shown. These findings suggest that the atrophy of the lean body mass and its component organs and the enlargement of the mass of adipose tissue that are characteristic of the elderly result at least in part from diminished secretion of growth hormone.1,2 If so, the age-related changes in body composition should be correctable in part by the administration of human growth hormone, now readily available as a biosyn- In this study we administered biosynthetic human growth hormone for six months to 12 healthy men from 61 to 81 years old whose plasma IGF-I concentrations were below 350 U per liter, and we measured the ef- *Tests included a complete blood count, hematocrit, blood indexes, and the measurement af- fects on plasma IGF-I concentration, lean body mass, ter an overnight fast of plasma glucose, urea nitrogen, creatinine, uric acid, sodium, potassium, adipose-tissue mass, skin (dermal plus epidermal) chloride, carbon dioxide, phosphate, calcium, total protein, albumin, alkaline phosphatase, as-partate aminotransferase, lactic dehydrogenase, bilirubin, cholesterol, triglyceride high-density thickness, regional bone density, and mandibular- lipoprotein cholesterol, and glycosylated hemoglobin levels. Tests were performed at theNorth Chicago Veterans Affairs Medical Center laboratories.
height ratio (the height of the alveolar ridge divided by †Total body potassium levels (lean body mass and adipose-tissue mass) were measured the total height of the mandible). The measurement of according to the method of Flynn et al.15 the mandible was included to test the hypothesis that ‡Calculated as the sum of the skin thicknesses of the right and left dorsal hand and right and left volar forearm measured with a Harpenden caliper according to the method of Lawrence and the age-related involution of dental bone results in part from the loss of stimulation by growth hormone.1 In ad- §Measured according to the method of Nagraj et al.17 dition, the men were monitored for possible adverse ef- ¶Measured according to the method of Goldberg et al.
Measured at Nichols Laboratory, Los Angeles, according to the method of Furlanetto et al.19 fects of the hormone by means of interviews, physical examinations, and standard laboratory tests. Nine menmatched for age and with similar plasma IGF-I concen- such that in each group of five men, three would be assigned to the growth hormone group and two to the control group. All 21 men (12in group 1 and 9 in group 2) completed the treatment period and constitute the study group for this report. Their clinical character-istics are summarized in Table 2. During the first week of the sev- Subjects
enth month, the men in group 1 were instructed in the subcutane- Healthy men who were 61 or older and living in the community ous administration of recombinant biosynthetic human growth were recruited through newspaper advertisements followed by an in- hormone (2.6 IU per milligram of hormone; Eli Lilly). The initial terview. Entry criteria (available from the authors on request) includ- dose was 0.03 mg per kilogram of body weight, injected three times ed body weight of 90 to 120 percent of the standard for age, the abil- a week at 8 a.m., the interval between injections being either one ity to administer growth hormone to oneself subcutaneously, and the or two days. A sample of venous blood for plasma IGF-I assay was absence of indications of major disease. Ninety-five men who an- obtained each month 24 hours after a growth hormone injection. If swered the advertisements met criteria that could be ascertained by the IGF-I level was below 500 U per liter, the dose of hormone was interview. Their plasma IGF-I concentrations were then determined increased by 25 percent; if the IGF-I level was above 1500 U per li- twice at an interval of four weeks. Consistent with the results of a ter, the dose was reduced by 25 percent. The men in group 2 re- previous study,13 the plasma IGF-I values in these men ranged from ceived no injections. The schedule of tests for both groups during 100 to 2400 U per liter, with an average of 500 U per liter. Thirty- the treatment period is shown in Table 1.
three of the men had plasma IGF-I values of less than 350 U per liter At the start of the base-line period, the project dietitian instructed on both occasions. These 33 men were then further evaluated by a each man to follow a diet that furnished 25 to 30 kcal per kilogram.
medical-history taking, physical examination, differential blood The distribution of kilocalories among protein, carbohydrate, and fat count, urinalysis, blood-chemistry tests, chest radiography, and elec- was approximately 15 percent, 50 percent, and 35 percent, respec- trocardiography. Twenty-six subjects (1 black and 25 white) met all tively. At each scheduled visit shown in Table 1, the dietitian analyzed the entry criteria and were enrolled in the 12-month protocol sum- each man’s diet on the basis of a 24-hour dietary recall and instructed the subjects again about the standard diet. The men were told notto alter their lifestyles (including their use of tobacco or alcohol and Study Periods
their level of physical activity) during the 12-month study period.
The study protocol was carried out with the informed consent of The men were seen at regular intervals and tested as shown in Ta- each subject and with the approval of the human-research commit- ble 1 during the first week of the first, third, and sixth months of the tees of the Medical College of Wisconsin, the Chicago Medical base-line period. Five men dropped out of the study during these six School, and the Veterans Affairs Medical Centers in North Chicago months (four for personal reasons and one because carcinoma of the At the beginning of the seventh month, the 21 men who had Statistical Analysis
completed the base-line period were randomly assigned to group 1(growth hormone group) or group 2 (control group) in a ratio of 3 to The methods used to measure each response variable and the lo- 2. The randomization table was generated by a computer program cations where the tests were performed are described in Table 1.
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Copyright 1990 Massachusetts Medical Society. All rights reserved.
EFFECTS OF HUMAN GROWTH HORMONE IN MEN — RUDMAN ET AL.
Table 2. Clinical Characteristics of the Study Subjects.
were significantly higher (P<0.05 by matched-pair t-test) at the end of the experimental period than at theend of the base-line period (127.2±5.2 vs. 119.1±3.6 mm Hg and 5.8±0.2 vs. 5.4±0.2 mmol per liter, re-spectively).
Plasma IGF-I Concentration
In group 1, the mean plasma IGF-I concentration ranged from 200 to 250 U per liter throughout the base-line period (Table 3). Within one month after the administration of growth hormone had been initiated, the mean IGF-I level rose to 830 U per liter (P<0.05), and it remained near this value for the next five months. Eight of the 12 men in group 1 required no adjustment in their initial dose of growth hormone.
Two required an upward adjustment of 25 percent, and two required a downward adjustment of 25 per-cent. The mean plasma IGF-I concentration in group *Defined as a history of myocardial infarction or electrocardiographic abnormality ascribed 2 remained in the range of 180 to 300 U per literthroughout the base-line and treatment periods.
Lean Body Mass, Adipose-Tissue Mass, Skin Thickness,
The interassay coefficients of variation for the response variables Bone Density, and Mandibular-Height Ratio
were as follows: plasma IGF-I, 7.2 percent; lean body mass, 3.6 per-cent; adipose-tissue mass, 6.9 percent; skin thickness, 5.4 percent; Table 4 shows the mean values for the other re- and bone density, 2.3 percent (average of nine measured sites).
sponse variables at the end of the base-line period (6 P values based on two-tailed, matched-pair t-tests were calculat- months) and the end of the treatment period (12 ed for the comparisons between the 6-month and 12-month valuesin group 1 and group 2. In addition, for each response variable the months). There was no significant change in weight in 6-month value was subtracted from the 12-month value to repre- either group. In group 1, several response variables sent the change in each subject. P values based on two-tailed, un- had changed significantly after 12 months. Lean body equal-variance, independent-sample t-tests were then calculated mass and the average density of the lumbar vertebrae for the comparison of the changes in response variables between increased by 8.8 percent (P<0.0005) and 1.6 percent (P<0.04), respectively, and adipose-tissue mass de- creased by 14.4 percent (P<0.005). The sum of skinthicknesses at four sites increased 7.1 percent (P = Clinical Observations
0.07). The small average change in lumbar vertebral All the men remained healthy, and none had any bone density (only 0.02 g per square centimeter) was changes in the results of differential blood count, uri- statistically significant because of very little variability nalysis, blood-chemistry profile, chest radiography, in individual results. The bone density of the radius electrocardiography, or echocardiography during the and proximal femur and the ratio of the height of the 12-month protocol. Specifically, none had edema, fast- alveolar ridge to total mandibular height did not ing hyperglycemia (>6.6 mmol of glucose per liter), change significantly. In group 2 none of these variables an increase in blood pressure to more than 160/90 changed significantly. The change in the lean body mm Hg, ventricular hypertrophy, or a local reaction to mass was significantly greater in group 1 than in human growth hormone, nor did their serum cholester- group 2 (P<0.018), but the differences in changes in ol or triglyceride concentrations change significantly. In skin thickness and adipose-tissue mass between group 1, however, both the mean (±SE) systolic blood groups did not reach statistical significance in this pressure and fasting plasma glucose concentration small series (P = 0.10 and 0.13, respectively).
Table 3. Effect of the Administration of Human Growth Hormone on Plasma IGF-I Concentrations in Healthy Older Men.* †P<0.05 for the comparison between groups.
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Copyright 1990 Massachusetts Medical Society. All rights reserved.
Table 4. Effect of the Administration of Human Growth Hormone on Weight, Lean Body Mass, Adipose-Tissue Mass, Skin Thickness, and Bone Density in Healthy were raised to the normal range foryoung adult men by the dose of people. That ‘‘replacement’’ rather *Plus–minus values are means ±SD.
†P values are for the change from base line, by matched-pair t-test.
‡The difference in changes (12-month value minus 6-month value) is the average change in group 1 minus the average change in group 2. Values in parentheses are 95 percent confidence intervals, calculated by independent-sample, unequal-variance t-tests.
not impaired, and the decline inplasma IGF-I concentrations in suchmen results from growth hormonedeficiency rather than growth hor- DISCUSSION
mone resistance. The increase in plasma IGF-I levels The 21 men studied were representative of the ap- that occurs when growth hormone is administered to proximately one third of all men 60 to 80 years old who children with growth hormone deficiency reflects not have plasma IGF-I concentrations of less than 350 U only augmented hepatic production of IGF-I, but also per liter (as compared with a range of 500 to 1500 U per increased production of one of the binding proteins liter in healthy men 20 to 40 years old).4 Our findings that transport IGF-I.26 The extent to which the pro- cannot be generalized to the approximately two thirds duction of IGF-I binding protein is increased by the of all men over 60 who have plasma IGF-I concentra- administration of growth hormone has not yet been tions of more than 350 U per liter or to women of a similar age. Furthermore, our entry criteria focused At the beginning of our study, adverse reactions to the study on an overtly healthy subgroup of older men.
human growth hormone were thought to be unlikely In the absence of obesity,4 below-normal weight,20 because physiologic doses were being used. Further- or liver disease,21 a plasma IGF-I concentration of less more, similar or larger doses have not caused undes- than 350 U per liter in older men generally signifies ired reactions in children or young adults.10-14,25 Never- that they secrete very little growth hormone.4 To verify theless, it remained possible that this dose, when this explanation for the low plasma IGF-I concentration given for six months to older subjects, might cause in these men, it would be necessary to measure serum some manifestation of hypersomatotropism, such as growth hormone levels at frequent intervals for 24 edema, hypertension, diabetes, or cardiomegaly.27-29 hours or to determine the 24-hour urinary excretion of Although none of these conditions developed, there growth hormone. We did not do this, but Ho et al. found were small increases in the mean systolic blood pres- that the 24-hour integrated serum growth hormone lev- sure and fasting plasma glucose concentration of the el was markedly lower in the men over 55 than in men group of men who received growth hormone.
18 to 33 years old.22 An alternative explanation for a low The magnitude of the increases in lean body mass plasma IGF-I concentration is decreased production of and the decreases in adipose-tissue mass (8.8 and –14.2 plasma IGF-I binding proteins. Most of the IGF-I plas- percent above and below base line, respectively) in the ma is bound to these proteins, but their concentrations aging men who received human growth hormone for vary little in healthy people who eat a normal diet.
six months was similar to the magnitude of these re- Downloaded from www.nejm.org on December 01, 2003.
Copyright 1990 Massachusetts Medical Society. All rights reserved.
EFFECTS OF HUMAN GROWTH HORMONE IN MEN — RUDMAN ET AL.
sponses in children8,9 and young adults10-13 treated questions are answered can the possible benefits of hu- with similar or lower doses for three to six months, a man growth hormone in the elderly be explored. Since comparison that provides further evidence that tissue atrophy of muscle and skin contributes to the frailty of responsiveness to growth hormone and IGF-I is not al- older people, the potential benefits of growth hormone tered in older men. Until now, the evidence for such a merit continuing attention and investigation.
conclusion came only from short-term nitrogen-bal-ance experiments.14,30-32 We are indebted to Dr. Ruth Hartmann, Milwaukee Veterans Af- Salomon et al. reported that the administration of fairs Medical Center, for assistance in the preparation of this report.
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10. Crist DM, Peake GT, Mackinnon LT, Sibbitt WL Jr, Kraner JC. Exogenous distribution of adipose tissue from abdominal to pe- growth hormone treatment alters body composition and increases natural ripheral areas.31 It is not known, however, whether the killer cell activity in women with impaired endogenous growth hormone se-cretion. Metabolism 1987; 36:1115-7.
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12. Crist DM, Peake GT, Egan PA, Waters DL. Body composition response to exogenous GH during training in highly conditioned adults. J Appl Physiol Biosynthetic human growth hormone had no detect- able effect on the bone density of the radius or proxi- 13. Salomon F, Cuneo RC, Hesp R, Sönksen PH. The effects of treatment with mal femur in the aging men, but it increased the den- recombinant human growth hormone on body composition and metabolismin adults with growth hormone deficiency. N Engl J Med 1989; 321:1797- sity of the lumbar vertebrae by about 1.6 percent.
Although the decrease in bone density with advancing 14. Jones AJS, O’Connor JV. Chemical characterization of methionyl human growth hormone. In: Hormone drugs: proceedings of the FDA–USP Work- age in men may be due in part to diminished secretion shop on Drug and Reference Standards for Insulins, Somatropins, and Thy- of growth hormone,1,33 longer periods of administration roid-axis Hormones, Bethesda, Maryland, May 19–21, 1982. Rockville, of human growth hormone will be required before a fi- Md.: United States. Pharmacopeial Convention, 1982:335-51.
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17. Nagraj HS, Gergans GA, Mattson DE, Rudman IW, Rudman D. Osteopenia The findings in this study are consistent with the hy- in the men of a Veterans Administration nursing home. Am J Clin Nutr 1990; pothesis that the decrease in lean body mass, the in- 18. Goldberg AF, Mattson DE, Rudman D. The relationship of growth hormone crease in adipose-tissue mass, and the thinning of the to alveolar ridge atrophy in an older male nursing home population. Spec skin that occur in older men are caused in part by re- duced activity of the growth hormone–IGF-I axis, and 19. Furlanetto RW, Underwood LE, Van Wyk JJ, D’Ercole AJ. Estimation of so- matomedin-C levels in normals and patients with pituitary disease by radio- can be restored in part by the administration of human immunoassay. J Clin Invest 1977; 60:648-57.
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22. Ho KY, Evans WS, Blizzard RM, et al. Effects of sex and age on the 24– questions that remain to be addressed are the follow- hour profile of growth hormone secretion in man: importance of endogenous ing: What will be the benefits and what will be the na- estradiol concentrations. J Clin Endocrinol Metab 1987; 64:51-8.
ture and frequency of any adverse effects when larger 23. Thompson RG, Rodriguez A, Kowarski A, Blizzard RM. Growth hormone: metabolic clearance rates, integrated concentrations, and production rates in numbers of elderly subjects and other doses of human normal adults and the effect of prednisone. J Clin Invest 1972; 51:3193-9.
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25. Gunnarsson R, Wilton P. Clinical experience with genotropin worldwide: an functional capacities change as well? Only when such update March 1987. Acta Paediatr Scand Suppl 1987; 337:147-52.
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26. Hintz RL. Plasma forms of somatomedin and the binding protein phenome- 31. Rosenbaum M, Gertner JM, Leibel RL. Effects of systemic growth hormone non. Clin Endocrinol Metab 1984; 13:31-42.
(GH) administration on regional adipose tissue distribution and metabolism 27. Ikkos D, Ljunggren H, Luft R. The relation between extracellular and intra- in GH-deficient children. J Clin Endocrinol Metab 1989; 69:1274-81.
cellular water in acromegaly. Acta Endocrinol 1956; 21:211-25.
32. Marcus R, Butterfield G, Holloway L, et al. Effects of short term adminis- 28. Penney DG, Dunbar JC Jr, Baylerian MS. Cardiomegaly and haemodynam- tration of recombinant human growth hormone to elderly people. J Clin En- ics in rats with a transplantable growth hormone-secreting tumour. Cardio- 33. Kelly PJ, Eisman JA, Stuart MC, Pocock NA, Sambrook PN, Gwinn TH.
29. Rizza RA, Mandarino LJ, Gerich JE. Effects of growth hormone on insulin Somatomedin-C, physical fitness, and bone density. J Clin Endocrinol Metab action in man: mechanisms of insulin resistance, impaired suppression of glucose production, and impaired stimulation of glucose utilization. Diabe- 34. Novak LP. Aging, total body potassium, fat-free mass, and cell mass in males and females between ages 18 and 85 years. J Gerontol 1972; 27:438- 30. Binnerts A, Wilson JH, Lamberts SW. The effects of human growth hormone administration in elderly adults with recent weight loss. J Clin Endocrinol 35. Shuster S, Black MM, McVitie E. The influence of age and sex on skin thickness, skin collagen and density. Br J Dermatol 1975; 93:639-43.
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