Premature mortality and hypopituitarism

Abstract

J W Tomlinson and colleagues1Tomlinson JW Holden N Hills RK et al.Association between premature mortality and hypopituitarism.Lancet. 2001; 357: 425-431Summary Full Text Full Text PDF PubMed Scopus (851) Google Scholar 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 lipid profiles in children and young adults with idiopathic GH deficiency during and after GH treatment.2Kohno 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: 953-955Summary Full Text Full Text PDF PubMed Scopus (32) Google Scholar, 3Kuromaru 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: 3890-3896PubMed Google Scholar, 4Kohno 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: 293-296Crossref PubMed Scopus (4) Google Scholar 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.5Fukushige 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: 22-27Crossref PubMed Scopus (16) Google Scholar No patient, however, had hypercholesterolemia after 3 years' GH treatment,3Kuromaru 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: 3890-3896PubMed Google Scholar 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.3Kuromaru 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: 3890-3896PubMed Google Scholar, 4Kohno 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: 293-296Crossref PubMed Scopus (4) Google Scholar 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 J W Tomlinson and colleagues1Tomlinson JW Holden N Hills RK et al.Association between premature mortality and hypopituitarism.Lancet. 2001; 357: 425-431Summary Full Text Full Text PDF PubMed Scopus (851) Google Scholar 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 lipid profiles in children and young adults with idiopathic GH deficiency during and after GH treatment.2Kohno 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: 953-955Summary Full Text Full Text PDF PubMed Scopus (32) Google Scholar, 3Kuromaru 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: 3890-3896PubMed Google Scholar, 4Kohno 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: 293-296Crossref PubMed Scopus (4) Google Scholar 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.5Fukushige 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: 22-27Crossref PubMed Scopus (16) Google Scholar No patient, however, had hypercholesterolemia after 3 years' GH treatment,3Kuromaru 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: 3890-3896PubMed Google Scholar 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.3Kuromaru 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: 3890-3896PubMed Google Scholar, 4Kohno 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: 293-296Crossref PubMed Scopus (4) Google Scholar 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