1131
13. Pulsinelli WA, Levy DE, Sigsbee B, et al. Increased damage after stroke in patients with hyperglycemia with or without established diabetes mellitus. Am J Med 1983; 74: 540-44. 14. Ginberg MD. Glycolytic metabolism in brain ischemia. In: Weinstein PR, Faden AI, eds. Protection of the brain from ischemia. Baltimore: Williams & Wilkins, 1990: 21-36. 15. Voll CL, Whishaw IQ, Auer RN. Post-ischemic insulin reduces spatial learning deficit following transient forebrain ischemia in rats. Stroke 1989; 20: 646-51. 16. Strong AJ, Fairchild JE, Monteiro E, et al. Insulin protects cognitive function in experimental stroke. J Neurol Neurosurg Psychiatry 1990;
53: 847-53. 17. Britton M, Carlsson A, de Faire U. Blood pressure course in patients with acute stroke and matched controls. Stroke 1986; 17: 861-64. 18. Italian Acute Stroke Study Group. Haemodilution in acute stroke: results of the Italian haemodilution trial. Lancet 1988; i: 318-21. 19. Bayer AJ, Palhy MS, Newcombe R. Double blind randomised trial of intravenous glycerol in acute stroke. Lancet 1987; i: 405-08. 20. Norris JW, Hachinski VC. High dose steroid treatment in cerebral infarction. Br Med J 1986; 292: 21-23. 21. Sapolsky RM, Pulsinelli WA. Glucocorticoids potentiate ischemic injury to neurons: therapeutic implications. Science 1985; 229: 1397-1400.
Growth hormone therapy in elderly
people (GH) release in childhood is necessary for linear growth; the hormone continues to Growth hormone
be secreted in adult life but for what purpose is unclear. GH secretion is pulsatile but decreases with age-integrated GH levels are 30% lower after the age of 55 than they are during the third decade. This decline in GH is matched by a decline in circulating levels of insulin-like growth factor 1 (IGF-1), which mediates many of the actions of GH.1 Is this decline in GH and IGF-1 important in human ageing? Ageing is associated with a decrease in metabolic rate and changes in body composition--eg, decrease in muscle mass, relative increase in adipose tissue, and decrease in skin thickness. Exercise performance declines. GH deficiency in early life leads to some of these changes.2 Thus lean body mass and skin thickness are decreased and adipose tissue mass is increased in GH-deficient children; body composition returns towards normal with GH
therapy. Studies of GH deficiency have
replacement in adults with GH provided information on the physiological role of the hormone once linear growth is complete. GH was replaced by daily subcutaneous injection at doses of 0-07 units/kg body weight or 2 units/m2 in patients with either isolated GH deficiency or GH deficiency as one of the components of hypopituitarism.-"-6 As in GH-treated children, therapy in adults resulted in an increase in lean body mass and a decrease in adipose tissue mass. Total body weight was unchanged. Waist: hip ratio decreased. Muscle volume assessed by computed tomography increased, isometric muscle strength improved, and exercise capacity on a cycle ergometer increased. Resting metabolic rate rose, as would be expected from the increase in muscle
mass. Bone mineral has been to increase after GH density reported for 12 months in one study,although no therapy significant change was observed after 6 months’ treatment in another.8
These beneficial effects of GH in GH-deficient adults and the fact that secretion of the hormone declines with normal ageing aroused hopes that GH supplementation might reverse some of the effects of old age. Short-term experiments in elderly patients showed that GH led to a positive nitrogen balance and an increase in circulating concentrations of osteocalcin, a marker of bone synthesis. In the first major trial of supplementation in normal elderly people,1O GH at a daily dose of 0-03 mg/kg subcutaneously three times weekly for 6 months to individuals with initially low IGF-1 concentrations resulted in circulating IGF-1 values in the young adult normal range. Lean body mass increased by 9%, adipose tissue decreased by 14%, and there was a small (7%) though statistically insignificant increase in skin thickness. Bone density of the lumbar vertebrae increased by 1-6%. These effects of GH supplementation will undoubtedly stimulate more studies of its role in elderly people. Nevertheless, it is as well to remember that low GH levels are a feature of and not the cause of human ageing. Young adults with GH deficiency are not the same as old people. Complications of GH supplementation in adult life remain to be clarified. Short-term side-effects of existing replacement regimens in GH-deficient adults include ankle oedema, arthralgia, hypertension, and carpal tunnel syndrome. Lower doses or a slow increase in dosage may help to lessen these complications. The thrice weekly regimen used in normal elderly people seemed to be free of short-term side-effects, but data on long-term effects will require years to accrue. The relation between GH status and vascular disease is complex. Long-term hypopituitarism is associated with an increased risk of death from premature vascular disease, to which GH deficiency may be a contributory factor.11 Increased serum triglyceride and cholesterol and an increase in waist: hip ratio, which occur in GH deficiency, are risk factors for vascular disease. GH replacement may therefore be beneficial and serum cholesterol decreases with GH replacement in deficient adults. However, over-treatment may be harmful. Acromegaly is associated with hypertension, cardiomyopathy, and a four-fold increased risk of premature death from vascular disease."," For normal elderly people, optimum treatment regimens and doses and means of monitoring therapy (total circulating IGF-1 concentrations are far from perfect), and even the best injection sites are unknown.
The possibility that GH treatment may increase the risk of cancer also needs long-term investigation. IGF-1 has mitogenic properties in addition to its stimulatory effects on growth. Patients with hypopituitarism have a lower than average risk of death from cancer (although deaths overall are raised), whereas acromegaly in both men and women is associated with an increased risk of malignant
1132
in various sites.12,13 Concerns exist about an increased prevalence of leukaemia in GH-treated children.14 For normal elderly people, it is unknown whether GH supplementation with the existing regimen carries any risk. GH supplementation to prevent or delay some of the manifestations of ageing raises ethical issues. If, after extensive clinical trials, the beneficial actions of GH are shown to predominate, the prolongation of useful, active life seems a legitimate aim of medical care. There are financial implications-the annual cost of the thrice weekly protocol in the UK is about
tumours
L6700 ($USll 000). 1. Florini JR, Prinz PN, Vitiello
MV, Hintz RL. Somatomedin-C levels in
healthy young and old men: relationship to peak and 24-hour integrated levels of growth hormone. J Gerontol 1985; 40: 2-7. 2. Goodman HG, Grumbach MM, Kaplan SL. Growth and growth hormone. II. Comparison of isolated growth hormone deficiency and multiple pituitary hormone deficiencies in 35 patients with idiopathic hypopituitary dwarfism. N Engl J Med 1968; 278: 57-68. 3. Jørgensen JOL, Thuesen L, Ingemann-Hansen T, et al. Beneficial effects of growth hormone treatment in GH-deficient adults. Lancet 1989; i: 1221-25. 4. Salomon F, Cuneo RC, Hesp R, Sönksen PH. The effects of treatment with recombinant human growth hormone on body composition and metabolism in adults with growth hormone deficiency. N Engl J Med 1989; 321: 1797-803. 5. Cuneo RC, Salomon F, Wiles CM, Hesp R, Sonksen PH. Growth hormone treatment in growth hormone-deficient adults. II. Effects on exercise performance. J Appl Physiol 1991; 70: 695-700. 6. Cuneo RC, Salomon F, Wiles CM, Hesp R, Sönksen PH. Growth hormone treatment in growth hormone-deficient adults. I. Effects on muscle mass and strength. J Appl Physiol 1991; 70: 688-94. 7. Thoren M, Degerblad M, Sääf M, Ringertz H, Sjöberg HE. Growth hormone treatment improves bone mineral density in adults with hypopituitarism. In: Ring EFJ, ed. Current research in osteoporosis and bone mineral measurement. London: British Institute of Radiology, 1990: 92. 8. Whitehead HM, McIlrath E, Atkinson AB, Kennedy AL, Hadden DR. Growth hormone treatment of adults with growth hormone deficiency: effect on protein, fat and bone metabolism. Proceedings of 72nd annual meeting, The Endocrine Society, Atlanta, USA, 1990: 293 (abstr
1074).
R, Butterfield G, Holloway L, et al. Effects of short term administration of recombinant human growth hormone to elderly people. J Clin Endocrinol Metab 1990; 70: 519-27. 10. Rudman D, Feller AG, Nagraj HS, et al. Effects of human growth hormone in men over 60 years old. N Engl J Med 1990; 323: 1-5. 11. Rosen T, Bengtsson B-A. Premature mortality due to cardiovascular 9. Marcus
disease in hypopituitarism. Lancet 1990; 336: 285-88. 12. Alexander L, Appleton D, Hall R, Ross WM, Wilkinson R. Epidemiology of acromegaly in the Newcastle region. Clin Endocrinol 1980; 12: 71-79. 13. Bengtsson B-A, Edén S, Ernest I, Odén A, Sjögren B. Epidemiology and long-term survival in acromegaly. Acta Med Scand 1988; 223: 327-35. 14. Stahnke N, Zeisel HJ. Growth hormone therapy and leukaemia. Eur J Pediatr 1989; 148: 591-96.
Ozone depletion quickens Last month’sannouncement by the U S space agency, NASA,1 that ozone depletion is occurring globally and is progressing faster than previously realised has once again focused attention on this important threat to human health and planetary ecosystems.2,3 Much has happened since a 1989 Lancet editorial4 in which the role of chlorofluorocarbons (CFCs) in depleting stratospheric ozone was mentioned, and not all of it is bad. In June last year the main producers and consumers of ozone-depleting
chemicals met in London to agree phase 2 of the Montreal Protocol, which commits signatory nations to a phase-out of CFCs, halons, and carbon tetrachloride by the year 2000. Unfortunately, the phase-out date for methylchlorofonn has been put back to 2005, there is a 10-year derogation for non-industrialised nations, and other ozonedepleting chemicals are not included in the Protocol. The new data from NASA will undoubtedly reopen this debate-the US Environmental Protection Agency has already called for these clauses to be
renegotiated.5 The atmospheric residence times of CFCs are so long that action taken now will not be reflected in falling levels of atmospheric chlorine for decades.6 Under the Protocol, chlorine levels will rise by the year 2000 to almost 5 parts per billion (ppb), and will not fall back to their current
levels until the year 2050. Natural levels of chlorine are around 0-6 ppb, the ozone hole over Antarctica appeared at concentrations between 1 -5 and 2 ppb, and existing levels are just below 3 ppb. To allow chlorine to rise from 3 to 5 ppb is a dangerous enterprise that might have catastrophic consequences for the stability of the stratosphere and the integrity of global ecosystems. The chemical industry has been promoting the benefits of chemical substitutes such as hydrochlorofluorocarbons (HCFCs) and
hydrofluorocarbons.4 Although hydrofluorocarbons are ozone-friendly, HCFCs have some ozonedepleting potential. Moreover, both classes of considerable contribution to global warming.4,7-9 Germany has already announced its intention to phase out HCFC 22 by the year 2000, and the chemical company ICI is abandoning its plans to produce HCFC 123. Meanwhile, both Du Pont and ICI are proceeding with plans to produce hydrofluorocarbon 134A as a substitute for the fully halogenated CFCs in air-conditioning systems, despite the fact that this compound is not very efficient as a refrigerant and has a global warming potential 2800 times greater than an equivalent weight of carbon dioxide. 10 Ultimately all of these substitutes are doomed to extinction. If they are not caught by phase 3 of the Montreal Protocol, they will be laid to rest by any international convention on global warming. Meanwhile, the Protocol needs to be strengthened by bringing forward the phase-out date to 1995, by including methylchloroform, and by abandoning all but the essential uses of halons immediately. In the UK, attempts to monitor ultraviolet flux at ground level have been pitiful. Ideally one needs a network of high-resolution spectral measurements at sites adjacent to and remote from heavily populated
chemical could make
There is
a
such device--an Optronics 742 spectroradiometer-which monitors UV flux at 2 nm intervals throughout the UVB range (280-320 nm). This machine has been functioning at Reading in Berkshire for the past 2 years, but it is too early to areas.
one
13. Pulsinelli WA, Levy DE, Sigsbee B, et al. Increased damage after stroke in patients with hyperglycemia with or without established diabetes mellitus. Am J Med 1983; 74: 540-44. 14. Ginberg MD. Glycolytic metabolism in brain ischemia. In: Weinstein PR, Faden AI, eds. Protection of the brain from ischemia. Baltimore: Williams & Wilkins, 1990: 21-36. 15. Voll CL, Whishaw IQ, Auer RN. Post-ischemic insulin reduces spatial learning deficit following transient forebrain ischemia in rats. Stroke 1989; 20: 646-51. 16. Strong AJ, Fairchild JE, Monteiro E, et al. Insulin protects cognitive function in experimental stroke. J Neurol Neurosurg Psychiatry 1990;
53: 847-53. 17. Britton M, Carlsson A, de Faire U. Blood pressure course in patients with acute stroke and matched controls. Stroke 1986; 17: 861-64. 18. Italian Acute Stroke Study Group. Haemodilution in acute stroke: results of the Italian haemodilution trial. Lancet 1988; i: 318-21. 19. Bayer AJ, Palhy MS, Newcombe R. Double blind randomised trial of intravenous glycerol in acute stroke. Lancet 1987; i: 405-08. 20. Norris JW, Hachinski VC. High dose steroid treatment in cerebral infarction. Br Med J 1986; 292: 21-23. 21. Sapolsky RM, Pulsinelli WA. Glucocorticoids potentiate ischemic injury to neurons: therapeutic implications. Science 1985; 229: 1397-1400.
Growth hormone therapy in elderly
people (GH) release in childhood is necessary for linear growth; the hormone continues to Growth hormone
be secreted in adult life but for what purpose is unclear. GH secretion is pulsatile but decreases with age-integrated GH levels are 30% lower after the age of 55 than they are during the third decade. This decline in GH is matched by a decline in circulating levels of insulin-like growth factor 1 (IGF-1), which mediates many of the actions of GH.1 Is this decline in GH and IGF-1 important in human ageing? Ageing is associated with a decrease in metabolic rate and changes in body composition--eg, decrease in muscle mass, relative increase in adipose tissue, and decrease in skin thickness. Exercise performance declines. GH deficiency in early life leads to some of these changes.2 Thus lean body mass and skin thickness are decreased and adipose tissue mass is increased in GH-deficient children; body composition returns towards normal with GH
therapy. Studies of GH deficiency have
replacement in adults with GH provided information on the physiological role of the hormone once linear growth is complete. GH was replaced by daily subcutaneous injection at doses of 0-07 units/kg body weight or 2 units/m2 in patients with either isolated GH deficiency or GH deficiency as one of the components of hypopituitarism.-"-6 As in GH-treated children, therapy in adults resulted in an increase in lean body mass and a decrease in adipose tissue mass. Total body weight was unchanged. Waist: hip ratio decreased. Muscle volume assessed by computed tomography increased, isometric muscle strength improved, and exercise capacity on a cycle ergometer increased. Resting metabolic rate rose, as would be expected from the increase in muscle
mass. Bone mineral has been to increase after GH density reported for 12 months in one study,although no therapy significant change was observed after 6 months’ treatment in another.8
These beneficial effects of GH in GH-deficient adults and the fact that secretion of the hormone declines with normal ageing aroused hopes that GH supplementation might reverse some of the effects of old age. Short-term experiments in elderly patients showed that GH led to a positive nitrogen balance and an increase in circulating concentrations of osteocalcin, a marker of bone synthesis. In the first major trial of supplementation in normal elderly people,1O GH at a daily dose of 0-03 mg/kg subcutaneously three times weekly for 6 months to individuals with initially low IGF-1 concentrations resulted in circulating IGF-1 values in the young adult normal range. Lean body mass increased by 9%, adipose tissue decreased by 14%, and there was a small (7%) though statistically insignificant increase in skin thickness. Bone density of the lumbar vertebrae increased by 1-6%. These effects of GH supplementation will undoubtedly stimulate more studies of its role in elderly people. Nevertheless, it is as well to remember that low GH levels are a feature of and not the cause of human ageing. Young adults with GH deficiency are not the same as old people. Complications of GH supplementation in adult life remain to be clarified. Short-term side-effects of existing replacement regimens in GH-deficient adults include ankle oedema, arthralgia, hypertension, and carpal tunnel syndrome. Lower doses or a slow increase in dosage may help to lessen these complications. The thrice weekly regimen used in normal elderly people seemed to be free of short-term side-effects, but data on long-term effects will require years to accrue. The relation between GH status and vascular disease is complex. Long-term hypopituitarism is associated with an increased risk of death from premature vascular disease, to which GH deficiency may be a contributory factor.11 Increased serum triglyceride and cholesterol and an increase in waist: hip ratio, which occur in GH deficiency, are risk factors for vascular disease. GH replacement may therefore be beneficial and serum cholesterol decreases with GH replacement in deficient adults. However, over-treatment may be harmful. Acromegaly is associated with hypertension, cardiomyopathy, and a four-fold increased risk of premature death from vascular disease."," For normal elderly people, optimum treatment regimens and doses and means of monitoring therapy (total circulating IGF-1 concentrations are far from perfect), and even the best injection sites are unknown.
The possibility that GH treatment may increase the risk of cancer also needs long-term investigation. IGF-1 has mitogenic properties in addition to its stimulatory effects on growth. Patients with hypopituitarism have a lower than average risk of death from cancer (although deaths overall are raised), whereas acromegaly in both men and women is associated with an increased risk of malignant
1132
in various sites.12,13 Concerns exist about an increased prevalence of leukaemia in GH-treated children.14 For normal elderly people, it is unknown whether GH supplementation with the existing regimen carries any risk. GH supplementation to prevent or delay some of the manifestations of ageing raises ethical issues. If, after extensive clinical trials, the beneficial actions of GH are shown to predominate, the prolongation of useful, active life seems a legitimate aim of medical care. There are financial implications-the annual cost of the thrice weekly protocol in the UK is about
tumours
L6700 ($USll 000). 1. Florini JR, Prinz PN, Vitiello
MV, Hintz RL. Somatomedin-C levels in
healthy young and old men: relationship to peak and 24-hour integrated levels of growth hormone. J Gerontol 1985; 40: 2-7. 2. Goodman HG, Grumbach MM, Kaplan SL. Growth and growth hormone. II. Comparison of isolated growth hormone deficiency and multiple pituitary hormone deficiencies in 35 patients with idiopathic hypopituitary dwarfism. N Engl J Med 1968; 278: 57-68. 3. Jørgensen JOL, Thuesen L, Ingemann-Hansen T, et al. Beneficial effects of growth hormone treatment in GH-deficient adults. Lancet 1989; i: 1221-25. 4. Salomon F, Cuneo RC, Hesp R, Sönksen PH. The effects of treatment with recombinant human growth hormone on body composition and metabolism in adults with growth hormone deficiency. N Engl J Med 1989; 321: 1797-803. 5. Cuneo RC, Salomon F, Wiles CM, Hesp R, Sonksen PH. Growth hormone treatment in growth hormone-deficient adults. II. Effects on exercise performance. J Appl Physiol 1991; 70: 695-700. 6. Cuneo RC, Salomon F, Wiles CM, Hesp R, Sönksen PH. Growth hormone treatment in growth hormone-deficient adults. I. Effects on muscle mass and strength. J Appl Physiol 1991; 70: 688-94. 7. Thoren M, Degerblad M, Sääf M, Ringertz H, Sjöberg HE. Growth hormone treatment improves bone mineral density in adults with hypopituitarism. In: Ring EFJ, ed. Current research in osteoporosis and bone mineral measurement. London: British Institute of Radiology, 1990: 92. 8. Whitehead HM, McIlrath E, Atkinson AB, Kennedy AL, Hadden DR. Growth hormone treatment of adults with growth hormone deficiency: effect on protein, fat and bone metabolism. Proceedings of 72nd annual meeting, The Endocrine Society, Atlanta, USA, 1990: 293 (abstr
1074).
R, Butterfield G, Holloway L, et al. Effects of short term administration of recombinant human growth hormone to elderly people. J Clin Endocrinol Metab 1990; 70: 519-27. 10. Rudman D, Feller AG, Nagraj HS, et al. Effects of human growth hormone in men over 60 years old. N Engl J Med 1990; 323: 1-5. 11. Rosen T, Bengtsson B-A. Premature mortality due to cardiovascular 9. Marcus
disease in hypopituitarism. Lancet 1990; 336: 285-88. 12. Alexander L, Appleton D, Hall R, Ross WM, Wilkinson R. Epidemiology of acromegaly in the Newcastle region. Clin Endocrinol 1980; 12: 71-79. 13. Bengtsson B-A, Edén S, Ernest I, Odén A, Sjögren B. Epidemiology and long-term survival in acromegaly. Acta Med Scand 1988; 223: 327-35. 14. Stahnke N, Zeisel HJ. Growth hormone therapy and leukaemia. Eur J Pediatr 1989; 148: 591-96.
Ozone depletion quickens Last month’sannouncement by the U S space agency, NASA,1 that ozone depletion is occurring globally and is progressing faster than previously realised has once again focused attention on this important threat to human health and planetary ecosystems.2,3 Much has happened since a 1989 Lancet editorial4 in which the role of chlorofluorocarbons (CFCs) in depleting stratospheric ozone was mentioned, and not all of it is bad. In June last year the main producers and consumers of ozone-depleting
chemicals met in London to agree phase 2 of the Montreal Protocol, which commits signatory nations to a phase-out of CFCs, halons, and carbon tetrachloride by the year 2000. Unfortunately, the phase-out date for methylchlorofonn has been put back to 2005, there is a 10-year derogation for non-industrialised nations, and other ozonedepleting chemicals are not included in the Protocol. The new data from NASA will undoubtedly reopen this debate-the US Environmental Protection Agency has already called for these clauses to be
renegotiated.5 The atmospheric residence times of CFCs are so long that action taken now will not be reflected in falling levels of atmospheric chlorine for decades.6 Under the Protocol, chlorine levels will rise by the year 2000 to almost 5 parts per billion (ppb), and will not fall back to their current
levels until the year 2050. Natural levels of chlorine are around 0-6 ppb, the ozone hole over Antarctica appeared at concentrations between 1 -5 and 2 ppb, and existing levels are just below 3 ppb. To allow chlorine to rise from 3 to 5 ppb is a dangerous enterprise that might have catastrophic consequences for the stability of the stratosphere and the integrity of global ecosystems. The chemical industry has been promoting the benefits of chemical substitutes such as hydrochlorofluorocarbons (HCFCs) and
hydrofluorocarbons.4 Although hydrofluorocarbons are ozone-friendly, HCFCs have some ozonedepleting potential. Moreover, both classes of considerable contribution to global warming.4,7-9 Germany has already announced its intention to phase out HCFC 22 by the year 2000, and the chemical company ICI is abandoning its plans to produce HCFC 123. Meanwhile, both Du Pont and ICI are proceeding with plans to produce hydrofluorocarbon 134A as a substitute for the fully halogenated CFCs in air-conditioning systems, despite the fact that this compound is not very efficient as a refrigerant and has a global warming potential 2800 times greater than an equivalent weight of carbon dioxide. 10 Ultimately all of these substitutes are doomed to extinction. If they are not caught by phase 3 of the Montreal Protocol, they will be laid to rest by any international convention on global warming. Meanwhile, the Protocol needs to be strengthened by bringing forward the phase-out date to 1995, by including methylchloroform, and by abandoning all but the essential uses of halons immediately. In the UK, attempts to monitor ultraviolet flux at ground level have been pitiful. Ideally one needs a network of high-resolution spectral measurements at sites adjacent to and remote from heavily populated
chemical could make
There is
a
such device--an Optronics 742 spectroradiometer-which monitors UV flux at 2 nm intervals throughout the UVB range (280-320 nm). This machine has been functioning at Reading in Berkshire for the past 2 years, but it is too early to areas.
one
