- Email: [email protected]
Premature mortality and hypopituitarism
CORRESPONDENCE
this hypothesis suggest that there would be only a 15% chance of observing a significant effect with this study design. We agree with Tomlinson and colleagues that previous studies have limitations that prevent clear conclusions about whether GH deficiency and increased mortality are linked. Unfortunately, their report has equal limitations and the question clearly remains open. *J P Monson, G M Besser Department of Endocrinology, St Bartholomew’s Hospital, West Smithfield, London ECIA 7BE, UK 1
2
3
Tomlinson JW, Holden N, Hills RK, et al. Association between premature mortality and hypopituitarism. Lancet 2001; 357: 425–31. Rahim A, Toogood AA, Shalet SM. The assessment of growth hormone status in normal young adult males using a variety of provocative agents. Clin Endocrinol 1996; 45: 557–62. Toogood AA, Beardwell CG, Shalet SM. The severity of growth hormone deficiency in adults with pituitary disease is related to the degree of hypopituitarism. Clin Endocrinol 1994; 41: 511–16.
Sir—J W Tomlinson and colleagues1 conclude that specific endocrine-axis deficiency, with the exception of untreated gonadotropin deficiency, does not seem to increase risk of premature death. They suggest that an overwhelming assumption has emerged that GH replacement will reverse increased cardiovascular risk factors and reduce vascular mortality. They also state that evidence that GH deficiency contributes to the increased mortality of hypopituitarism is lacking. There may be, however, several issues to be argued before drawing this conclusion. First, accurate assessment of differences in mortality is difficult between GH-treated and non-treated patients, since the few patients had GH deficiency. Only 111 of 1014 were tested for GH secretory dynamics, and 98 had GH deficiency. Second, the association between premature mortality and GH deficiency and the influence of GH therapy on life expectancy should be established in similar groups of patients with idiopathic GH deficiency. The diverse underlying causes and treatments used in the management of hypopituitarism might increase mortality. Third, epidemiological studies have limitations for measurement of lipid profiles in patients with hypopituitarism, despite the excess mortality related to cardiovascular and cerebrovascular disease, which account for 45·9% of 181 recorded deaths. We have been prospectively assessing changes in body composition and
THE LANCET • Vol 357 • June 16, 2001
lipid profiles in children and young adults with idiopathic GH deficiency during and after GH treatment.2–4 Patients have lost a striking amount of body fat during GH therapy, with a steep increase after GH is stopped. The incidence of hypercholesterolaemia (total cholesterol, more than 5·17 mmol/L) before GH treatment, even in children with idiopathic GH deficiency, was much higher3 than that in the normal population.5 No patient, however, had hypercholesterolemia after 3 years’ GH treatment,3 which suggests that GH replacement therapy prevented the values from worsening. Total cholesterol and LDL cholesterol, defined as atherogenic cholesterol, decrease during GH therapy and increase after GH is stopped.3,4 Our results suggest beneficial effects of GH on arteriosclerotic risk factors even in children and young adults. Many studies have documented increased arteriosclerotic risk in adults with GH deficiency, as reflected in visceral obesity, hyperlipidaemia, intima-media thickness, increased frequency of atherosclerotic plaques in the carotid arteries, and vascular endothelial dysfunction. These abnormalities are improved during GH replacement therapy, as noted in many reports referenced by Tomlinson and colleagues. Studies of GH secretory dynamics have shown age-related alterations, with GH concentrations rising during puberty, peaking at late puberty, and subsequently declining into old age; GH is thus continuously secreted throughout life in normal individuals. Deficient hormones including GH should be replaced to maintain homoeostasis. In contrast to the opinion of Tomlinson and colleagues, long-term studies of the effects of GH withdrawal on lipid profiles and adiposity in young adults with GH deficiency who have completed height growth, and of the consequences of continuing GH therapy on life expectancy in idiopathic GH deficiency must be done. This work is supported by grants from the Clinical Research Foundation of Fukuoka Children’s Hospital and the Foundation for Growth Science
*H Kohno, R Kuromaru, N Ueyama, K Miyako *Department of Endocrinology and Metabolism, Fukuoka Children’s Hospital, 2-5-1 Tojin-machi, Chuo-ku, Fukuoka 810-0063, Japan; Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University; and Department of Pediatrics, School of Medicine, Fukuoka University (e-mail: [email protected]) 1
Tomlinson JW, Holden N, Hills RK, et al. Association between premature mortality and hypopituitarism. Lancet 2001; 357: 425–31.
2
3
4
5
Kohno H, Ueyama N, Yanai S, Ukaji K, Honda S. Beneficial effect of growth hormone on atherogenic risk in children with growth hormone deficiency. J Pediatr 1995; 126: 953–55. Kuromaru R, Kohno H, Ueyama N, Hassan HMS, Honda S, Hara T. Long-term prospective study of body composition and lipid profiles during and after growth hormone (GH) treatment in children with GH deficiency: gender-specific metabolic effects. J Clin Endocrinol Metab 1998; 83: 3890–96. Kohno H, Ueyama N, Honda S. Unfavourable impact of growth hormone (GH) discontinuation on body composition and cholesterol profiles after the completion of height growth in GH-deficient young adults. Diabetes Obesity Metab 1999; 1: 293–96. Fukushige J, Igarashi H, Ueda K, Akazawa K, Nose T. Serum cholesterol levels in school-aged Japanese children: the Hisayama study. Acta Paediatr Jpn 1996; 38: 22–27.
Authors’ reply Sir—Despite the comments of H Erfurth and colleagues, our study is prospective. Time of diagnosis is irrelevant since we assessed mortality only in the census period. We achieved nearly 100% follow-up, whereas retrospective studies might lose patients to clinic follow-up or because of death. Furthermore, patients’ data were compared with annual regional and national mortality data held centrally at the Office of National Statistics and we could accommodate changes in patterns of mortality nationally and in different regions. Our study was well powered to analyse the impact of several variables on mortality, including age at onset, sex, treatment method (surgery, radiotherapy), and underlying diagnosis. We also assessed the impact of pituitary hormonal deficiencies, and although a highly significant harmful effect of untreated gonadotrophin deficiency on mortality was reported, the ensuing correspondence relates almost exclusively to the potential impact of growth hormone (GH) deficiency. Debate continues on the diagnosis of GH deficiency in hypopituitary adults. We agree that the clonidine test1 is now redundant. Only 11 patients were assessed in this way. We used the latest results from pituitary-function tests (before January, 2000, or before death) for analysis and did tests annually on all non-deficient patients. However, when the study was started, the diagnosis and consequences of adult GH deficiency was unclear, which contributed to few patients being formally tested for GH reserve. We did not design the study to address the issue of whether or not GH deficiency is implicated in any excess mortality and, as H Kohno and colleagues state,
1973
this hypothesis suggest that there would be only a 15% chance of observing a significant effect with this study design. We agree with Tomlinson and colleagues that previous studies have limitations that prevent clear conclusions about whether GH deficiency and increased mortality are linked. Unfortunately, their report has equal limitations and the question clearly remains open. *J P Monson, G M Besser Department of Endocrinology, St Bartholomew’s Hospital, West Smithfield, London ECIA 7BE, UK 1
2
3
Tomlinson JW, Holden N, Hills RK, et al. Association between premature mortality and hypopituitarism. Lancet 2001; 357: 425–31. Rahim A, Toogood AA, Shalet SM. The assessment of growth hormone status in normal young adult males using a variety of provocative agents. Clin Endocrinol 1996; 45: 557–62. Toogood AA, Beardwell CG, Shalet SM. The severity of growth hormone deficiency in adults with pituitary disease is related to the degree of hypopituitarism. Clin Endocrinol 1994; 41: 511–16.
Sir—J W Tomlinson and colleagues1 conclude that specific endocrine-axis deficiency, with the exception of untreated gonadotropin deficiency, does not seem to increase risk of premature death. They suggest that an overwhelming assumption has emerged that GH replacement will reverse increased cardiovascular risk factors and reduce vascular mortality. They also state that evidence that GH deficiency contributes to the increased mortality of hypopituitarism is lacking. There may be, however, several issues to be argued before drawing this conclusion. First, accurate assessment of differences in mortality is difficult between GH-treated and non-treated patients, since the few patients had GH deficiency. Only 111 of 1014 were tested for GH secretory dynamics, and 98 had GH deficiency. Second, the association between premature mortality and GH deficiency and the influence of GH therapy on life expectancy should be established in similar groups of patients with idiopathic GH deficiency. The diverse underlying causes and treatments used in the management of hypopituitarism might increase mortality. Third, epidemiological studies have limitations for measurement of lipid profiles in patients with hypopituitarism, despite the excess mortality related to cardiovascular and cerebrovascular disease, which account for 45·9% of 181 recorded deaths. We have been prospectively assessing changes in body composition and
THE LANCET • Vol 357 • June 16, 2001
lipid profiles in children and young adults with idiopathic GH deficiency during and after GH treatment.2–4 Patients have lost a striking amount of body fat during GH therapy, with a steep increase after GH is stopped. The incidence of hypercholesterolaemia (total cholesterol, more than 5·17 mmol/L) before GH treatment, even in children with idiopathic GH deficiency, was much higher3 than that in the normal population.5 No patient, however, had hypercholesterolemia after 3 years’ GH treatment,3 which suggests that GH replacement therapy prevented the values from worsening. Total cholesterol and LDL cholesterol, defined as atherogenic cholesterol, decrease during GH therapy and increase after GH is stopped.3,4 Our results suggest beneficial effects of GH on arteriosclerotic risk factors even in children and young adults. Many studies have documented increased arteriosclerotic risk in adults with GH deficiency, as reflected in visceral obesity, hyperlipidaemia, intima-media thickness, increased frequency of atherosclerotic plaques in the carotid arteries, and vascular endothelial dysfunction. These abnormalities are improved during GH replacement therapy, as noted in many reports referenced by Tomlinson and colleagues. Studies of GH secretory dynamics have shown age-related alterations, with GH concentrations rising during puberty, peaking at late puberty, and subsequently declining into old age; GH is thus continuously secreted throughout life in normal individuals. Deficient hormones including GH should be replaced to maintain homoeostasis. In contrast to the opinion of Tomlinson and colleagues, long-term studies of the effects of GH withdrawal on lipid profiles and adiposity in young adults with GH deficiency who have completed height growth, and of the consequences of continuing GH therapy on life expectancy in idiopathic GH deficiency must be done. This work is supported by grants from the Clinical Research Foundation of Fukuoka Children’s Hospital and the Foundation for Growth Science
*H Kohno, R Kuromaru, N Ueyama, K Miyako *Department of Endocrinology and Metabolism, Fukuoka Children’s Hospital, 2-5-1 Tojin-machi, Chuo-ku, Fukuoka 810-0063, Japan; Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University; and Department of Pediatrics, School of Medicine, Fukuoka University (e-mail: [email protected]) 1
Tomlinson JW, Holden N, Hills RK, et al. Association between premature mortality and hypopituitarism. Lancet 2001; 357: 425–31.
2
3
4
5
Kohno H, Ueyama N, Yanai S, Ukaji K, Honda S. Beneficial effect of growth hormone on atherogenic risk in children with growth hormone deficiency. J Pediatr 1995; 126: 953–55. Kuromaru R, Kohno H, Ueyama N, Hassan HMS, Honda S, Hara T. Long-term prospective study of body composition and lipid profiles during and after growth hormone (GH) treatment in children with GH deficiency: gender-specific metabolic effects. J Clin Endocrinol Metab 1998; 83: 3890–96. Kohno H, Ueyama N, Honda S. Unfavourable impact of growth hormone (GH) discontinuation on body composition and cholesterol profiles after the completion of height growth in GH-deficient young adults. Diabetes Obesity Metab 1999; 1: 293–96. Fukushige J, Igarashi H, Ueda K, Akazawa K, Nose T. Serum cholesterol levels in school-aged Japanese children: the Hisayama study. Acta Paediatr Jpn 1996; 38: 22–27.
Authors’ reply Sir—Despite the comments of H Erfurth and colleagues, our study is prospective. Time of diagnosis is irrelevant since we assessed mortality only in the census period. We achieved nearly 100% follow-up, whereas retrospective studies might lose patients to clinic follow-up or because of death. Furthermore, patients’ data were compared with annual regional and national mortality data held centrally at the Office of National Statistics and we could accommodate changes in patterns of mortality nationally and in different regions. Our study was well powered to analyse the impact of several variables on mortality, including age at onset, sex, treatment method (surgery, radiotherapy), and underlying diagnosis. We also assessed the impact of pituitary hormonal deficiencies, and although a highly significant harmful effect of untreated gonadotrophin deficiency on mortality was reported, the ensuing correspondence relates almost exclusively to the potential impact of growth hormone (GH) deficiency. Debate continues on the diagnosis of GH deficiency in hypopituitary adults. We agree that the clonidine test1 is now redundant. Only 11 patients were assessed in this way. We used the latest results from pituitary-function tests (before January, 2000, or before death) for analysis and did tests annually on all non-deficient patients. However, when the study was started, the diagnosis and consequences of adult GH deficiency was unclear, which contributed to few patients being formally tested for GH reserve. We did not design the study to address the issue of whether or not GH deficiency is implicated in any excess mortality and, as H Kohno and colleagues state,
1973