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Research Notes: Growth Hormone SafetyNote: This page is a collection of notes and research abstracts about issues related to the safety of growth hormone treatment. Please see here for the article about the consensus recommendations for growth hormone treatment for PWS. Neurosci Lett. 2007 Aug 19. Insulin-like Growth Factor 1 (IGF-1) has broad-range neuroprotective effects and is a therapeutic candidate for Huntington's disease (HD). IGF-1 protects striatal neurons from the toxicity of mutated huntingtin in vitro and improves neuronal survival in vivo in a phenotypic model of HD involving excitotoxic cell death. Because HD is a multifactorial disease, it is important to evaluate the neuroprotective role of IGF-1 in other pathological situations involved in HD progression. We have evaluated the neuroprotective effects of IGF-1 in vivo, using the 3-nitropropionic acid (3NP) rat model which replicates the mitochondrial dysfunction observed in HD. Continuous intracerebroventricular infusion of recombinant IGF-1 at a low dose (0.025mug/h for 5 days) did not alleviate motor impairment and weight loss induced by 3NP treatment. In addition, histological evaluation and quantification of DNA fragmentation evidenced no improvement in neuronal survival. Of interest, we found that a higher concentration of IGF-1 (0.25mug/h) resulted in an exacerbation of 3NP toxicity on striatal neurons. These results suggest that intracerebral delivery of IGF-1 may not provide a fully effective therapeutic strategy for HD or other disorders involving mitochondrial impairment. Endocrinology. 2007 Jun 21. Epidemiologic studies suggest that the growth hormone/insulin-like growth factor I (GH/IGF-I) axis may promote human cancers. Animal models in which the GH/IGF-I axis can be controlled may be helpful in elucidating the role of these hormones during mammary cancer progression. Beginning at 3 or 5 weeks of age, Spontaneous Dwarf Rats (SDR, Gh(dr/dr)), which lack GH and have very low serum IGF-I, were treated with either rat or bovine GH twice daily. Other Gh(dr/dr) rats received vehicle, and wild-type Sprague Dawley rats (Gh(+/+), parent strain to SDR) received vehicle. One week later, all rats were exposed to a single injection of N-methyl-N-nitrosourea. Body weight gain and serum IGF-I levels were similar in Gh(+/+) and GH-treated Gh(dr/dr) rats. Furthermore, mammary tumor incidence, latency and multiplicity were similar in Gh(+/+) and GH-treated Gh(dr/dr) rats. Vehicle treated Gh(dr/dr) rats developed no tumors. Once advanced (>/= 1 cm(3)) mammary cancers were established in GH-treated Gh(dr/dr) rats, GH treatments were halted and nearly all tumors regressed completely within two weeks. Tumor regression was associated with loss of phospho-STAT3, but not alterations in IGF-I, IGF-I receptor or GH receptor. These results demonstrate that Gh(dr/dr) rats, which are nearly refractory to mammary carcinogenesis, can be made vulnerable by restoring GH and IGF-I. Furthermore, advanced rat mammary cancers are dependent upon GH and/or IGF-I for their survival. Therefore, therapeutics that target either GH or IGF-I may be effective at treating even advanced mammary cancers. Am J Med Genet A. 2007 Jun 13. Short stature is characteristic of children with Prader-Willi syndrome (PWS). While previous studies have demonstrated acceleration of linear height velocity with growth hormone (GH) treatment, the long-term benefit on final adult height (AH) has not been reported. The objective of this study was to compare AH attained in PWS subjects with and without GH treatment. We reviewed the records of 21 children (aged 8.3 +/- 2.7 years) with PWS and confirmed GH deficiency that attained AH after receiving human GH treatment (0.25 +/- 0.06 mg/kg/week) for a period of 7.9 +/- 1.7 years. A group of 39 non-GH-treated adults with matched initial height standard deviation score (SDS) at age 6.8 +/- 1.3 years was used as control. In the GH-treated group the mean initial height and AH-SDS was -1.9 +/- 1.7 and -0.3 +/- 1.2 respectively (P < 0.0001), whereas the mean initial and AH-SDS in the control group was -1.9 +/- 1.3 and -3.1 +/- 1 respectively (P < 0.0001). Scoliosis was seen in 43% and 39% in the GH-treated and control group respectively. Premature adrenarche (PA) was noticed in 57% of GH-treated group. Six subjects in the control group but none of the GH-treated subjects developed type 2 diabetes mellitus. Our data show that administration of GH to children with PWS restores linear growth and final AH without significant adverse effects other than PA. Further studies will be necessary to determine related morbidity and mortality in individuals with PWS that reached final AH with or without GH treatment. Clin Endocrinol (Oxf). 2007 Jun 4. Objective. Children with autism are known to have larger head circumferences; whether they are above average in height and weight is less clear. Moreover, little is known about growth-related hormone levels in children with autism. We investigated whether children with autism were taller and heavier, and whether they had higher levels of growth-related hormones than control children did. Design. A case-control study design was employed. Patients. Boys with autism spectrum disorder (ASD) or autism (n = 71) and age-matched control boys (n = 59) were evaluated at Cincinnati Children's Hospital. Measurements. Height, weight and head circumference were measured. Blood samples were assayed for IGF-1 and 2, IGFBP-3, growth hormone binding protein (GHBP) and for dehydroepiandrosterone (DHEA) and DHEA sulphate (DHEAS). Results. Subjects with autism/ASD had significantly (P = 0.03) greater head circumferences (mean z-score 1.24, SD 1.35) than controls (mean z-score 0.78, SD 0.93). Subjects with autism also had significantly (P = 0.01) greater weights (mean z-score 0.91, SD 1.13) than controls (mean z-score 0.41, SD 1.11). Height did not differ significantly between groups (P = 0.65); subjects with autism/ASD had significantly (P = 0.003) higher body mass indices (BMI) (mean z-score 0.85, SD 1.19) than controls (mean z-score 0.24, SD 1.17). Levels of IGF-1, IGF-2, IGFBP-3 and GHBP in the group with autism/ASD were all significantly higher (all P </= 0.0001) than in controls. Conclusions. Children with autism/ASD had significantly higher levels of many growth-related hormones: IGF-1, IGF-2, IGFBP-3 and GHBP. These findings could help explain the significantly larger head circumferences and higher weights and BMIs seen in these subjects. Future studies should examine the potential role of growth-related hormones in the pathophysiology of autism. Pharmacol Res. 2007 May. Anabolic steroid and peptide hormones or growth factors are utilized to increase the performance of athletes of professional or amateur sports. Despite their well-documented adverse effects, the use of some of these agents has significantly grown and has been extended also to non-athletes with the aim to improve appearance or to counteract ageing. Pre-clinical studies and epidemiological observations in patients with an excess of hormone production or in patients chronically treated with hormones/growth factors for various pathologies have warned about the potential risk of cancer development and progression which may be also associated to the use of certain doping agents. Anabolic steroids have been described to provoke liver tumours; growth hormone or high levels of its mediator insulin-like growth factor-1 (IGF-1) have been associated with colon, breast, and prostate cancers. Actually, IGF-1 promotes cell cycle progression and inhibits apoptosis either by triggering other growth factors or by interacting with pathways which have an established role in carcinogenesis and cancer promotion. More recently, the finding that erythropoietin (Epo) may promote angiogenesis and inhibit apoptosis or modulate chemo- or radiosensitivity in cancer cells expressing the Epo receptor, raised the concern that the use of recombinant Epo to increase tissue oxygenation might favour tumour survival and aggressiveness. Cancer risk associated to doping might be higher than that of patients using hormones/growth factors as replacement therapy, since enormous doses are taken by the athletes often for a long period of time. Moreover, these substances are often used in combination with other licit or illicit drugs and this renders almost unpredictable all the possible adverse effects including cancer. Anyway, athletes should be made aware that long-term treatment with doping agents might increase the risk of developing cancer. J Clin Endocrinol Metab. 2007 Apr. CONTEXT: In Prader-Willi syndrome (PWS), an altered GH secretion has been related to reduced cardiac mass and systolic function when compared with controls. OBJECTIVES: The objective of the study was to evaluate the cardiovascular response to GH therapy in adult PWS patients. STUDY PARTICIPANTS: Thirteen obese PWS adults (seven males and six females, aged 26.9+/-1.2 yr, body mass index 46.3+/-1.6 kg/m2) participated in the study. METHODS: Determination of IGF-I, metabolic parameters, echocardiography, and cardioscintigraphy with dobutamine stimulation was made during 12 months GH therapy, with results analyzed by repeated-measures ANOVA. RESULTS: GH therapy increased IGF-I (P<0.0001); decreased C-reactive protein levels (P<0.05); and improved lean mass (P<0.001), fat mass (P<0.05), and visceral fat (P<0.001). Echocardiography showed that 6- and 12-month GH therapy increased left ventricle mass in 76 and in 61% of patients, respectively (P<0.05), did not change diastolic function, and slightly decreased the left ventricle ejection fraction (LVEF) (P=0.054). Cardioscintigraphy documented stable values of LVEF throughout the study, whereas right ventricle ejection fraction decreased significantly (P<0.05) being normally responsive to dobutamine infusion. A positive association between IGF-I z-scores and LVEF occurred at the 6- and 12-month follow-up (P<0.05). CONCLUSIONS: In PWS, GH therapy increased cardiac mass devoid of diastolic consequences. The observation of a slight deterioration of right heart function as well as the association between IGF-I and left ventricular function during GH therapy suggest the need for appropriate cardiac and hormonal monitoring in the therapeutic strategy for Prader-Willi syndrome. J Pediatr Endocrinol Metab. 2007 Apr. In addition to its growth promoting properties, growth hormone (GH) has anti-insulin effects that could cause hyperglycemia. Development of diabetes mellitus as a result of GH therapy has been an ever-present, albeit rarely reported, concern. This report is that of two adolescent boys who developed diabetes mellitus after the initiation of treatment with GH. Clin Endocrinol (Oxf). 2007 Apr. The growth hormone-insulin-like growth factor 1 (GH-IGF-1) axis plays an important role in modulating the peripheral metabolism of glucocorticoids mainly through its effect on the isoenzyme 11 beta-hydroxysteroid dehydrogenase 1 (11beta-HSD1) which, in vivo, functions as a reductase catalysing the conversion of cortisone to cortisol. Several in vivo and ex vivo studies have shown that the GH-IGF-I system inhibits the expression and activity of 11beta-HSD1 in adipose tissues and the liver resulting in reduced local regeneration of cortisol. This interaction has clinically significant implications as it may at least partly explain the phenotypes of acromegaly and adult GH deficiency and the effects that treatment of these conditions has on body composition. In addition, by accelerating the peripheral metabolism of cortisol, GH therapy may precipitate adrenal insufficiency in susceptible hypopituitary patients, and endocrinologists should be mindful of this phenomenon when starting hypopituitary patients on GH replacement therapy. Eur Neurol. 2007. No abstract available. Horm Res. 2007. No abstract available. Horm Res. 2007. Background: Growth hormone (GH) has long been implicated in the pathogenesis of diabetic retinopathy, although its precise role remains ill-defined. In 1998, an association between exogenous human GH and retinal pathology in non-diabetic subjects was described. Case report: A female child with extreme short stature of unknown aetiology (height -7.38 SD at 11.3 years) and severe hypermetropia [farsightedness] developed retinopathy with visual deterioration during two separate empiric trials of GH therapy. On the first occasion, a relatively high dose of GH (10.5 mg/m2/week) administered from age 4.4 to age 4.7 years was associated with the development of central serous retinopathy, resulting in marked reduction in visual acuity. On cessation of GH, the macular oedema resolved, and visual acuity improved. At age 5.6 years, GH therapy was re-introduced at a lower dose (3.9 mg/m2/week) and her vision monitored closely. Bilateral retinal oedema recurred after 3 months, and GH therapy was stopped. Once again, the macular oedema regressed, and visual acuity improved following withdrawal of GH. These ophthalmic changes contra-indicated further GH therapy. Conclusion: We suggest that GH may be a risk factor in the development of retinopathy in certain non-diabetic patients, especially in the presence of a severe refractive error. Ann Pharmacother. 2006 Dec 19. Objective: To report a case of psoriasis that developed following growth hormone treatment. Case summary: An 8-year-old boy was admitted to our pediatric endocrinology department because of short stature (<3rd percentile). A dopamine stimulation test and an insulin tolerance test revealed growth hormone (GH) deficiency with a normal cortisol response. His insulin-like growth factor 1 (IGF-1) level (9 ng/mL; reference range 113-261) was under the limits for his age and sex. Six months after the initiation of treatment with recombinant human GH 0.33 mg/kg/wk, the patient presented with a 10 day history of desquamation and a burning sensation in his right knee and hip. Lesions of erythematous papules consistent with plaques of psoriasis were present. Histologic findings from skin biopsies were consistent with psoriasis. The GH dose was reduced to 0.2 mg/kg/wk and treatment for psoriasis (including hydrocortisone and clemastine) was started. Three months after those interventions, the plaques had resolved. Discussion: Previous studies proposed that the extent and severity of psoriasis correlate with GH levels, although psoriatic patients, in general, have normal GH and IGF-1 levels. The Naranjo probability scale indicated that the development of psoriasis was probably associated with GH therapy. Conclusions: This case suggests that the development of psoriasiform lesions in a previously unaffected individual represents an adverse effect of GH treatment, occurring at higher doses, with higher IGF-1 levels. J Clin Endocrinol Metab. 2006 Dec. CONTEXT: Recently, several cases of sudden death in GH-treated and non-GH-treated, mainly young Prader-Willi syndrome (PWS), patients were reported. GH treatment in PWS results in a remarkable growth response and an improvement of body composition and muscle strength. Data concerning effects on respiratory parameters, are however, limited. OBJECTIVE: The objective of the study was to evaluate effects of GH on respiratory parameters in prepubertal PWS children. DESIGN: Polysomnography was performed before GH in 53 children and repeated after 6 months of GH treatment in 35 of them. PATIENTS: Fifty-three prepubertal PWS children (30 boys), with median (interquartile range) age of 5.4 (2.1-7.2) yr and body mass index of +1.0 sd score (-0.1-1.7). INTERVENTION: Intervention included treatment with GH 1 mg/m2.d. RESULTS: Apnea hypopnea index (AHI) was 5.1 per hour (2.8-8.7) (normal 0-1 per hour). Of these, 2.8 per hour (1.5-5.4) were central apneas and the rest mainly hypopneas. Duration of apneas was 15.0 sec (13.0-28.0). AHI did not correlate with age and body mass index, but central apneas decreased with age (r = -0.34, P = 0.01). During 6 months of GH treatment, AHI did not significantly change from 4.8 (2.6-7.9) at baseline to 4.0 (2.7-6.2; P = 0.36). One patient died unexpectedly during a mild upper respiratory tract infection, although he had a nearly normal polysomnography. CONCLUSIONS: PWS children have a high AHI, mainly due to central apneas. Six months of GH treatment does not aggravate the sleep-related breathing disorders in young PWS children. Our study also shows that monitoring during upper respiratory tract infection in PWS children should be considered. J Clin Endocrinol Metab. 2006 Sep 26. Context: Recently, several cases of sudden death in growth hormone (GH)-treated and non-GH-treated, mainly young Prader-Willi Syndrome (PWS) patients, were reported. GH-treatment in PWS results in a remarkable growth response, and an improvement of body composition and muscle strength. Data concerning effects on respiratory parameters, are however limited. Objective: To evaluate effects of GH on respiratory parameters in pre-pubertal PWS children. Design: Polysomnography (PSG) was performed before GH in 53 children and repeated after 6 months of GH-treatment in 35 of them. Patients: 53 pre-pubertal PWS children (30 boys), with median (interquartile range (iqr)) age of 5.4 (2.1-7.2) years and body mass index (BMI) of +1.0 SD score (-0.1-1.7). Intervention: Treatment with GH 1 mg/m(2)/day. Results: Apnea Hypopnea Index (AHI) was 5.1/h (2.8-8.7) (normal 0-1/h). Of these, 2.8/h (1.5-5.4) were central apneas and the rest mainly hypopneas. Duration of apneas was 15.0 sec (13.0-28.0). AHI did not correlate with age and BMI, but central apneas decreased with age (r= -0.34, P = 0.01). During 6 months of GH-treatment, AHI did not significantly change, from 4.8 (2.6 - 7.9) at baseline to 4.0 (2.7 - 6.2; P = 0.36). One patient died unexpectedly during mild upper respiratory tract infection (URTI), although he had a nearly normal PSG. Conclusions: PWS children have a high AHI, mainly due to central apneas. Six months of GH does not aggravate the sleep-related breathing disorders in young PWS children. Our study also shows that monitoring during URTI in PWS children should be considered. [Note: This study was funded by Pfizer and one of the study authors "has delivered lectures and received reimbursement of travel/accommodation expenses at meetings sponsored by Pfizer."] Excerpts from the full text article: Introduction [...] Several reports have demonstrated that GH-treatment results in a remarkable growth response, but also in an impressive improvement of body composition, with decline in fat-percentage and increment in lean body mass, muscle strength and agility (9-11). Preliminary studies suggested that GH might improve psychosocial development in PWS (12). Data on effects of GH on respiratory parameters in young, pre-pubertal PWS children are however very limited. Haqq et al found after 6 months of GH a slight reduction in sleep apnea incidence in 12 PWS children, aged 4.5 to 14.5 years (13). Lindgren et al found improved CO2-responsiveness in 12 children with PWS after 6-9 months of GH compared to baseline (14). Recently, several reports have been published on sudden death in children with PWS during GH-treatment (15, 16). Unexpected death, however, has also been described in non-GH-treated children with PWS (17, 18). In fact, Whittington reported an overall death rate of 3% per year for PWS patients in one UK Health Region (19). In our study we evaluated the occurrence of sleep-related breathing disorders (SRBD) in 53 young, pre-pubertal children with PWS and the effects of 6 months of GH-treatment in 35 of them. Patients and Methods Patients In April 2002, a multicenter, randomised, controlled, prospective GH trial in PWS children was started investigating the effects of GH-treatment versus no GH on growth, body composition, activity level and psychosocial development. Participants fulfilled the following inclusion criteria: (1) genetically confirmed diagnosis of PWS by positive methylation test; (2) age between 6 months and 16 years; (3) bone age less than 14 years (girls) or 16 years (boys); (4) in children over 3 years: height standard deviation score (SDS) for age below zero (5) in children over 3 years: if height is > 0 SDS, weight-for-height SDS must be over +2 SDS, according to Dutch standards (20, 21). Patients with non-cooperative behaviour or patients receiving medication to reduce fat were excluded. All patients over 3 years started a diet and exercise program 3 months prior to start of the study. Children were enrolled in the study irrespective of their GH status. Patients received Genotropin® (Somatropin) in a dose of 1 mg/m2/day. The first 4 weeks of treatment, they received only 0.5 mg/m2/day in order to prevent fluid retention. In April 2003, we started a polysomnography (PSG) study in addition to the original protocol. For the PSG study we used the following inclusion criteria: (1) pre-pubertal at baseline and at repeated PSG (2) no upper respiratory tract infection (URTI) during PSG (3) no previous GH-treatment. On November 11, 2005, 83 patients had been included in the original study. Twenty-five were excluded from the PSG study, because they received GH-treatment, before start of the PSG study. For one patient, parents refused PSG, 3 were pubertal at repeated PSG and one was excluded because of treatment with nasal continuous positive airway pressure. As a result, 53 patients were eligible for analysis of baseline PSG. Thirty-nine children had a PSG repeated after 6 months of GH-treatment. Fourteen patients were followed in the control group of the original study. Their PSG will be repeated at 6 months after start of GH-treatment. As all patients were stratified for age and BMI before randomisation in the original study, these patients were not different from those who had repeated PSG. Of the 39 patients with repeated PSG, 4 had URTI during second PSG and were therefore excluded from group analysis. [...] Methods Anthropometry Supine length was recorded below the age of 2.5 years, and thereafter standing height, measured with a Harpenden stadiometer. Weight was assessed on an accurate scale, and body mass index (BMI) (kg/m2) was calculated. Height and BMI were converted into SDS according to Dutch references for age (20, 21). Calculations were performed with Growth Analyser Version 3.0 (www.growthanalyser.org). Polysomnography PSG was performed before and after 6.6 (6.1-7.3) months of GH-treatment. All PSG's were performed in one specialized sleep center (A.W., sleep specialist). Children were admitted to the sleep center at 5.00 p.m., accompanied by one parent. Patients underwent complete overnight PSG. Recordings included electroencephalogram, electro-oculogram, one channel derivation of electrocardiogram, and surface electromyography of the submental muscle and both anterior tibial muscles. Nasal-oral airflow was monitored by nasal pressure prongs fixed in the nose, respiratory effort by thoraco-abdominal strain gauges and oxygen saturation (SaO2) by pulse oximetry. All PSG studies were evaluated independently by two persons, both certified in PSG analysis. In case of major discrepancies between both assessments a third expert opinion was asked. The polygraphic records were scored according to standard criteria of Rechtschaffen and Kales (22). A period of apnea or hypopnea was defined as more than 90% (apnea) or 50% (hypopnea) reduction of airflow for 3 breaths or longer. For hypopneas, the additional criterion was a reduction of SaO2 of 4% or more. Periods of apnea and hypopnea were counted over the period of sleep during the night and calculated as mean per hour of sleep (apnea hypopnea index, AHI). An AHI above 1/hour is considered pathological (23). Apneas were considered obstructive when absence of airflow occurred without a decrease in respiratory effort and central, when thoracic movements were absent. Abnormal SaO2 was defined as SaO2 below 92% or more than 4% below baseline values during 3 breaths or longer. Otorhinolaryngologic examination consisted of 3-monthly tonsillar inspection according to Brodsky staging system (24). Snoring was recorded in a structured interview with parents. When snoring or obstructive sleep apnea (OSA) was diagnosed, fiberoptic endoscopy was performed by an ear-nose-throat (ENT) surgeon. If adenoid or tonsillar hypertrophy was found, adenotonsillectomy was performed. [...] Results Clinical characteristics at baseline Fifty-three pre-pubertal PWS children (30 boys) participated in the PSG study. The median (iqr) age was 5.4 years (2.1 – 7.2) and the median (iqr) BMI was 1.0 SDS (-0.1 – 1.7). Sixteen patients had paternal deletion, 21 had maternal disomy, 4 had an imprinting center mutation. In 12 patients diagnosis was confirmed by a positive methylation test for PWS, but was not yet further specified. Thirty-nine patients (23 boys) started GH at a dose of 1mg/m2/day. The first month of GH, they received only 0.5 mg/m2/day, to avoid fluid retention. Respiratory parameters at baseline At baseline, the median (iqr) AHI was 5.1 (2.8 – 8.7). Of these, 2.8/h (1.5 – 5.4) were identified as central apneas, 0.0/h (0.0 – 0.3) as obstructive apneas and 0.9 (0.0 - 2.7) as hypopneas. The longest median (iqr) duration was 15.0 sec (13.0 – 28.0). In all children, the AHI exceeded the normal range of 0-1/hr, indicating that SRBD do frequently occur, even in normal-weight pre-pubertal children with PWS. In the total patient group, no correlation was found between BMI SDS and AHI. Forty-five of our 53 patients were not obese. Of them, only 9% had OSA (4/45), defined as obstructive apnea index over 1/h. In contrast, in our 8 patients who were obese (i.e. BMI over +2SDS) 50% had OSA (4/8) (prevalence of OSA in normal weight versus obese patients, p=0.01). We found a negative correlation between both age and BMI and the number of central apneas (r=-0.34, p=0.01 and r=-0.33, p=0.017 respectively). There was no significant difference in AHI with regard to gender or genetic defect. Tonsil size as assessed by Brodsky staging system, was not associated with the AHI (data not shown). Respiratory parameters after 6 months of GH Thirty-five pre-pubertal children had PSG repeated after 6 months of GH-treatment. (Table 2) This group of 35 children had a median (iqr) age of 6.0 years (2.4 – 8.6), and median (iqr) BMI of 0.8 SDS (-0.1 – 1.5) before GH. At baseline, median (iqr) AHI in this group was 4.8/h (2.6 – 7.9), of which 2.9/h (1.5 – 5.2) were indicated as central and 0.0 (0.0 – 0.3) as obstructive. After 6 months of GH (1mg/m2/day), a non-significant decline in the AHI was found to 4.0 (2.7 – 6.2). This decline was mainly due to a reduction in central apneas to 2.2/h (0.8 – 4.1). In 5, adenoidectomy and/or tonsillectomy was performed because adenoidal and/or tonsil hypertrophy developed during the follow-up period. There was no association between changes in AHI and changes in number of awakenings or REM sleep-percentage (data not shown). Breathing disorders during illness Four patients were excluded from analysis because of URTI. The results of their PSG's during health and illness are listed in table 3. In one of them, PSG was repeated after recovery and adenoidectomy. In this particular patient, the AHI before GH-treatment was 7.9/h (100% central), during illness after 6 months of GH-treatment, the AHI had impressively increased to 38.6/h (1.2 central apneas/h, 12.4 obstructive apneas/h, and 25.1 hypopneas/h), whereas after recovery and adenoidectomy, AHI was 3.4/h (100% central). One patient in our study died unexpectedly. This 3-year old boy had GH-treatment for 13 months. He responded very well in terms of growth and body composition. In this particular patient, PSG was performed before (AHI 1.7/h, 100% central) and after 6 months of GH (AHI 1.4/h, 67% central, 33% hypopnea). Six weeks before his death, BMI was 1.6 SDS and tonsils were assessed as Brodsky I-II. He had mild URTI and was clinically evaluated by his paediatrician the day prior to his death. At that time he had URTI, but was in good condition, running around and not generally ill. During the night, he suddenly deteriorated and was found dead in the morning. Autopsy did not reveal the cause of death. Discussion We found an increased AHI in 53 young, pre-pubertal children with genetically confirmed diagnosis of PWS. The high AHI was mainly due to central apneas and hypopneas. In the total group of mainly non-obese PWS children, obstructive apneas were rare. In contrast, obstructive apneas were found in 4 of the 8 overweight patients. After 6 months of GH-treatment a non-significant decrease of AHI was found, mainly due to a decrease in central apneas. No significant change in obstructive apneas was found during GH. Illness or adenoid/tonsil hypertrophy, however did result into a marked increase in sleep-related breathing disorders, and particularly obstructive sleep apnea. Our study also shows that a relatively normal PSG does not exclude the possibility of unexpected death during mild URTI. The increased number of central apneas, in our young PWS children suggests a central origin of SRBD. A hypothalamic origin of SRBD in PWS was already postulated 20 years ago (25). A decreased number of oxytocin neurons in the hypothalamic paraventricular nucleus was reported, which might also be involved in reduced neural modulation of breathing (26,27). Recently, Ren et al (28) proposed that necdin (neurally differentiated embryonal carcinoma-cell derived factor) deficiency may contribute to the observed respiratory abnormalities in individuals with PWS as Necdin is one of the protein-coding genes that are deficient in PWS (29). Deficiency of Necdin in mice results in neonatal hypoventilation, which is usually fatal (30). We found a negative association of both age and BMI, with number of central apneas. Because in PWS children, age and BMI are highly correlated, we cannot distinguish whether this is an effect of age or BMI. From a pathophysiological point of view, we consider it more likely to be an effect of age. In fact, our data are in line with a previous report, indicating that central apneas are more common in younger, healthy children, although within the normal range (31). The mechanism is unclear, and might be related to a relatively more immature respiratory control in younger children. However, we cannot exclude that underweight in young PWS infants might contribute to as well. OSA was uncommon in normal-weight PWS patients. However, 4 of the 8 overweight (defined as BMI over +2 SDS) patients (50%) had signs of OSA. Increased BMI has been associated with decreased SaO2 and higher AHI in older PWS children and adults (32). Harris et al reported an improvement of OSA and hypoventilation after weight-loss in children and adults with PWS (33). Tonsillar hypertrophy may also play a role in OSA. Children with PWS might have a smaller naso- and oropharynx, which could contribute to obstruction (3). Recently an improvement in AHI and oxygen saturation was reported after adenotonsillectomy in 5 PWS children with OSA (34). After 6 months of GH-treatment, a non-significant decline in AHI was found compared to baseline, mainly due to a lower number of central apneas. Thus, our study indicates that GH had no adverse effects on the respiration of PWS children. Several publications reported sudden death in infants and children with PWS during GH treatment (15, 16, 35). Several ones suggested a causal relationship between GH and sudden death in PWS. Until now only limited data were available on the effects of GH on PSG. Miller et al recently reported an improvement of AHI after 6 weeks of GH in most of her PWS patients. She performed PSG in children and adults of which 12 were children under the age of 12 years. A subset of patients, however, had an increased AHI after 6 weeks of GH. Most of these patients had URTI during the second evaluation (36). Haqq et al reported in a cross-over study a decrease in AHI after 6 months of GH in 12 PWS children, aged 4.5 to 14.5 years, although not statistically significant (13). Myers et al demonstrated that inspiratory and expiratory muscle strength improved in 20 children with PWS, aged 4 to 16 years after 12 months of GH compared to 10 controls (11). Lindgren et al found improved CO2-responsiveness in 12 children with PWS after 6-9 months of GH compared to baseline (14). A number of hormones, including GH and IGF1, are involved in the physiologic regulation of breathing (37). IGF1 receptors are located around the central chemoreceptors in the brainstem, and also in the cerebellum where the inputs from chemoreceptors are integrated (38). GH may therefore theoretically improve breathing via a direct mechanism. In our study we found only a small number of obstructive apneas both before and during GH-treatment. There was no increase in obstructive apneas during GH treatment. Five children had adenotonsillectomy before the second PSG was performed, because of adenoid and/or tonsillar hypertrophy. Unfortunately this might confound our results, but for obvious safety reasons we could not avoid this. The AHI of these patients during both PSG's was not different compared to the rest of the study group. We found no significant association between tonsil size or snoring and the AHI. Sleep apnea, both obstructive and central, occurs more frequently in adults with GH excess (acromegaly)(39) and is associated with thickening of the pharyngeal wall in the acromegalic patients (40). We cannot rule out that GH might have resulted in some adenoidhypertrophy, as we only performed fiberoptic endoscopy when indicated by snoring or OSA during PSG. It has been suggested that GH-treatment might increase tonsil size, however, to our knowledge, no controlled, prospective study has been performed. One of our patients died unexpectedly during an episode of URTI. One of the most alarming findings is that this patient had near-normal sleep-related breathing during PSG, both before and during GH-treatment. This points out that a near-normal PSG in a healthy PWS child does not guarantee he/she won't die during mild URTI. It might be related to a rise of apneas (both central and obstructive) during illness as shown in 4 of our patients who had a PSG during an episode of mild URTI. Unexpected deaths have been described in PWS children both without and during GH and have been attributed to several possible causes, such as respiratory dysfunction, cardiomyopathy, temperature instability and adrenal insufficiency or combinations of these. We recommend monitoring of SRBD by PSG and regular ENT-evaluation in all PWS children, both before and during GH-treatment. If adenoidhypertrophy or tonsillar hypertrophy occurs, adenotonsillectomy should be considered. It is important to mention that a relatively normal PSG does not exclude the possibility of unexpected death during mild URTI. Based on our results cardiorespiratory monitoring during URTI in children with PWS before and during GH-treatment should be considered. Future studies are required for evaluating SRBD in PWS during URTI in order to give recommendations with regard to monitoring during URTI. In conclusion, our study shows that many pre-pubertal children with PWS have sleep-related breathing disorders, mainly due to central apneas. BMI or age cannot explain the variability in the severity of the SRBD, although OSA was more prevalent in children with obesity than in normal weight children. After 6 months of GH, a nonsignificant decrease in AHI was found. Thus our data are reassuring with respect to the effects of GH on SRBD. Our study also shows that a normal PSG does not exclude the possibility of unexpected death during mild upper respiratory tract infections. During URTI, AHI may rise and obstructive apneas may occur. Clin Endocrinol (Oxf). 2006 Aug. OBJECTIVE: To evaluate the response to recombinant GH treatment and adverse events in children with Prader-Willi syndrome (PWS) from KIGS, the Pfizer International Growth Database. PATIENTS: A total of 328 children (274 prepubertal, median age 6.0 years; 54 pubertal, median age 12.7 years) were treated for 1 year and 161 children were treated for 2 years with GH. RESULTS: Height standard deviation score (SDS) increased significantly during treatment; the response was greater in prepubertal (-0.7 vs.-1.8 pretreatment) compared with pubertal children (-1.5 vs.-1.8). Predictors of first-year height velocity in multiple regression analysis were GH dose, body weight (positively correlated), height SDS minus mid-parental height SDS and chronological age (negatively correlated), together accounting for 39% of the variation in response to GH. Body mass index (BMI) SDS did not change significantly during 2 years of treatment. Of all the 675 GH-treated PWS patients in KIGS, there were five cases of sudden death (age range 3-15 years). Three were obese (weight for height > 200%) and causes of death included bronchopneumonia, respiratory insufficiency and sleep apnoea. Scoliosis was the most commonly reported adverse event (n = 24), four children developed hyperglycaemia and six had presumptive diabetes (type 2 in five, and one case of type 1). CONCLUSIONS: Short-term growth improved in response to conventional doses of GH in children with PWS. Prior to commencement of GH, examination of the upper airways and sleep studies should be performed in PWS patients. GH should be used with caution in those with extreme obesity or disordered breathing and all patients should be closely monitored for adverse events. Am J Med Genet A. 2006 Jun 12. Growth hormone (GH) therapy for short stature in patients with Prader-Willi syndrome (PWS) has started worldwide, and various favorable effects have been reported. However, the possibility of progression of scoliosis arises as a new problem of the GH therapy. In this study, we analyzed whether 72 patients who have been followed up in our hospital have such a problem. They included 46 males and 26 females (41 patients with the GH therapy and 31 without it) aged from one to 49 years. Consequently, 33 (45.8%) of 72 patients had scoliosis with the Cobb angle of >10 degrees. Twenty (48.8%) of forty-one patients who received a GH therapy and 13 (41.9%) of 31 patients without the therapy had scoliosis, the frequency of scoliosis between the two groups showing no statistical difference (P = 0.56). Height velocity of scoliotic and non-scoliotic patients during the first year of the therapy was 8.59 +/- 1.92 and 10.70 +/- 2.54 cm, respectively, showing a significant difference (P < 0.001). This shows that accelerated height velocity may not induce scoliosis. Comparison of starting age of a GH treatment revealed that non-scoliotic patients received the therapy earlier than scoliotic patients (P = 0.021). Among 20 scoliotic patients who received the GH therapy, the degree of scoliosis progressed during the therapy in six patients, improved in three and fluctuated in one. Many patients showed progression of scoliosis with age irrespective of the use of GH, and some patients improved their scoliosis during the GH therapy. These findings showed that a GH therapy increases height velocity of PWS patients but does not necessarily develop scoliosis, and early start of the therapy may not be an exacerbating factor of scoliosis. Horm Res. 2006 May 9. Background: In Prader-Willi syndrome (PWS) obesity and partial growth hormone (GH) deficiency are frequently observed. The risks of cardiovascular diseases and early death are increased. We examined inflammatory markers in adult PWS, before and during 12 months of GH treatment. Method: Twelve PWS adults, median age 23.5 years (17-37) and median BMI 33.8 kg/m2 (21.2-50.4), participated. Serum interleukin-6, tumour necrosis factor alpha, high sensitive protein C-reactive protein (HCRP), cholesterol, triglycerides, leptin, adiponectin, glucose, insulin, insulin-like growth factor I and body composition were measured at baseline and after 6 and 12 months of GH treatment. Results: Median and range at baseline for interleukin-6 was 9.87 ng/l (1.76-10.72), for tumour necrosis factor alpha 2.39 ng/l (1.00-3.26) and for HCRP 7.64 mg/l (0.41-41.1) (normal values < 5 ng/l, < 8 ng/l and<5 mg/l, respectively). At baseline correlations between inflammatory markers and age, anthropometry, body composition and the metabolic parameters were non-significant; only positive associations were found between tumour necrosis factor alpha and body weight (r = 0.617, p = 0.033) and between HCRP and BMI (r = 0.594, p = 0.041). GH treatment non-significantly decreased the levels of the inflammatory markers. Conclusion: In this pilot study, levels of interleukin-6 and HCRP were increased, and GH intervention did not significantly reduce the levels. Chronic inflammation might contribute to the increased cardiovascular morbidity and mortality in PWS. Nat Clin Pract Endocrinol Metab. May 2006. The introduction of recombinant DNA-derived human growth hormone (rhGH) in the mid-1980s allowed studies to be undertaken in a number of growth disorders other than the classic indication - growth-hormone deficiency (GHD). In patients with GHD, optimizing the dose and frequency of rhGH administration, and early instigation of therapy, has led to near-normalization of final height. The use of rhGH in the treatment of Turner syndrome, Prader-Willi syndrome, intrauterine growth restriction, and chronic renal failure demonstrated the efficacy of therapy, although the increase in final height (5-7 cm) is less than that achieved in GHD. Cost-benefit implications need to be considered in the next phases of evaluating the role of rhGH therapy in these indications. To date, rhGH has only received approval for the management of idiopathic short stature in the US; as with the other wider growth indications, the lack of formal randomized, controlled trials hampers the full evaluation of efficacy, and a cautious approach should, therefore, be adopted for this particular indication. rhGH has a good safety record, although there are current concerns about the possible long-term increased risk of colonic and lymphatic malignancy, which will require monitoring through national cancer registries. Arch Dis Child. 2006 Apr. Recombinant human growth hormone (rhGH) therapy in Prader-Willi syndrome (PWS) causes increased basal metabolic rate and oxygen consumption, and hence increased ventilatory load. The case of an adolescent with PWS who experienced respiratory deterioration with an increase in rhGH and improvement with cessation of therapy is reported. J Clin Endocrinol Metab. 2006 Feb. CONTEXT: GH was approved for Prader-Willi Syndrome (PWS) in 2000. Fatalities in individuals with PWS soon after beginning GH treatment prompted concern about GH worsening sleep apnea. OBJECTIVE: We sought to determine whether GH affects sleep apnea in individuals with PWS. DESIGN: Twenty-five patients with PWS had overnight polysomnography (PSA) at baseline and 6 wk after starting GH. SETTING: The study was conducted in a sleep lab using a standardized procedure. PATIENTS: The patients studied had genetically confirmed PWS. MAIN OUTCOME MEASURES: PSA results were analyzed for frequency and severity of central and obstructive apnea/hypopnea events and total apnea/hypopnea index. RESULTS: As a group, GH improved apnea/hypopnea index by a mean of 1.2 events per hour (P = 0.02) and central events by a median of 1.7 events per hour (P < 0.001). Fourteen patients had improvement in obstructive events by a mean of 1.7 events per hour. Six patients had worsening of obstructive events on GH. Four of these patients had upper respiratory tract infections at the time of the second PSA and had tonsil/adenoid hypertrophy on otorhinolaryngological evaluation. Two patients with high serum IGF-I levels had increased obstructive events. CONCLUSIONS: Most of our PWS patients had improvement after short-term GH treatment, but 32% had worsening of sleep disturbance. A subset of PWS patients are at risk during this window of vulnerability shortly after initiation of GH. Because it is difficult to predict who will worsen with GH, patients with PWS should have PSA before and after starting GH and should be monitored for sleep apnea with upper respiratory tract infections. Otorhinolaryngological evaluation is warranted if sleep apnea worsens on GH. IGF-I levels should be monitored, with the goal being physiological levels. J Clin Endocrinol Metab. 2006 Feb. CONTEXT: GH was approved for Prader-Willi Syndrome (PWS) in 2000. Fatalities in individuals with PWS soon after beginning GH treatment prompted concern about GH worsening sleep apnea. OBJECTIVE: We sought to determine whether GH affects sleep apnea in individuals with PWS. DESIGN: Twenty-five patients with PWS had overnight polysomnography (PSA) at baseline and 6 wk after starting GH. SETTING: The study was conducted in a sleep lab using a standardized procedure. PATIENTS: The patients studied had genetically confirmed PWS. MAIN OUTCOME MEASURES: PSA results were analyzed for frequency and severity of central and obstructive apnea/hypopnea events and total apnea/hypopnea index. RESULTS: As a group, GH improved apnea/hypopnea index by a mean of 1.2 events per hour (P = 0.02) and central events by a median of 1.7 events per hour (P < 0.001). Fourteen patients had improvement in obstructive events by a mean of 1.7 events per hour. Six patients had worsening of obstructive events on GH. Four of these patients had upper respiratory tract infections at the time of the second PSA and had tonsil/adenoid hypertrophy on otorhinolaryngological evaluation. Two patients with high serum IGF-I levels had increased obstructive events. CONCLUSIONS: Most of our PWS patients had improvement after short-term GH treatment, but 32% had worsening of sleep disturbance. A subset of PWS patients are at risk during this window of vulnerability shortly after initiation of GH. Because it is difficult to predict who will worsen with GH, patients with PWS should have PSA before and after starting GH and should be monitored for sleep apnea with upper respiratory tract infections. Otorhinolaryngological evaluation is warranted if sleep apnea worsens on GH. IGF-I levels should be monitored, with the goal being physiological levels. Excerpts from (02/24/06) Science Daily: Growth Hormone, Obesity Can Trigger Sleep Apnea In Some Kids Growth hormone helps hundreds of children with a rare disorder that causes them to gorge on food, but for some, starting treatment can worsen a dangerous nighttime breathing problem, University of Florida researchers have found. Sleep apnea disrupts breathing during sleep and is common among morbidly obese children, including those with Prader-Willi syndrome, a disease that compels them to eat nonstop. Researchers say that uncovering how to treat obesity and related problems in children genetically wired to be overweight could help them better battle childhood obesity in general. Growth hormone has shown to be one of the most effective ways to treat children and adults with Prader-Willi. But UF researchers found that starting treatments can worsen or trigger sleep apnea in obese children exposed to colds, potentially leading to death, according to findings published online recently in The Journal of Clinical Endocrinology and Metabolism. "Every kid we studied had abnormal sleep at the beginning, before growth hormone," said Jennifer Miller, M.D., a UF assistant professor of pediatrics and the study's lead author. "On growth hormone, most of them got better but not all of them. The ones that got worse tended to be school age. Some of them were just entering school and then they were coming home with upper-respiratory infections. "The combination of starting growth hormone, still having weak muscle tone, having an illness and/or being obese tends to put you at risk for having really bad obstructive sleep apnea." The researchers urge doctors to monitor patients' sleep before and during treatment for signs of obstructive sleep apnea, such as loud snoring or abnormal daytime sleepiness. Sleep studies are recommended for all obese children, not just those with Prader-Willi, Miller added. [...] Obesity also can lead to severe respiratory problems as fat accumulates in the upper body and throat, and these effects cause the most problems for obese patients, including those with Prader-Willi, said [Bryan E. Hainline, M.D., Ph.D., an Indiana University associate professor of pediatrics who specializes in pediatric metabolism and genetics]. The UF study highlights this, he added. Growth hormone was approved in the United States to treat Prader-Willi in 2000, but several children with the disease died after beginning the treatments. All died in their sleep and had been battling infections. To understand the problem, UF researchers decided to study how growth hormone affected sleep, monitoring patients on the therapy closely and performing sleep studies before and during treatment, Miller said. The researchers studied 25 children and adults with Prader-Willi syndrome, a large sample for such a rare disorder. Four school-age children had increased difficulty breathing at night shortly after the treatment began. All began having problems after they were exposed to upper respiratory infections in school, the findings show. The children's muscles were so weak at the beginning of the treatment they couldn't breathe with a stuffed-up nose, Miller said. Growth hormone worsened the problem, causing the tonsils to swell and exacerbating their sleep apnea. "We realized it was an infection issue," Miller said. "They didn't have the strength to overcome any resistance." To keep patients safe, the researchers suggest doctors perform sleep studies on children before and during treatment. Some children may also need to have their tonsils removed if necessary. This helps, but because of their poor muscle tone and obesity, Prader-Willi patients have more risks to anesthesia, Miller said. "The important part is for parents to realize that being on growth hormone, while it's good for most people, there is a subset that's vulnerable to having problems during sleep," she said. "That's why the sleep study should be done, because we don't know who it's going to be." Clin Endocrinol (Oxf). 2006 Feb. The ability of GH, via its mediator peptide IGF-1, to influence regulation of cellular growth has been the focus of much interest in recent years. In this review, we will explore the association between GH and cancer. Available experimental data support the suggestion that GH/IGF-1 status may influence neoplastic tissue growth. Extensive epidemiological data exist that also support a link between GH/IGF-1 status and cancer risk. Epidemiological studies of patients with acromegaly indicate an increased risk of colorectal cancer, although risk of other cancers is unproven, and a long-term follow-up study of children deficient in GH treated with pituitary-derived GH has indicated an increased risk of colorectal cancer. Conversely, extensive studies of the outcome of GH replacement in childhood cancer survivors show no evidence of an excess of de novo cancers, and more recent surveillance of children and adults treated with GH has revealed no increase in observed cancer risk. However, given the experimental evidence that indicates GH/IGF-1 provides an anti-apoptotic environment that may favour survival of genetically damaged cells, longer-term surveillance is necessary; over many years, even a subtle alteration in the environmental milieu in this direction, although not inducing cancer, could result in acceleration of carcinogenesis. Finally, even if GH/IGF-1 therapy does result in a small increase in cancer risk compared to untreated patients with GH deficiency, it is likely that the eventual risk will be the same as the general population. Such a restoration to normality will need to be balanced against the known morbidity of untreated GH deficiency. Horm Res. 2006. BACKGROUND: In Prader-Willi syndrome (PWS) obesity and partial growth hormone (GH) deficiency are frequently observed. The risks of cardiovascular diseases and early death are increased. We examined inflammatory markers in adult PWS, before and during 12 months of GH treatment. METHOD: Twelve PWS adults, median age 23.5 years (17-37) and median BMI 33.8 kg/m2 (21.2-50.4), participated. Serum interleukin-6, tumour necrosis factor alpha, high sensitive protein C-reactive protein (HCRP), cholesterol, triglycerides, leptin, adiponectin, glucose, insulin, insulin-like growth factor I and body composition were measured at baseline and after 6 and 12 months of GH treatment. RESULTS: Median and range at baseline for interleukin-6 was 9.87 ng/l (1.76-10.72), for tumour necrosis factor alpha 2.39 ng/l (1.00-3.26) and for HCRP 7.64 mg/l (0.41-41.1) (normal values < 5 ng/l, < 8 ng/l and<5 mg/l, respectively). At baseline correlations between inflammatory markers and age, anthropometry, body composition and the metabolic parameters were non-significant; only positive associations were found between tumour necrosis factor alpha and body weight (r = 0.617, p = 0.033) and between HCRP and BMI (r = 0.594, p = 0.041). GH treatment non-significantly decreased the levels of the inflammatory markers. CONCLUSION: In this pilot study, levels of interleukin-6 and HCRP were increased, and GH intervention did not significantly reduce the levels. Chronic inflammation might contribute to the increased cardiovascular morbidity and mortality in PWS. Horm Metab Res. 2005 Dec. Background: Growth hormone (GH) treatment in patients with GH deficiency (GHD) can determine changes in the thyroid function. The clinical significance of these changes remains controversial, and all studies have so far covered rather a short period - usually no longer than one year. Objective: To determine the effect of long-term recombinant hGH treatment in children with idiopathic GHD on the thyroid function. Patients and methods: Nineteen prepubertal children (12 boys and 7 girls, mean age 9.2 +/- 3.1 years) with idiopathic GHD were studied and followed for twenty-four months. None of the patients showed multiple pituitary hormone deficiencies. Nineteen healthy children matched for age and sex acted as controls. Results: Patients with GHD showed a significant increase in TT (3) at twelve months and in FT (3) at six and twelve months after starting GH treatment, with a significant decrease at eighteen and twenty-four months. TT (4) level decreased significantly at twelve months and increased significantly at eighteen and twenty-four months. FT (4) also decreased, but only slightly, after twelve months of hGH treatment, and then increased significantly at twenty-four months. TSH levels did not vary significantly during the course of therapy. TT (3)/TT (4) and FT (3)/FT (4) ratios increased significantly after six and twelve months of therapy and significantly decreased later, approaching pre-therapy values. The SDS of Growth Velocity (SDS-GV) increased remarkably during the first year of therapy and then decreased significantly during the second year, although it remained significantly higher than the pre-therapy values. TT (3) and TT (3)/TT (4) ratio displayed a significant correlation with SDS-GV at twelve months of therapy. In a multiple regression analysis with age, bone age, parental height, GH dose, TT (3,) TT (3)/TT (4), and the SDS of IGF-I, only the TT (3)/TT (4) ratio at twelve months of therapy (p < 0.001) was identified as a significant predictor of SDS-GV. Conclusion: Our data confirm that changes in thyroid function are present in GHD children during long-term hGH therapy. These changes probably resulted from the effect of hGH on the peripheral metabolism of thyroid hormones and appear to be transitory, disappearing during the second year of hGH treatment. We speculate on the functional significance of these changes, and in particular, on their role in catch-up growth after hGH therapy. Am J Med Genet A. 2005 Jul 1. Patients with Prader-Willi syndrome (PWS) are recognized to have a tendency of sudden, unexpected death (SED), but its exact cause is unknown because of paucity of such case reports. Since growth hormone (GH) treatment was applied to PWS patients worldwide, several cases of death have been reported. However, whether the therapy is directly related to their SED remains unknown, too. We collected 13 deceased PWS patients (Group A, aged 9 months to 34 years) who had never received GH therapy, and seven deceased patients (Group B, all boys aged 0.7-15 years) having received the therapy from the registration in PWS-patient-support associations and from the literature, respectively. We then compared the cause of SED between the two groups. Irrespective of GH therapy, SED of infants under age 1 year was associated with milk aspiration or hypothalamic dysregulation of respiration, while SED of patients in early childhood or adolescence occurred at sleeping in association with preceding viral infections. In contrast, SED of four adult (>20 years of age) patients who never received GH therapy was associated with complications, such as leg cellulites and pulmonary embolism, secondary to massive obesity and diabetes mellitus (DM). Two Group-B patients (aged 14 and 20 years) without any obesity-related or diabetes-related complications died of drowning in a bath tub, and their drowning death could be related to poor respiratory control [or cataplexy?]. These findings indicated that the cause of SED is not essentially different between PWS patients with and without GH treatment. Deceased PWS patients may have had underlying respiratory dysregulation and hypothalamic dysfunction, and GH therapy might have led to certain obstructive respiratory disturbances that exacerbated the respiratory conditions. This will call clinicians' attention when using GH in PWS patients, for example, careful determination of the dose of GH and careful monitoring of patient's respiratory conditions, especially in male obese patients with respiratory problems. Acta Paediatr. 2005 Jul. Reports on sudden death in Prader-Willi syndrome (PWS) patients after the start of growth hormone (GH) treatment have been published recently. We observed a 4.7-y-old girl who showed a continuous increase in pulmonary artery pressure and died of cardiorespiratory failure 7 wk after GH therapy had been initiated, and a 9.3-y-old girl with additional trisomy 21 who died during a minor respiratory infection 6 mo after GH had been started. Both patients were overweight (weight for height 127% and 224%, respectively). GH-induced fluid retention may have occurred in the younger girl. In contrast to the reported cases, our PWS patients were female. CONCLUSION: Our cases illustrate the difficulty of differentiation between possible GH side effects and the natural course of disease, in particular with respect to obesity-related comorbidity and mortality. Pediatr Int. 2005 Jun. No abstract available. J Endocrinol Invest. 2005 Jun. A few cases of death worldwide during GH treatment in pediatric patients with Prader-Willi syndrome (PWS) have been recently described. The evaluation of further cases is needed to better identify possible causal mechanism(s), as well as to suggest some additional guidelines for prevention. We report the death of 2 additional children with genetically confirmed PWS in the first months of GH therapy. Case 1: This 3.9-yr-old girl was born at 39 weeks gestation. Low GH response to two stimulation tests was observed. GH administration was started at the age of 3.5 yr (0.33 mg/kg per week), when the patient was at 130% of her ideal body weight (ibw). Hypertrophy of adenoids was previously demonstrated. Snoring and sleep apnea were present before GH treatment, and did not increase during therapy. Four months later she died at home suddenly in the morning. Case 2: This patient was a 6.3-yr-old boy. He was born at term after an uneventful pregnancy. At the age of 6 yr, his weight was at 144% of his ibw. He showed reduced GH secretion during provocation tests, and GH therapy was started (0.20 mg/kg per week). The previously reported nocturnal respiratory impairment had worsened after beginning GH administration. Tonsils and adenoids hypertrophy were noted. At the age of 6.3 yr he died at home in the morning following an acute crisis of apnea. These additional cases seem to confirm that some children with PWS may be at risk of sudden death at the beginning of GH therapy. Horm Res. 2005. We describe a child with Prader-Willi syndrome (PWS) aged 3 years and 11 months who suddenly died 7 months after the initiation of GH therapy. The child never showed respiratory problems, but suffered from severe obesity. This case raises the question about the association between sudden death in children with PWS (with or without respiratory problems) and GH therapy, as already suspected in the recent past. We suggest that further epidemiological studies are required in order to determine more accurately the frequency of this causal connection and better understand its pathogenesis. Horm Res. 2005. Irrespective of GH treatment, children with Prader-Willi syndrome (PWS) suffer more frequently and more seriously from respiratory problems than healthy children. The pathogenesis of such respiratory problems in PWS seems to be multifactorial in origin, but mainly related to insufficiency of respiratory muscles and pharyngeal narrowness. Deaths of children with PWS are reported among GH treated as well as untreated children. Our data show that also disturbed body composition plays an important role in fatal outcomes, possibly enhancing the ventilation disorder. For several years, in our recommendations we have pointed out the secondary risks of increasing obesity. In addition, it is recommended for all children with PWS, in particular before institution of GH therapy, to have polysomnography and an otorhinolaryngologic examination performed, and tonsillectomy in the case of enlarged tonsils. Furthermore, upper airway infections should be treated aggressively. J Pediatr Endocrinol Metab. 2004 Sep. Prader-Willi syndrome (PWS) is characterized by hypothalamic dysfunction resulting in obesity, hypotonia, hypogonadism, and behavioral abnormalities. Clinical features of PWS resemble those of GH deficiency (decreased total lean body mass, IGF-I levels, and poor linear growth). Marked reductions in muscle mass are associated with diminished strength, physical function, and energy expenditure. Lifelong morbidities of PWS include osteoporosis, type 2 diabetes mellitus, respiratory disorders, and cardiorespiratory failure related to obesity and hypotonia. Recent studies show that GH therapy improves linear growth, final height, physical strength, and agility in patients with PWS. Some effects of GH therapy wane with time, however, and strategies for treating adults with PWS remain uncertain. In addition, deaths in markedly obese, GH-treated children with PWS have been reported, and a possible contribution of GH to these events has not yet been definitively excluded. Consequently, critical evaluation should continue of the long-term benefits, risks, and costs of GH therapy for patients with PWS. J Pediatr Endocrinol Metab. 2004 Mar. A 13 year-old boy with Prader-Willi syndrome and steatohepatitis presented with diabetic ketoacidosis 4 weeks after the initiation of growth hormone (GH) treatment. He did not have signs or symptoms of type 2 diabetes mellitus (DM2) before the initiation of GH treatment. Hyperglycemia resolved 2 months after discontinuation of GH. He redeveloped DM2 6 months later associated with excessive weight gain. Diabetic ketoacidosis as a rare complication of GH therapy emphasizes the importance of screening for carbohydrate intolerance before and during GH treatment in patients with Prader-Willi syndrome. Steatohepatitis may be the only manifestation of insulin resistance and warrants further evaluation. [Note: Steatohepatitis is characterized by inflammation of the liver together with the accumulation of fat in the liver. It is classically found in alcoholics, but is also frequently found in people with diabetes and obesity, in which case it is called "non-alcoholic steatohepatitis" (NASH). Both types can progress to cirrhosis.] J Pediatr. 2004 Jan. A 4-year-old boy with Prader-Willi syndrome died suddenly while asleep on day 67 of growth hormone treatment. During treatment, snoring had worsened. Autopsy showed multifocal bronchopneumonia. This case and two others recently published suggest that growth hormone may be associated with obstructive apnea, respiratory infection, and sudden death in this condition. Int J Clin Pharmacol Ther. 2004 Jan. Background and objective: There are numerous, often contradictory reports on the effects of growth hormone (GH) therapy on thyroid function. The aim of this study was to assess the effect of such therapy on serum concentrations of thyroid hormones in GH-deficient children euthyroid prior to the treatment, and to determine the necessity of thyroid hormone administration in these patients. Material and methods: The study included 32 GH-deficient patients in the first stage of sexual development, in whom disorders of thyroid function could be excluded. The inclusion criteria were based on clinical examination and levels of thyroxine (T4), triiodothyronine (T3), free thyroxine (fT4), free triiodothyronine (fT3), reverse triiodothyronine (rT3), thyrotropin (TSH) before and after stimulation with thyrotropin-releasing hormone (TRH). Recombinant growth hormone (rGH) (Genotropin 16U, Pharmacia) was administered at a dose of 0.7 U/kg/week. Fasting blood samples were drawn before treatment and after 3, 6, 9 and 12 months of therapy. Thyroid hormones were measured using RIA and IRMA methods. Results: There were no physical signs of hypothyroidism in the patients examined during 12 months of rGH administration, and the satisfactory growth rate was achieved. T4 levels decreased in the first 3 months but remained within the normal range, and then returned to the values prior to the treatment. A similar trend was observed for fF4, with 28.5% of patients exhibiting fF4 levels below the normal in the 3rd month. An increase during the first 3 months of therapy was observed in the cases of T3 (statistically non-significant) and fT3, and these values then fell to levels within the normal range of patients' age. During treatment, TSH levels decreased but remained within the normal range. Conclusions: A transient decrease in T4 concentrations in the 3rd month with unchanged T3 and an increase in fT3 concentrations probably result from the effect of rGH on the peripheral metabolism of thyroid hormones. The results obtained do not support the use of thyroid hormone therapy with levothyroxine during the first year of rGH therapy in patients who are initially euthyroid. Treat Endocrinol. 2004. Prader-Willi syndrome is a complex genetic disorder with a characteristic cognitive, behavioral, and endocrinologic phenotype. Obesity, partial growth hormone (GH) secretion, and hypogonadism are common. Results of several somatropin (GH therapy) studies in children with Prader-Willi syndrome have shown improvement in growth, body composition, physical strength, and agility. GH deficiency in adults without Prader-Willi syndrome is associated with abdominal obesity, insulin resistance, and an unfavorable lipid profile, and the partial state of GH deficiency seen in Prader-Willi syndrome thus renders these patients exposed to a lifelong risk of metabolic diseases. The nongrowth effects of somatropin in children with Prader-Willi syndrome have directed interest towards adults in preventing long-term consequences of GH deficiency, but the potential impact of somatropin therapy in adults with Prader-Willi syndrome is not known in detail. To date, only one study has been published. In this study, 17 patients (9 men and 8 women) with a mean age of 25 years and a mean body mass index of 35 +/- 3.2 kg/m2 were examined. Eleven had the Prader-Willi syndrome genotype. They were treated with somatropin (Genotropin) for 12 months after an initial placebo-controlled period of 6 months. Compared with placebo, somatropin increased insulin-like growth factor-1 levels (p < 0.01) and decreased body fat (p = 0.04). During the 12-month period with somatropin therapy, the mean reduction in body fat was 2.5% (p < 0.01), concomitant with a mean increase in lean body mass of 2.2kg (p < 0.05). Lipid profiles were normal in most patients before treatment and did not change. The oral glucose tolerance test was impaired in one patient at study start and in five patients at 12 months. No patients developed diabetes mellitus. Furthermore, insulin levels remained unchanged, and estimation of insulin resistance by homeostasis model assessment did not disclose any change. Transient adverse effects attributed to water retention occurred in three patients. In conclusion, the one published study of somatropin therapy in adults with Prader-Willi syndrome showed beneficial effects on body composition without pronounced adverse effects. However, further studies are required to establish the definite role and optimal dosage of somatropin, as well as long-term effects, in adults with Prader-Willi syndrome. Drug Saf. 2004. The therapeutic use of growth hormone (GH) has caused concern, as it is anabolic and mitogenic, and its effector hormone, insulin-like growth factor (IGF)-I is anti-apoptotic. As both hormones can cause proliferation of normal and malignant cells, the possibility that GH therapy may induce cancer, increase the risk of tumour recurrence in those previously treated for a malignancy, or increase the risk of cancer in those with a predisposition, has resulted in concerns over its use. There are theoretical and epidemiological reasons that suggest GH and IGF-I may be important in tumour formation and proliferation. Malignant tumours have been induced in animals exposed to supraphysiological doses of GH, whereas hypophysectomy appears to protect animals from carcinogen-induced neoplasms. In vitro, proliferation and transformation of normal haemopoetic and leukaemic cells occurs with supraphysiological doses of GH, but not with physiological levels. IGF, IGF binding proteins (IGFBP) and IGFBP proteases influence the proliferation of cancer cells in vitro; however, GH is probably not involved in this process. Epidemiological studies have suggested an association between levels of IGF-I and cancer, and an inverse relationship between IGFBP-3 and cancer; however, these associations have been inconsistent. A number of studies have been undertaken to determine the risk of the development of cancer in children treated with GH, either de novo, or the recurrence of cancer in those previously treated for a malignancy. Despite early concerns following a report of a cluster of cases of leukaemia in recipients of GH, there appears to be no increased risk for the development of leukaemia in those treated with GH unless there is an underlying predisposition. Even in children with a primary diagnosis of cancer, subsequent GH use does not appear to increase the risk of tumour recurrence. However, a recent follow-up of pituitary GH recipients has suggested an increase in colorectal cancer. In addition, follow-up of oncology patients has suggested an increase in second neoplasms in those who also received GH therapy. These studies emphasise the importance of continued surveillance both internationally with established databases and also nationally through single-centre studies. Clin Endocrinol (Oxf). 2003 Dec. Objective: Recombinant hGH treatment may alter thyroid hormone metabolism and we have recently reported that 50% of patients with GH deficiency (GHD) due to organic lesions, previously not treated with thyroxine, developed hypothyroidism during treatment with recombinant human GH (rhGH). These results prompted us to evaluate the impact of rhGH treatment on thyroid function in children with GHD. Design: Open study of GH treatment up to 12 months. Investigations were performed at baseline, and after 6 and 12 months of GH therapy. Measurement and study subjects: Serum TSH, FT4, FT3, AbTg and AbTPO, IGF-I, height and weight, were evaluated in 20 euthyroid children (group A) with idiopathic isolated GHD and in six children (group B) with multiple pituitary hormone deficiencies (MPHD) due to organic lesions. Among the latter, four already had central hypothyroidism and were on adequate LT4 replacement therapy, while two were euthyroid at the beginning of the study. Results: Serum IGF-I levels normalized in all patients. In both groups, a significant reduction in FT4 levels (P < 0.01) occurred during rhGH therapy. No patient in group A had FT4 values into the hypothyroid range, while in four of six patients in group B, fell FT4 levels into the hypothyroid range during rhGH. In particular, the two euthyroid children developed central hypothyroidism during rhGH treatment, and their height velocities did not normalize until the achievement of euthyroidism through appropriate LT4 substitution. No variation in serum FT3 and TSH levels was recorded in either groups. Conclusion: Contrary to that observed in patients with MPHD, rhGH replacement therapy does not induce central hypothyroidism in children with idiopathic isolated GHD, further supporting the view that in children with MPHD, as in adults, GHD masks the presence of central hypothyroidism. Slow growth (in spite of adequate rhGH substitution and normal IGF-I levels) is an important clinical marker of central hypothyroidism, therefore a strict monitoring of thyroid function is mandatory in treated children with MPHD. J Clin Endocrinol Metab. 2003 May. The objective of this study was to investigate the effects of GH administration on pulmonary function, sleep, behavior, cognition, linear growth velocity, body composition, and resting energy expenditure (REE) in children with Prader-Willi syndrome. The study used a 12-month, balanced, randomized, double-blind, placebo-controlled, cross-over experimental design. Twelve subjects were randomized to GH (0.043 mg/kg x d) or placebo intervention for 6 months and then crossed over to the alternate intervention for 6 months. Differences in outcome variables were determined by paired t tests. Peak flow rate, percentage vital capacity, and forced expiratory flow rate improved and number of hypopnea and apnea events and duration of apnea events trended toward improvement after GH intervention. The only difference in cognition or behavior was an increase in hyperactivity scale on the Behavior Assessment System for Children after GH intervention. Linear growth velocity, REE, and lean mass were higher (67%, 19%, and 7.6%, respectively), and fat mass and percentage body fat were lower (10.3% and 8.1%, respectively) after GH intervention. GH administration did not change mean fasting ghrelin concentration. GH intervention improved body composition and REE and may contribute to better sleep quality and pulmonary function. J Clin Endocrinol Metab. 2003 Apr. The effects of GH replacement therapy on energy metabolism are still uncertain, and long-term benefits of increased muscle mass are thought to outweigh short-term negative metabolic effects. This study was designed to address this issue by examining both short-term (1 wk) and long-term (6 months) effects of a low-dose (9.6 µg/kg body weight·d) GH replacement therapy or placebo on whole-body glucose and lipid metabolism (oral glucose tolerance test and euglycemic hyperinsulinemic clamp combined with indirect calorimetry and infusion of 3-[3H]glucose) and on muscle composition and muscle enzymes/metabolites, as determined from biopsies obtained at the end of the clamp in 19 GH-deficient adult subjects. GH therapy resulted in impaired insulin-stimulated glucose uptake at 1 wk (-52%; P = 0.008) and 6 months (-39%; P = 0.008), which correlated with deterioration of glucose tolerance (r = -0.481; P = 0.003). The decrease in glucose uptake was associated with an increase in lipid oxidation at 1 wk (60%; P = 0.008) and 6 months (60%; P = 0.008) and a concomitant decrease in glucose oxidation. The deterioration of glucose metabolism during GH therapy also correlated with the enhanced rate of lipid oxidation (r = -0.508; P = 0.0002). In addition, there was a shift toward more glycolytic type II fibers during GH therapy. In conclusion, replacement therapy with a low-dose GH in GH-deficient adult subjects is associated with a sustained deterioration of glucose metabolism as a consequence of the lipolytic effect of GH, resulting in enhanced oxidation of lipid substrates. Also, a shift toward more insulin-resistant type II X fibers is seen in muscle. Glucose metabolism should be carefully monitored during long-term GH replacement therapy. Selections from the full text article: Introduction Growth hormone has marked effects on energy metabolism, influencing all major pathways of substrate metabolism. Many studies have been performed to establish the effect of GH on glucose and lipid metabolism in GH-deficient (GHD) man, but the results have been quite divergent due to differences in dose, route of administration, and duration of treatment. Several placebo-controlled studies using higher doses (12–23 µg/kg·d) of GH have reported constant elevation of fasting blood (B)-glucose and serum (S)-insulin concentrations (1, 2, 3, 4). Similarly, high-dose GH treatment for 6 wk resulted in reduced insulin sensitivity determined by a hyperinsulinemic euglycemic clamp, but after 6 months of treatment, insulin sensitivity returned to pretreatment levels (5). Another study using the modified insulin suppression test did not observe any untoward effects on insulin sensitivity after 12 months of treatment (6). Also, a 50% lower GH dose resulted in an exaggerated insulin response and a decreased insulin-mediated glucose disposal after 1 wk of treatment, but insulin sensitivity returned to baseline after 3 months of treatment (7). In contrast, Weaver et al. (8) reported persistent decreased insulin sensitivity after 6 months of treatment with a physiological (9 µg/kg·d) GH dose. Some of the different temporal effects may be ascribed to the acute lipolytic effect of GH, which later on could be counteracted by positive effects of increased lean body mass on insulin sensitivity. This study was designed to address some of these controversies, examining short- and long-term effects of physiological GH replacement on different aspects of glucose and lipid metabolism in GHD adults. Patients and Methods Patients. Nineteen consecutive patients (7 women and 12 men; mean age, 42 ± 2.6 yr; estimated duration of GHD, 134 ± 25 months) from the outpatient clinic of the Department of Endocrinology, University Hospital, Malmö, Sweden, were included (Table 1). Inclusion criteria were: an estimated duration of GHD for more than 1 yr; patients were on stable hormonal replacement therapy; and patients did not have impaired glucose tolerance. Informed consent was obtained from all subjects. The diagnosis of GHD was based on a maximal GH peak less than 9 mU/liter (3 µg/liter) after a provocation stimulus such as insulin-induced hypoglycemia, arginine, or clonidine applied within 6 months before inclusion in the study. All patients were hormonally replaced for pituitary insufficiencies, except one premenopausal woman who did not receive estrogens. The hormone substitution therapy had been stable for at least 6 months before inclusion in the study. One patient who had hypercholesterolemia and recurrent thrombosis was treated with simvastatin, cholestyramine, and dicumarol. The treatment was unchanged throughout the study. The patients were randomized in a double-blind manner to either GH substitution (Genotropin, Pharmacia, Stockholm, Sweden), 0.067 mg/kg body weight (BW)·wk divided into daily sc doses at bedtime, or the corresponding volume of the preservatives given as placebo. [...] Results At baseline, there was no difference between the placebo and GH-treated groups with respect to gender, age, and body mass index (BMI; Tables 1 and 2). There was no difference in GH peak after stimulatory testing, estimated duration of GHD, and the number of additional pituitary deficiencies (median, 2.2 vs. 2.7). All subjects were clinically and biochemically euthyroid throughout the study. There was no difference in baseline IGF-I concentrations between the placebo and GH-treated groups. After 1 wk (P = 0.008) and 6 months (P = 0.011) of treatment, IGF-I increased in the GH-treated group compared with before treatment, and also compared with the placebo group (P = 0.0002 and 0.0019, respectively). IGF-I SD score increased compared with before treatment from -4.2 ± 1.1 at baseline to 0.7 ± 0.6 after 1 wk (P = 0.008) and 0.3 ± 0.7 after 6 months (P = 0.011) in the GH-treated group and compared with the placebo group (P = 0.0002 and 0.0015, respectively). BW, BMI, body fat (BF), and lean body mass were similar in the placebo and GH groups before treatment. There was no significant change in body composition during GH treatment in all subjects. After 6 months of GH treatment, there was, however, a decrease in percentage BF in men but not in women. TBW was similar before treatment in the placebo and GH groups. There was no significant change in TBW after 1 wk or 6 months of treatment with GH, compared with before treatment, but TBW increased at 6 months compared with placebo (P = 0.0158). Fasting glucose and insulin did not differ between the placebo and GH groups at baseline. There was, however, a significant increase in fasting B-glucose (P = 0.033) and insulin (P = 0.018) levels after 1 wk on GH replacement therapy compared with before treatment and also between the changes in the GH and placebo groups (P = 0.0042 and 0.0092, respectively). When compared with baseline, the increase in insulin was sustained after 6 months of treatment (P = 0.017), whereas fasting B-glucose had returned to baseline levels. The changes in fasting B-glucose and insulin in the GH-treated group were significantly increased (P = 0.0271 and 0.0415, respectively) compared with placebo after 6 months. The AUC of glucose and insulin during the OGTT did not differ before treatment between the placebo and GH groups. In the GH-treated group, the AUC of glucose increased after 1 wk (P = 0.0499) and 6 months (P = 0.036) compared with before treatment and compared with the placebo group (P = 0.0113 and 0.0113, respectively). The AUC of insulin was unchanged after 1 wk and 6 months of treatment in the GH group compared with baseline, but increased after 1 wk (P = 0.0055) compared with the placebo group; at 6 months, there was no difference. Glucose metabolism (Fig. 2 and Table 4) Before treatment, there was no difference in insulin-stimulated glucose disposal between the placebo and GH-treated groups. After 1 wk (P = 0.008) and 6 months (P = 0.008), glucose storage decreased by 52% and 39%, respectively, during GH treatment compared with baseline, but it was unchanged during placebo treatment. Glucose disposal was significantly lower in the GH-treated group compared with the placebo group at both 1 wk and 6 months (P = 0.0008 and 0.0412, respectively). The rate of glucose disposal correlated negatively with the IGF-I concentration (r = -0.493; P = 0.0002) and AUC glucose (r = -0.481; P = 0.0003). Basal rate of glucose oxidation did not differ between the placebo and GH groups before treatment. During GH treatment, there was a decrease in basal glucose oxidation after 1 wk (P = 0.021), which was sustained after 6 months of treatment (P = 0.016) compared with before treatment and compared with placebo after 1 wk (P = 0.0152). In the placebo group, the basal rate of glucose oxidation was unchanged during the 6-month period. The rate of insulin-stimulated glucose oxidation was similar in the placebo and GH groups before treatment and decreased after 1 wk (P = 0.015) and 6 months (P = 0.045) of GH replacement compared with baseline and compared with placebo after 1 wk (P = 0.0275). The rate of nonoxidative glucose metabolism during insulin stimulation was similar in the placebo and GH groups before treatment. During GH treatment, there was a significant decrease in nonoxidative glucose metabolism after both 1 wk (P = 0.008) and 6 months (P = 0.011) compared with before treatment, and also when compared with placebo (P = 0.0019 and 0.0469, respectively). It was unchanged in the placebo group. Before treatment, basal HGP did not differ between the two groups. Neither was there any effect on basal HGP after 1 wk or 6 months in the GH-treated group, compared with before treatment or compared with the placebo group. There was no difference in residual HGP during the clamp, which was completely suppressed in both groups at baseline, after 1 wk, and after 6 months of GH replacement therapy. The basal rate of lipid oxidation did not differ between the placebo and GH groups before treatment. The basal rate of lipid oxidation increased in the GH-treated group after 1 wk (P = 0.008) and 6 months (P = 0.007), both compared with before treatment and with the placebo group (P = 0.0009 and 0.0269, respectively). Before treatment, there was no difference in insulin-suppressed lipid oxidation in the placebo and GH groups. GH treatment increased the rate of lipid oxidation during the clamp after 1 wk (P = 0.008) and after 6 months (P = 0.011), compared with before treatment and with the placebo group (P = 0.009 and 0.0469, respectively). The rate of lipid oxidation correlated positively with FFA (r = 0.629; P < 0.0001) and IGF-I (r = 0.311; P = 0.001) and negatively with glucose disposal (r = -0.508; P = 0.0002), particularly glucose oxidation (r = -0.648; P < 0.0001). There was also an inverse correlation between lipid oxidation and nonoxidative glucose metabolism (r = -0.473; P = 0.004). There was no difference in FFA and leptin levels between the groups before treatment. Neither was there any significant change in FFA or leptin concentrations during GH treatment, compared with before treatment or placebo (Table 3). There was a negative correlation between leptin levels and glucose disposal (r = -0.313; P = 0.019) and between leptin levels and nonoxidative glucose metabolism (r = -0.306; P = 0.023). Energy expenditure and protein metabolism (Table 4) There was no difference in energy expenditure between the placebo and GH groups before treatment. After 1 wk (P = 0.008) and 6 months (P = 0.008) of GH replacement therapy, basal energy expenditure increased compared with before treatment and with placebo (P = 0.0092 and 0.0029, respectively). Basal energy expenditure correlated positively to the basal rate of lipid oxidation (r = 0.667; P < 0.0001), and the change in basal energy expenditure after 1 wk and 6 months was strongly correlated to the change in basal rate of lipid oxidation (r = 0.72; P < 0.0001). There was no difference in insulin-stimulated energy expenditure between the placebo and GH groups, and this did not change after 1 wk and 6 months with either GH or placebo. Protein oxidation was similar in both groups before treatment and did not significantly change during the insulin clamp. There was no significant change during the 6-month period during either fasting or insulin-stimulated conditions in the placebo and GH-treated groups, compared with before treatment and with the placebo group. Muscle biopsies Fiber typing (Table 5). There was no difference in relative distribution of the mean area type I, IIA, IIX, and IIC fibers between the GH and placebo groups before treatment. After 6 months of GH therapy, the relative distribution of type IIX fibers increased (P = 0.018) compared with before treatment. In the placebo group, fiber type composition did not change. The change in mean area distribution of type IIA fibers correlated with the change in fasting insulin (r = 0.353; P = 0.0255). Muscle triglyceride levels (Table 6). There was no difference in muscle triglyceride content between the placebo and GH groups before treatment. After 1 wk and 6 months of treatment, there was no significant change in muscle triglycerides in either the GH-treated or placebo group. GS activity (Table 6). Before treatment, GS activity was lower in the placebo group compared with the GH group. There was no significant effect of GH on GS activity compared with before treatment and with the placebo group. Discussion In the present study, physiological GH replacement (IGF-I SD score, 0.3 ± 0.7 after 6 months of treatment) in GHD adults resulted in persistent impairment of glucose tolerance and insulin sensitivity. This is only partially in agreement with previous studies using higher doses of GH (5, 7), in which fasting glucose returned to baseline after 3–12 months and insulin sensitivity improved. Part of this improvement in insulin sensitivity with time in GH-treated adult subjects with GHD has been ascribed to a GH-induced decrease in body fat and an increase in lean body mass, which is usually accompanied by enhanced insulin sensitivity (6). In contrast to this, Christopher et al. (29) found a persistent decrease in insulin sensitivity despite improved body composition. We observed impaired insulin-stimulated glucose uptake after both 1 wk and 6 months in the GH-treated subjects, affecting both oxidative and nonoxidative pathways of intracellular glucose metabolism. The most likely explanation for the impairment of insulin-stimulated glucose metabolism was concomitant increase in lipid oxidation, which correlated inversely with glucose uptake (r = -0.508) and oxidation (r = -0.648). This is supported by a recent study in which we found that inhibition of lipolysis with acipimox partially prevented GH-induced insulin resistance (30). The increased rate of lipid oxidation is likely a consequence of the lipolytic action of GH as demonstrated by the close correlation between S-FFA and the rate of lipid oxidation (r = 0.699; P < 0.0001) and the S-IGF-I levels as a measure of GH action and the rate of lipid oxidation (r = 0.311; P = 0.001). We did not observe any significant change in the rate of HGP, either in the basal state or during insulin clamp. It could be argued that our estimates of residual rate of glucose production during the clamp were not sensitive enough because we used a constant infusion of the 3-[3H]glucose tracer (31, 32). We acknowledge this problem, but do not think that this can explain the difference in insulin-stimulated glucose uptake between GH and placebo, which was in the order of 20 µmol/kg BW·min. Other studies using an insulin dose similar to the dose in this study and a variable infusion of 3-[3H]glucose did not show any effect, or only moderate effect, of GH on residual HGP during the clamp (29, 33). Therefore, it is unlikely that GH exerts a major effect on HGP during these conditions. The situation may be different during prolonged starvation because GH might stimulate glucagon release and thereby gluconeogenesis (34). We observed a slight but significant increase in basal energy expenditure after both 1 wk and 6 months of GH substitution. No such increase was seen during the clamp. The increase in the rate of energy expenditure can partially be ascribed to the increased rate of lipid oxidation, which correlated with energy expenditure (r = 0.72; P < 0.0001). The lack of stimulation of energy expenditure by insulin (thermogenesis) can probably be ascribed to the insulin resistance induced by GH. A thermogenetic response to insulin is usually lacking in insulin-resistant states (35). Enhanced energy expenditure has previously been demonstrated during short-term (14 h) GH infusion in GHD patients (36), who if untreated are characterized by a low rate of energy expenditure. The mechanism by which GH therapy increases energy expenditure could also involve increased conversion of T4 to T3 (37, 38, 39), an increase in lean body mass (40, 41, 42), which is a strong determinant of energy expenditure (43), and an increase in IGF-I (33, 39). In contrast to some previous studies, the negative effect of GH on glucose metabolism was not attenuated after 6 months. There is no reason to believe that the lipolytic effect of GH would disappear with time. Instead, in some previous studies the subsequent increase in lean body mass seen during GH therapy has been considered to counterbalance the negative effect of GH on glucose metabolism. In this study, we observed no significant effect of GH on lean body mass. There may be several reasons for this. First, our method for estimating body composition (bioimpedance) is not optimal in GH-treated patients if there is a simultaneous fluid retention. Second, the GH dose used in this study was quite modest. Third, it is possible that the patients included in this study already had more preserved lean body mass than patients in previous studies at the start of the GH therapy. Regardless of this, the untoward effect of GH on glucose metabolism persisted after 6 months. However, we have observed impaired insulin sensitivity even after 2 yr of GH treatment (44). This is also supported by Johnston et al. (45), who found increased fasting insulin levels even after 10 yr of GH treatment. There may also be another explanation for the absence of improved insulin sensitivity with time. Muscle fiber composition changed after 6 months of GH replacement therapy, resulting in increased fast-twitch glycolytic type IIX fibers. An increased amount of type IIX fibers has been associated with insulin resistance (46), but it is not known whether this represents the cause or the consequence of insulin resistance. Interestingly, in rats 7 d of insulin infusion resulted in a similar switch from type I to type IIX fibers (47). We can therefore not exclude the possibility that hyperinsulinemia associated with GH treatment (possibly in association with increased IGF-I levels) was the cause of the change in fiber type composition observed in these patients. In conclusion, GH therapy for 6 months in GHD adults results in impaired insulin-stimulated glucose metabolism and a change in muscle fiber type toward glycolytic type IIX fibers. The impairment of glucose metabolism correlates strongly with an increased rate of lipid oxidation and could reflect a switch from using glucose to lipids, i.e. activated glucose fatty acid cycle. It is thus important to monitor glucose tolerance during long-term treatment with even moderate doses of GH. [...] Hua Xi Yi Ke Da Xue Xue Bao. 2002 Jan. OBJECTIVE: To investigate the immunogenicity of a domestic recombinant human growth hormone (rhGH) preparation and assess its influence on the growth-promoting effect. METHODS: We developed a specific and sensitive radioimmuno-precipitation assay to determine the anti-hGH-antibody (GH-Ab) in serum of GH-deficient (GHD) children treated with rhGH preparation. The study included 61 GHD children (49 boys and 12 girls) who were treated with daily subcutaneous injections of rhGH (0.1 IU/Kg) before sleep for six months. The patients' height, growth velocity an |