• Growth hormone replacement in patients with Langerhan's cell histiocytosis.

      Howell, Simon J; Wilton, P; Shalet, Stephen M; Department of Endocrinology, Christie Hospital NHS Trust, Withington, Manchester, UK. (1998-05)
      OBJECTIVES: To assess the impact of growth hormone on growth and the underlying disease in children with growth hormone deficiency as a result of Langerhan's cell histiocytosis. STUDY DESIGN: Retrospective analysis of data from the Kabi (Pharmacia & Upjohn) international growth database (KIGS) for 82 children with Langerhan's cell histiocytosis treated with recombinant growth hormone. RESULTS: At the start of treatment the median (10-90th centile) age was 9.0 (5.2 to 14.7) years, with a median height standard deviation score (SDS) of -2.0 (-3.5 to -0.9). The median pretreatment height velocity (measured in cm/year) was 3.6 (0.9 to 6.4); this increased to 8.8 (3.8 to 12.0) in the first year of treatment with growth hormone, and then remained significantly greater than the pretreatment height velocity at 7.3 (4.4 to 9.7) and 7.1 (4.1 to 9.3) cm/year in the second and third years, respectively. The median height SDS increased from -2.0 to -0.8 (-2.3 to 0.6) by the end of three years of treatment. There was no increase in the recurrence rate of the underlying disease and no adverse event could be directly attributed to growth hormone treatment, apart from one case of benign intracranial hypertension that resolved on stopping treatment with growth hormone. CONCLUSIONS: Growth hormone replacement treatment for patients with Langerhan's cell histiocytosis with growth hormone deficiency is beneficial and safe.
    • Growth hormone replacement therapy (GHRT) in children and adolescents: skeletal impact.

      Mukherjee, Annice; Shalet, Stephen M; Department of Endocrinology, Christie Hospital, Withington, Manchester, United Kingdom. (2003-09)
      In addition to its well-established effects on linear growth in childhood and adolescence, growth hormone has both direct and indirect actions on bone remodelling and homeostasis. In this review the limitations of methods of assessment of bone mineral density are highlighted. The influence of growth hormone deficiency of childhood-onset, on bone mineral accretion and, the specific skeletal implications of GHD in long-term survivors of childhood cancers, are discussed. Specific influential factors, which affect peak bone mass achievement and therefore skeletal health in later life, are evaluated.
    • Growth hormone replacement therapy during transition of patients with childhood-onset growth hormone deficiency into adulthood: what are the issues?

      Shalet, Stephen M; Rosenfeld, R G; Department of Endocrinology, Christie Hospital NHS Trust, Manchester, UK. (1998-04)
    • Growth hormone replacement therapy in the elderly with hypothalamic-pituitary disease: a dose-finding study.

      Toogood, Andy; Shalet, Stephen M; Department of Endocrinology, Christie Hospital National Health Service Trust, Manchester, United Kingdom. (1999-01)
      Adults over the age of 60 yr with organic disease of the hypothalamic-pituitary axis have a 90% reduction in GH secretion. This is distinct from the hyposomatotropism associated with increasing age and results in a significant reduction in serum insulin-like growth factor I (IGF-I), an increase in fat mass, abnormal bone turnover, and an adverse lipid profile compared with those in healthy subjects of the same age. These findings suggest that the elderly with organic GH deficiency might benefit from GH replacement therapy. However, the dose of GH required to maintain serum IGF-I levels in the normal range while minimizing side-effects in this group of patients is unknown. We have studied 12 patients with organic GH deficiency, aged 62.4-85.2 (median, 67.9 yr), each treated with three doses of GH (0.167, 0.33, and 0.5 mg/day). Each dose was administered for 12 weeks. The serum IGF-I level rose in a dose-related manner over the course of the study (P < 0.0001). From a baseline median (range) IGF-I concentration of 101 (49-148) microg/L to 149 (49-227) microg/L at 12 weeks (P = 0.003 vs. baseline), 200 (70-453) microg/L at 24 weeks (P = 0.002 vs. baseline; P = 0.04 vs. 12 weeks), and 239 (122-502) microg/L at 36 weeks (P = 0.002 vs. baseline; P = 0.07 vs. 24 weeks). The age-specific IGF-I SD score exceeded normal in two subjects taking 0.33 mg/day and in six subjects taking 0.5 mg/day. Serum IGF-binding protein-3 also rose over the course of the study (P < 0.001); however, the greatest increase occurred during the first 12 weeks, after which the IGFBP-3 level plateaued. Body composition changed significantly during the study, with a fall in fat mass (P = 0.0003) and an increase in lean body mass (P = 0.0001). GH was well tolerated in this elderly group, all of whom completed the study. Three patients developed side-effects while taking 0.5 mg/day; two developed headaches, and one developed arthralgia. This study has demonstrated that the GH replacement dose in elderly subjects is considerably lower than that required by younger adults with GH deficiency. In 50% of the subjects a dose of 0.5 mg/day was excessive, whereas 83% maintained their serum IGF-I within normal limits while taking 0.33 mg/day. No patient exhibited a supranormal IGF-I level on 0.17 mg/day.
    • Growth hormone replacement throughout life: Insights into age-related responses to treatment.

      Clayton, Peter E; Gleeson, Helena K; Monson, John; Popovic, Vera; Shalet, Stephen M; Christiansen, J Sandahl; Endocrine Science Research Group, Division of Human Development, The Medical School, University of Manchester, UK. (2007-10)
      The adult growth hormone deficiency (GHD) syndrome is a well-defined clinical entity. Although the symptoms of GHD are not age specific, their relative importance differs depending on the patient's age, and the impact of GHD varies throughout adult life. Ceasing growth hormone (GH) therapy soon after final height in patients with severe GHD potentially limits somatic development by reducing accrual of bone and muscle mass. It is now recognized that the continuation of GH therapy in the transition years is required to achieve adult levels of somatic development. In middle age, the most worrying feature of GHD is the increase in cardiovascular risk, an important component of which is GHD-related dyslipidemia. One of the most profound effects of GH therapy in this age group is the durable reduction in cholesterol levels. Elderly GH-deficient patients experience the symptoms of GHD over and above the signs of normal aging. Perhaps most importantly, these patients have impaired quality of life, with fatigue as a major component. Evidence is growing for improved quality of life with GH therapy in the elderly. This review describes the diagnosis, symptoms and treatment of GHD specific to the different age groups.
    • Growth Hormone Research Society perspective on biomarkers of GH action in children and adults.

      Johannsson, G; Bidlingmaier, M; Biller, B; Boguszewski, M; Casanueva, F; Chanson, P; Clayton, P; Choong, C; Clemmons, D; Dattani, M; et al. (2018-03)
      The Growth Hormone Research Society (GRS) convened a Workshop in 2017 to evaluate clinical endpoints, surrogate endpoints and biomarkers during GH treatment of children and adults and in patients with acromegaly.
    • Growth hormone status during long-term hexarelin therapy.

      Rahim, Asad; O'Neill, Paul A; Shalet, Stephen M; Department of Endocrinology, Christie Hospital, Withington, Manchester, United Kingdom. (1998-05)
      Hexarelin, a powerful GH-releasing peptide, is capable of causing profound GH release in normal subjects after oral, intranasal, i.v., and s.c. administration. The effect of long-term administration on GH levels in adults is unknown. We have, therefore, assessed the effects of 16 weeks of twice-daily s.c. hexarelin therapy (1.5 micrograms/kg BW) on the GH response to a single injection of hexarelin, and also the GH response to hexarelin 4 weeks after cessation of hexarelin therapy. We have also assessed the effects of chronic hexarelin therapy on serum insulin-like growth factor (IGF)-I, IGF binding protein-3, markers of bone formation (osteocalcin, procollagen-type-III-N-terminal-peptide, and C-terminal propeptide of type I collagen), and resorption (urinary deoxypyridinoline and pyridinoline), body composition, and bone mineral density. The mean (+/- SEM) area under the GH curve (AUCGH) at weeks 0, 1, 4, 16, and 20 were 19.1 +/- 2.4 micrograms/L.h, 13.1 +/- 2.3 micrograms/L.h, 12.3 +/- 2.4 micrograms/L.h, 10.5 +/- 1.8 micrograms/L.h, and 19.4 +/- 3.7 micrograms/L.h, respectively. There was a significant change in AUCGH over the study period (P = 0.0003). Further analysis showed that, compared with baseline, the decrease in AUCGH at week 4 and week 16 were significant (P < 0.05 and P < 0.01, respectively). Four weeks after completion of hexarelin therapy, the AUCGH increased significantly, compared with AUCGH at week 16 (P < 0.05), and was not significantly different from that at week 0. Serum IGF-I and IGF binding protein-3 did not change significantly over the 20-week period (P = 0.24 and P = 0.74, respectively). Of the bone markers measured, only serum C-terminal propeptide of type I collagen changed significantly and was higher at week 16, compared with baseline (P = 0.019). Total body fat, lean body mass, and bone mineral density had not changed significantly at week 16, compared with baseline (P = 0.6, P = 0.3, and P = 0.3, respectively). In summary, we have demonstrated that chronic hexarelin therapy results in a partial and reversible attenuation of the GH response to hexarelin. In the present study, the biological impact of this hexarelin schedule on the GH-IGF-I axis seems to be minimal. The therapeutic potential of chronic hexarelin requires further investigation.
    • Growth hormone status following treatment for Cushing's syndrome.

      Hughes, N R; Lissett, Catherine A; Shalet, Stephen M; Department of Endocrinology, Christie Hospital, Manchester, UK. (1999-07)
      OBJECTIVE: Both pituitary surgery and radiotherapy for Cushing's disease can lead to growth hormone (GH) deficiency. Studies to date have, however, described the incidence of impaired GH secretion and not the incidence of severe GH deficiency following treatment of Cushing's disease. Furthermore, following cure of Cushing's disease and resolution of hypercortisolaemia, recovery of GH secretory status is seen, thus creating uncertainty as to the persistence of any documented GH deficiency. This study has two aims; to determine the incidence of severe persistent GH deficiency following treatment of Cushing's disease and to assess the time scale of any recovery of GH secretory status following surgical cure of Cushing's disease. DESIGN AND PATIENTS: The case notes of 37 patients either cured or in clinical and biochemical remission following treatment for Cushing's syndrome were reviewed to determine the incidence of severe GH deficiency. Of 34 patients with Cushing's disease, 20 were treated by pituitary surgery, and 14 with radiotherapy. Three patients with adrenal adenomas underwent unilateral adrenalectomy. MEASUREMENTS: GH secretory status was assessed by provocative testing using an insulin tolerance test (ITT, 85% of all tests), glucagon stimulation test (GST) or arginine stimulation test (AST). RESULTS: Thirty-six percent (5/14) of radiotherapy treated patients demonstrated severe GH deficiency at a mean time of 99 months following remission. Fifty-nine percent (10/17) of surgically treated patients assessed in the two years following remission demonstrated severe GH deficiency, whilst only 22% (2/9) of patients assessed beyond two years following remission demonstrated severe GH deficiency. This latter cohort is biased, with patients in whom severe GH deficiency had been demonstrated on earlier tests being over-represented. It is more accurate to estimate the incidence of persistent severe GH deficiency following surgically induced remission of Cushing's disease by incorporating data from patients in whom original testing demonstrated adequate GH reserve. Collating such data, 13% (2/15) of patients had persistent severe GH deficiency. Across all time periods five surgically treated patients demonstrated recovery of GH secretory status over a median time course of 19 months. In the surgically treated cohort, seven (35%) patients had anterior pituitary hormone deficits other than GH deficiency: 14% (2/14) of patients with normal GH secretory status at the last assessment, 83% (5/6) of patients with severe GHD at the last assessment. Of the 5 patients who demonstrated recovery of GH secretory status 40% (2) had additional anterior pituitary hormone deficits. Within the radiotherapy treated cohort 14% (2/14) of patients demonstrated additional anterior pituitary hormone deficits: 11% (1/9) of patients with normal GH secretory status and 20% (1/5) of patients with severe GH deficiency. None of the patients with adrenal adenomas treated by unilateral adrenalectomy demonstrated any abnormality of GH secretory status CONCLUSIONS: The incidence of severe persistent GH deficiency following surgically induced or radiotherapy induced remission of Cushing's disease is lower than has been suggested by previous studies, although these latter studies have assessed GH insufficiency and not severe GH deficiency. In the presence of additional pituitary hormone deficits severe GHD is common and is likely to be persistent. Recovery of GH secretory status is seen in a high proportion of patients reassessed, at a median time of 19 months following surgically induced remission of Cushing's disease. Thus, we recommend that definitive assessment of GH secretory status is delayed for at least two years following surgical cure of Cushing's disease. This has important implications for patients in whom GH replacement therapy is being considered.
    • Growth hormone status in adults treated for acute lymphoblastic leukaemia in childhood.

      Brennan, B M; Rahim, A; Mackie, E M; Eden, Tim O B; Shalet, Stephen M; Department of Paediatric Oncology, Royal Manchester Children's Hospital, UK. (1998-06)
      OBJECTIVE: Growth hormone status was assessed in a cohort of 32 (16 male) adults who had received cranial irradiation (XRT) in childhood as part of their treatment for acute lymphoblastic leukaemia (ALL) and compared with 35 age matched young adults (18 male). DESIGN: Height and weight were measured in all subjects and the heights of the patients at XRT were obtained from their case notes. Each patient and control underwent two provocative tests of growth hormone (GH) secretion using insulin (0.2 IU/kg body weight) and arginine (20 g/m2). Basal serum insulin like growth factor-1 (IGF-1) and IGFBP-3 (binding protein-3) concentrations were also measured. RESULTS: The patient group had a significantly lower peak GH response to both provocative tests (P < 0.01), and lower IGF-1 and IGFBP-3 levels compared with the normal controls (P < 0.01). Nine of the patient group were severely GH deficient (peak GH response < 9 mU/l to both provocative agents) and a further 12 patients were GH insufficient (peak GH response < 20 mU/l to both tests with at least one peak GH response > 9 mU/l). Overall a significant median change in height from XRT to final height of -0.5 SDS was found which was even greater in the severely GH deficient group (median change in height of -2.1 SDS). CONCLUSION: These data suggest that a significant proportion of adults treated with cranial XRT in childhood with irradiation doses between 18-25 Gy, as part of their treatment for ALL, are severely GH deficient now and should be considered for GH replacement. Changes in GH secretion evolve with time following irradiation-induced damage to the hypothalamic-pituitary axis; therefore long-term surveillance will be required in those remaining patients, in whom GH status is considered currently to be insufficient or even normal.
    • Growth hormone therapy and malignancy.

      Shalet, Stephen M; Brennan, Bernadette M; Reddingius, R E; Department of Endocrinology, Christie Hospital, Manchester, UK. (1997)
      The possibility that human growth hormone (GH) replacement therapy might either increase the risk of cancer recurrence in a child who has previously been treated for a brain tumour or leukaemia, or induce de novo cancer, has worried paediatricians for a number of years. Concern arises from animal experiments, the association of acromegaly with malignancy, and the Japanese experience of a cluster of de novo leukaemia cases in children treated with GH. It is reassuring that so far the results from single centre studies and from the pharmaceutical industry surveillance programmes have shown no evidence of an increased risk of malignancy, recurrent or de novo. The confidence intervals, however, are wide and the scientific nature of these studies is flawed as there has never been a prospective randomized study of GH replacement in children with radiation-induced GH deficiency. For clinical reasons, such a study is unlikely to be performed and therefore surveillance must be maintained at a very high level.
    • Growth hormone therapy following bone marrow transplantation in childhood.

      Shalet, Stephen M; Department of Endocrinology, Christie Hospital, Manchester, England. (1991)
    • Growth hormone therapy for adult growth hormone deficiency.

      Shalet, Stephen M; Department of Endocrinology, Christie Hospital, Manchester, UK. (1998-03)
      Growth hormone deficiency in adult life is associated with a number of adverse biological changes which include osteopenia, reduced exercise capacity, altered body composition, deleterious alterations in the lipid profile and insulin status, and reduced quality of life. Most of these changes can be reversed by growth hormone replacement therapy, but in an era of health rationing, such therapy is unlikely to be offered to every growth hormone deficient adult. Therefore we have proposed a strategy aimed at delineating which adults with growth hormone deficiency might benefit most from growth hormone therapy.
    • Growth Hormone therapy for adult Growth Hormone deficiency.

      Shalet, Stephen M; Rahim, Asad; Toogood, Andy; Department of Endocrinology, Christie Hospital NHS Trust, Manchester, United Kingdom. (1996-10)
      GH deficiency in adult life is associated with a number of adverse biological changes including osteopenia, reduced exercise capacity, altered body composition, deleterious alterations in the lipid profile and insulin status, and reduced quality of life. Potentially, most of these changes can be reversed by GH replacement therapy. In an era of health rationing, however, GH replacement is unlikely to be offered to every GH-deficient adult. Therefore, we have proposed a strategy aimed at delineating which adults with GH deficiency might benefit most from GH therapy.
    • Growth hormone: current and future therapeutic applications.

      Murray, Robert D; Shalet, Stephen M; Department of Endocrinology, Christie Hospital, NHS Trust, Wilmslow Road, Manchester, M20 4BX, UK. (2000-07)
      The increased availability of growth hormone (GH) in the mid-1980s, as a result of advances in recombinant DNA techniques, has allowed research into the use of this hormone at physiological dosage, as replacement therapy for adults with GH deficiency (GHD) and at pharmacological dosages as a possible therapeutic agent, for a number of disease states. GHD adults have increased body fat and reduced muscle mass and consequently, reduced strength and exercise tolerance. In addition, they are osteopenic, have unfavourable cardiac risk factors and impaired quality of life. In these individuals, replacing GH reverses these anomalies, although it may not alter the reduced insulin-sensitivity. A proportion of adults with GHD perceive a dramatic improvement in their well-being, energy levels and mood following replacement. GH has protein and osteoanabolic, lipolytic and antinatriuretic properties. GH has been considered for the therapeutic treatment of frailty associated with ageing, osteoporosis, morbid obesity, cardiac failure, major thermal injury and various acute and chronic catabolic conditions. Initial small, uncontrolled studies for many of these clinical problems suggested a beneficial effect of GH, although, later placebo-controlled studies have not observed such dramatic effects. Furthermore, with a recent publication demonstrating an approximate 2-fold increase in mortality in critically ill patients receiving large doses of GH, the use of GH should remain in the realms of replacement therapy and research, until there are significant advances in our understanding.
    • Growth impairment following treatment for childhood brain tumours.

      Shalet, Stephen M; Clayton, P; Price, D; Department of Endocrinology, Christie Hospital, Manchester, UK. (1988)
    • Growth impairment in children treated for brain tumours.

      Shalet, Stephen M; Beardwell, Colin G; Aarons, B M; Pearson, D; Morris Jones, P H; Christie Hospital, Withington, Manchester, M20 4BX, UK (1978-06)
      Growth and growth hormone (GH) secretion were studied in 14 children with brain tumours before radiation and chemotherapy and at various time intervals afterwards. The peak GH response to hypoglycaemia was normal in all patients before radiation. In 6 patients the peak GH response was impaired 1 year after radiation, and in a seventh it was normal at 1 year but impaired 2 years after radiation. In 12 of 13 patients the growth velocity during the first year of chemotherapy was below the 3rd centile, although none of these had an initial standing height below the 3rd centile. Thus it appears that poor growth in such children occurs irrespective of whether radiation-induced GH deficiency develops. The cause of this impaired growth is unknown.
    • Growth in children treated for acute lymphoblastic leukaemia.

      Clayton, P E; Shalet, Stephen M; Morris Jones, P H; Price, David A; Royal Manchester Children's Hospital. (1988-02-27)
      Growth was assessed in 82 children with acute lymphoblastic leukaemia (ALL) who achieved complete continuous first remission following treatment. 34 received prophylactic cranial irradiation at a total dose over 2000 cGy (group I) and 48 at a dose of 1800 cGy (group II). Chemotherapy was given over two or three years and was more intense in group II. Both groups showed a similar significant decrease in height standard deviation score (SDS) over four years (group I -0.31, group II -0.39). 15 children in group I were followed to ten years and continued to show restricted growth with a mean height SDS decrease of -0.84 (range 0 to -1.7). The greatest reduction in yearly decrements in height SDS occurred in the first year after diagnosis. In both groups height SDS increased significantly on completion of chemotherapy. Thus chemotherapy protocols contribute to growth retardation in ALL. In most of these children the mean loss of height over ten years was not sufficiently great to justify long-term growth hormone (GH) therapy.
    • The Growth of a NHS Joint Ventures Private Haematology and Transplant Unit

      Cleaver, S; Clout, Ruth; Newson, A; Shearn, J; Christie Clinic, Manchester (2016)
    • Growth of fibroblasts as a potential confounding factor in soft agar clonogenic assays for tumour cell radiosensitivity.

      Lawton, P A; Hodgkiss, R J; Eyden, Brian P; Joiner, M C; CRC Gray Laboratory, Mount Vernon Hospital, Northwood, Middlesex, UK. (1994-09)
      Soft agar clonogenic assays are considered to be a standard method for measuring tumour cell radiosensitivity and it has been widely reported that fibroblast contamination does not occur. We report here that human fibroblasts can proliferate to form colonies in a modified form of the Courtenay-Mills soft agar clonogenic assay. It was observed that early passage skin fibroblasts could form colonies in soft agar, although the plating efficiencies were reduced compared with growth on plastic. It was demonstrated that normal lung could proliferate in agar with similar plating efficiencies to fresh tumours and that fibroblastic cells were present in these cultures. Characterisation of primary lung tumour cultures also showed that fibroblastic cells were present in these cultures. Characterisation of primary lung tumour cultures also showed that fibroblastic cells were present which lacked epithelial features and which resembled closely the cells found in cultures of normal lung. This is an important finding for workers using soft agar assays to culture human tumour cells and is of interest in understanding the processes of normal growth control of human fibroblasts.
    • Growth response to growth hormone therapy following cranial irradiation.

      Clayton, P; Shalet, Stephen M; Price, D; Department of Child Health, Royal Manchester Children's Hospital, Pendelbury, UK. (1988-08)
      The growth response to growth hormone (GH) therapy has been studied in 12 children who received irradiation to the cranium alone either for brain gliomas, distant from the hypothalamic-pituitary axis, or as prophylaxis against CNS leukaemia. Seven children have completed GH treatment (mean duration 4 years) and five are presently on GH (mean duration 1.2 years). This response has been compared to that seen in 14 children with isolated idiopathic GH deficiency (IGHD), following GH therapy. Before treatment, the cranially irradiated patients (C-PRGHD) had higher standard deviation scores (SDS) for standing height, sitting height and leg length, and less bone age (BA) retardation, but started treatment at a similar age, and with a similar pre-treatment growth velocity and GH peak to standard provocative tests, compared to IGHD patients. GH produced a significant and similar increase in growth velocity (cm/year and SDS for BA) over the first 2 years' treatment in both groups. However C-PRGHD patients entered puberty and thus completed growth earlier than the IGHD group. As a result, cranially-irradiated children showed no change in height SDS with GH therapy, compared to catch-up growth in IGHD. Nevertheless, GH has enabled C-PRGHD patients to maintain their centile position and to achieve a more acceptable final height.