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Glucocorticoid use in Duchenne and Becker muscular dystrophy prolongs ambulation but cause significant skeletal toxicity. Our analysis has immediate clinical implications, suggesting that growth hormone and testosterone have a stronger effect prior to first and subsequent vertebral fracture, respectively, relative to bisphosphonates alone in children with dystrophinopathies on chronic glucocorticoids., Purpose: Glucocorticoids prolong ambulation in boys with Duchenne muscular dystrophy; however, they have significant endocrine side effects. We assessed the impact of growth hormone (GH), testosterone, and/or zoledronic acid (ZA) on vertebral fracture (VF) incidence in patients with dystrophinopathies on chronic glucocorticoids., Methods: We conducted a longitudinal retrospective review of 27 males with muscular dystrophy. Accelerated failure time (AFT) models were used to estimate the relative time to VF while on GH, testosterone, and/or ZA compared to ZA alone. Results are reported as failure time ratio, where >1 indicates prolonged time versus <1 indicates shorter time to next VF., Results: The prevalence of growth impairment was 96% (52% utilized GH), pubertal delay was 86% (72% utilized testosterone), and low trauma fractures were 87% (72% utilized ZA). Multivariable analysis of the AFT models showed that participants on either GH or testosterone treatment relative to ZA alone experienced prolonged time to next VF (1.253, P<0.001), with GH being the significant contributor when analyzed independently from testosterone (1.229, P<0.001). Use of ZA with GH or testosterone relative to ZA alone resulted in prolonged time to next VF (1.171, P<0.001), with testosterone being a significant contributor (1.130, P=0.033)., Conclusion: GH and testosterone each decreased VF risk in patients independent of or in combination with ZA, respectively., (© 2023. The Author(s).)

Daily administration of growth hormone (GH) treatment has been in clinical use for treatment for GH deficiency (GHD) in adults for more than 30 years. Numerous studies have demonstrated evidence that GH treatment improves body composition, cardiovascular risk factors and quality of life with few side effects. Less frequent GH injections are hypothesized to improve adherence and several long-acting GH (LAGH) formulations have been developed and a few have been approved and marketed. Different pharmacological modifications have been applied and the pharmacokinetics and pharmacodynamics of LAGH are different to each other and to those of daily injections and require different dosing and monitoring specific for each LAGH. Studies have shown improved adherence with LAGH, and short-term efficacy and side effects are comparable between daily GH injections and LAGHs. Long-term treatment with daily GH injections is effective and safe, while long-term studies for LAGHs are awaited. In this review challenges, benefits, and risks of treatment with daily and long-acting GH preparations will be compared., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: The growth potential in pubertal boys with short stature is limited by the effect of estrogen on epiphyseal fusion. This study aims to identify the efficacy and safety of the combination of growth hormone (GH) and letrozole on adult height (AH) in pubertal boys with short stature., Methods: This is a retrospective record based study. Pubertal boys with short stature who were treated with GH and letrozole were followed up at outpatient clinics in our hospital. Twenty subjects who reached AH are reported here., Results: Baseline chronological age was 12.12 ± 1.14 yr and bone age was 13.00 ± 0.93 yr. The period of GH/letrozole treatment was 1.94 ± 0.67 yr. Height standard deviation score for bone age was increased from -1.46 ± 0.51 before treatment to -0.12 ± 0.57 after treatment (P < 0.001). The predicted AH before treatment, predicted AH after treatment, AH, and genetic target height were 161.02 ± 4.12 cm, 172.11 ± 4.20 cm, 172.67 ± 2.72 cm, and 167.67 ± 3.56 cm, respectively. There was a significant predicted AH difference before and after treatment (P < 0.001). There was a significant difference between predicted AH before treatment and genetic target height (P < 0.001). Predicted AH after therapy was higher than that of gene target height (P < 0.001), as well as AH and genetic target height (P < 0.001). There was no significant side effect., Conclusions: GH and letrozole combination can enhance AH in pubertal boys with short stature., (© 2022. The Author(s).)

A wide variety of medications have been associated with lichenoid drug eruption. They present similarly or even identically to idiopathic lichen planus, both clinically and histologically. Lichenoid eruption has been associated with recombinant human growth hormone intake in two previous patients. Herein, we describe a young boy who developed a lichenoid eruption following growth hormone injection for dwarfism.

Background: Short stature is the most consistent characteristic feature of Turner syndrome (TS). To improve final heights of children with TS effectively, it is important to provide them with early and appropriate treatment using growth hormone (GH). The objective of this study was to assess the efficacy and safety of a new recombinant human GH, Growtropin®-II (DA-3002, Dong-A ST Co., Ltd) versus a comparator (Genotropin®, Pfizer Inc.) for Korean children with TS., Methods: This open-label, active-controlled, parallel-group, randomized controlled phase III trial was conducted at 11 hospitals in Korea. Eligible patients (n = 58) were randomized to two groups: 1) DA-3002 group (administrated with DA-3002 at 0.14 IU [0.0450-0.050 mg] /kg/day); and 2) comparator group (administrated with the comparator at 0.14 IU [0.0450-0.050 mg] /kg/day)., Results: The change from baseline in annualized height velocity (HV) after a 52-week treatment period was 4.15 ± 0.30 cm/year in the DA-3002 group and 4.34 ± 0.29 cm/year in the comparator group. The lower bound of 95% two-sided confidence interval for group difference in the change of annualized HV (- 1.02) satisfied the non-inferiority margin (- 1.5). The change in height standard deviation score (HtSDS) at 52-week was 0.70 ± 0.23 for the DA-3002 group and 0.66 ± 0.39 for the comparator group, showing no significant (p = 0.685) difference between the two groups. The change of skeletal maturity defined as change in bone age/change in chronological age between the two groups was not significantly different (1.25 ± 0.58 for the DA-3002 group and 1.47 ± 0.45 for the comparator group, p = 0.134). Changes from baseline in serum insulin-like growth factor-1 (IGF-1) and insulin-like growth factor binding protein-3 (IGFBP-3) after 52 weeks of treatment did not differ significantly between the two groups (p = 0.565 and p = 0.388, respectively) either. The occurrence of adverse events was not statistically different between groups., Conclusions: This study demonstrates that the efficacy and safety of GH treatment with DA-3002 in children with TS are comparable with those of the comparator. It is expected to analysis the long-term effect of DA-3002 on the increase of final adult height in children with TS and possible late-onset complications in the future., Trial Registration: The study was registered at ClinicalTrials.gov. ClinicalTrials.gov identifier: NCT01813630 (19/03/2013)., (© 2021. The Author(s).)

Somatopause refers to the gradual declines in growth hormone (GH) and insulin-like growth factor-1 throughout aging. To define how induced somatopause affects skeletal integrity, we used an inducible GH receptor knockout (iGHRKO) mouse model. Somatopause, induced globally at 6 months of age, resulted in significantly more slender bones in both male and female iGHRKO mice. In males, induced somatopause was associated with progressive expansion of the marrow cavity leading to significant thinning of the cortices, which compromised bone strength. We report progressive declines in osteocyte lacunar number, and increases in lacunar volume, in iGHRKO males, and reductions in lacunar number accompanied by ~20% loss of overall canalicular connectivity in iGHRKO females by 30 months of age. Induced somatopause did not affect mineral/matrix ratio assessed by Raman microspectroscopy. We found significant increases in bone marrow adiposity and high levels of sclerostin, a negative regulator of bone formation in iGHRKO mice. Surprisingly, however, despite compromised bone morphology, osteocyte senescence was reduced in the iGHRKO mice. In this study, we avoided the confounded effects of constitutive deficiency in the GH/IGF-1 axis on the skeleton during growth, and specifically dissected its effects on the aging skeleton. We show here, for the first time, that induced somatopause compromises bone morphology and the bone marrow environment., (© 2021 The Authors. Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.)

Fibroma of tendon sheath (FTS) is an uncommon mass that arises from the tendon sheath of extremities. The tumor typically affects adults between ages 20 and 50 years with a predominance in males. To date, growth hormone (GH) treatment is safe for children with Turner syndrome without risk factors and is accepted worldwide. This article reports the case of a nine-year-old female patient with Turner syndrome and FTS during GH treatment. She had been treated with daily subcutaneous GH to improve growth failure with a mean dose of 0.28 mg/kg/week and the level of insulin-like growth factor-1 was within the normal range. During the follow-up period, she complained about a mass in her hand, subsequently diagnosed as FTS. This report illustrates the clinical impact of Turner syndrome and GH treatments on the occurrence of this tumor through literature reviews. Further studies are needed to highlight the association between FTS and GH treatment, especially in Turner syndrome.

Purpose: Osteoarthritis (OA) of the temporomandibular joint (TMJ) elicits cartilage and subchondral bone defects. Growth hormone (GH) promotes chondrocyte growth. The aim of this study was to evaluate the efficacy of intra-articular injections of GH to treat TMJ-OA., Materials and Methods: Monosodium iodoacetate (MIA) was used to induce OA in the TMJs of rats. After confirming the induction of OA, recombinant human GH was injected into the articular cavities of rats. Concentrations of GH and IGF-1 were measured in the blood and synovial fluid, and OA grades of cartilage and subchondral bone degradation were recorded by histological examination and micro-computed tomography., Results: MIA-induced OA in the rat TMJ upregulated insulin-like growth factor-1 (IGF-1) rather than GH levels. GH and IGF-1 concentrations were increased after local injection of GH, compared with controls. Locally injected GH lowered osteoarthritic scores in the cartilage and subchondral bone of the TMJ., Conclusion: Intra-articular injection of GH improved OA scores in rat TMJs in both cartilage and subchondral bone of the condyles without affecting condylar bone growth. These results suggest that intra-articular injection of human GH could be a suitable treatment option for TMJ-OA patients in the future., Competing Interests: The authors have no potential conflicts of interest to disclose., (© Copyright: Yonsei University College of Medicine 2020.)

Aims: Although preliminary studies have demonstrated safety and effectiveness of single replacement therapy for growth hormone deficiency or testosterone deficiency in heart failure (HF), no data are available regarding the combined treatment with both GH and T in this setting. Thus, the aim of the present hypothesis generating pilot study was to evaluate the effectiveness and safety of multiple hormonal replacement therapies in chronic HF., Methods and Results: Five stable HF with reduced ejection fraction patients, with a concomitant diagnosis of growth hormone deficiency and testosterone deficiency, on top of guideline-based HF treatment underwent 1 year of GH replacement therapy by subcutaneous injections of somatotropin at a dose of 0.012 mg/kg every second day. After 12 months, a T replacement treatment was added at a dosage of 1000 mg every 3 months. Each patient underwent a complete M-mode, two-dimensional, and Doppler echocardiographic examination, and an incremental symptom-limited cardiopulmonary exercise test on a bicycle ergometer at baseline (BL), after 1 year of GH treatment (V1), and after 1 year of combined GH + T treatments (V2). One-year of GH treatment resulted in a significant improvement in left ventricular ejection fraction (+5.4%, P < 0.01), New York Heart Association functional class (P < 0.05), and peak oxygen consumption (VO 2 peak) (+19.3%, P < 0.01), and in a significant reduction in NT-proBNP levels (-35.1%, P < 0.01). Notably, one additional year of combined GH and T replacement therapy induced a further increase in VO 2 peak (+27.7%, final delta change + 52.44%, P < 0.01), as well as a significant improvement in muscular strength, as assessed by handgrip dynamometry (+17.5%, final delta change + 25.8%, P < 0.01). These beneficial effects were paralleled with an improvement of the overall clinical status (as assessed by New York Heart Association class). Of note, neither adverse effects nor cardiovascular events were reported during the follow-up period., Conclusions: Our preliminary data suggest for the first time that combined replacement therapy with GH and T could be considered safe and therapeutic in HF patients with multiple hormone deficiencies, supporting the hypothesis that multiple hormone deficiencies syndrome can be considered as a novel and promising therapeutic target in HF. Further studies with a more robust design and larger population are needed., (© 2019 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of the European Society of Cardiology.)

Objective: Imprinting disorders (ID), such as Prader-Willi syndrome (PWS), are associated with sleep-disordered breathing (SDB). No data are available for Silver-Russell syndrome (SRS), another ID that shares clinical features with PWS, although many patients describe excessive daytime sleepiness, disturbed sleep, and snoring. The aim of this study was to characterize sleep in children with SRS and to evaluate the impact of recombinant growth hormone (rGH) therapy., Methods: We performed a retrospective analysis of sleep recordings in 40 patients with molecularly proven SRS (methylation anomaly in 11p15 [n = 32] or maternal uniparental disomy of chromosome 7 [n = 16]). Sleep recordings were either by means of polygraphy or polysomnography (PSG) (n = 16). A total of 34 patients received rGH therapy., Results: We collected 61 sleep recordings. The mean apnea-hypopnea index (AHI) was 3.4 events/h (0-12.4), with a mean central AHI of 0.5 events/h (0-2.4). SDB was identified in 73.8% (n = 45) of the recordings and was severe in 4.9%. SDB was present in 86.4% of patients before rGH therapy and was severe in 13.6%. AHI worsened for 5 of 12 patients with sleep recordings before and after rGH therapy initiation, reaching mild impairment. The mean rGH dose was 32.3 μg/kg/(12.9-51.4), with a mean insulin-like growth factor 1 plasma level of 1.7 SDS (-1.9 to 6.6)., Conclusion: Most patients with SRS present with SDB with an obstructive profile, possibly explained by narrowing of the airways and lymphoid organ hypertrophy. We recommend systematic ear-nose-throat evaluation of SRS patients and PSG if there are clinical anomalies, preferably before initiating rGH therapy, to monitor and adapt the management of patients with SDB., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Objective: Some features of subjects with Prader-Willi syndrome (PWS) resemble those seen in growth hormone deficiency (GHD). Children with PWS are treated with growth hormone (GH), which has substantially changed their phenotype. Currently, young adults with PWS must discontinue GH after attainment of adult height when they do not fulfil the criteria of adult GHD. Limited information is available about the prevalence of GHD in adults with PWS. This study aimed to investigate the GH/insulin-like growth factor (IGF-I) axis and the prevalence of GHD in previously GH-treated young adults with PWS., Design: Cross-sectional study in 60 young adults with PWS., Measurements: Serum IGF-I and IGFBP-3 levels, GH peak during combined growth hormone-releasing hormone (GHRH)-arginine stimulation test., Results: Serum IGF-I was <-2 standard deviation scores (SDS) in 2 (3%) patients, and IGFBP-3 was within the normal range in all but one patient. Median (IQR) GH peak was 17.8 μg/L (12.2; 29.7) [~53.4 mU/L] and below 9 μg/L in 9 (15%) patients. Not one patient fulfilled the criteria for adult GHD (GH peak < 9 μg/L and IGF-I < -2 SDS), also when BMI-dependent criteria were used. A higher BMI and a higher fat mass percentage were significantly associated with a lower GH peak. There was no significant difference in GH peak between patients with a deletion or a maternal uniparental disomy (mUPD)., Conclusions: In a large group of previously GH-treated young adults with PWS, approximately 1 in 7 exhibited a GH peak <9 μg/L during a GHRH-arginine test. However, none of the patients fulfilled the consensus criteria for adult GHD., (© 2019 The Authors. Clinical Endocrinology Published by John Wiley & Sons Ltd.)

BACKGROUND Growth hormone insensitivity and reduced levels of insulin-like growth factor-1 (IGF-1) are associated with metabolic syndrome that includes obesity, hyperglycemia, type 2 diabetes mellitus, and dyslipidemia. Laron syndrome is a rare autosomal recessive condition associated with insensitivity to growth hormone that results in short stature and metabolic syndrome and is usually diagnosed in childhood. This report is of a 42-year-old Mexican woman with untreated growth hormone insensitivity and diabetic retinopathy, in whom gene sequencing supported the identification of a variant of Laron syndrome. CASE REPORT A 42-year-old Mexican woman with untreated growth hormone insensitivity, metabolic syndrome, and type 2 diabetes mellitus was diagnosed with cataracts, severe retinopathy and hearing loss. She was investigated for genetic causes of reduction in IGF-1. Next-generation sequencing (NGS) showed genetic changes in the growth hormone and IGF-1 axis. The patient's phenotype and genetic changes were consistent with Laron syndrome. CONCLUSIONS The early detection of reduced IGF-1 and identification of the cause of growth hormone insensitivity require international consensus on the approach to diagnosis and treatment methods, including effective IGF-1 replacement therapy. Early diagnosis may reduce the clinical consequences of complications that include short stature the development of metabolic syndrome, type 2 diabetes mellitus, and retinopathy.

Several components of the GH axis are involved in tumor progression, and GH-induced intracellular signaling has been strongly associated with breast cancer susceptibility in genome-wide association studies. In the general population, high IGF-I levels and low IGF-binding protein-3 levels within the normal range are associated with the development of common malignancies, and components of the GH-IGF signaling system exhibit correlations with clinical, histopathological, and therapeutic parameters in cancer patients. Despite promising findings in preclinical studies, anticancer therapies targeting the GH-IGF signaling system have led to disappointing results in clinical trials. There is substantial evidence for some degree of protection against tumor development in several animal models and in patients with genetic defects associated with GH deficiency or resistance. In contrast, the link between GH excess and cancer risk in acromegaly patients is much less clear, and cancer screening in acromegaly has been a highly controversial issue. Recent studies have shown that increased life expectancy in acromegaly patients who attain normal GH and IGF-I levels is associated with more deaths due to age-related cancers. Replacement GH therapy in GH deficiency hypopituitary adults and short children has been shown to be safe when no other risk factors for malignancy are present. Nevertheless, the use of GH in cancer survivors and in short children with RASopathies, chromosomal breakage syndromes, or DNA-repair disorders should be carefully evaluated owing to an increased risk of recurrence, primary cancer, or second neoplasia in these individuals., (Copyright © 2019 Endocrine Society.)

Purpose: Growth hormone (GH) replacement decreases insulin sensitivity in healthy individuals. However, the effects of GH on organ-specific insulin sensitivity and glucose effectiveness are not well characterized. The purpose of this study was to evaluate the effects of GH administration for 26 weeks on muscle and hepatic insulin sensitivity and glucose effectiveness in healthy older individuals., Methods: This report is from a 26-week randomized, double-blind, placebo-controlled parallel-group trial in healthy, ambulatory, community-dwelling older women and men. We compared surrogate indices of insulin sensitivity [quantitative insulin-sensitivity check index (QUICKI), muscle insulin sensitivity index (MISI), hepatic insulin resistance index (HIRI)] and glucose effectiveness [oral glucose effectiveness index (oGE)] derived from oral glucose tolerance tests (OGTTs) in subjects before and after 26 weeks of administration of GH (n = 17) or placebo (n = 15) as an exploratory outcome., Results: GH administration for 26 weeks significantly increased fasting insulin concentrations and HIRI but did not significantly change MISI or oGE compared to placebo., Conclusions: GH administration for 26 weeks in healthy older subjects impairs insulin sensitivity in the liver but not skeletal muscle and does not alter glucose effectiveness.

Craniofacial and dental morphology is influenced by different circulating hormones, but it is of particular importance that there is growth hormone (GH) in normal craniofacial and teeth development. Craniofacial morphometry studies in children with GH deficiency show different changes in certain anthropometric variables in the sense of reducing their values compared to normal children's developmental norms in different stages of childhood and adolescence. Therefore, the early establishment of GH replacement therapy can correct craniofacial morphological changes induced by GH deficiency. In our study, we evaluated different anthropometric craniofacial variables at children with GH deficiency and we established some anthropometric and morphological characteristics associated with this pathology.

Objectives: Preliminary data from the French cohort of the Safety and Appropriateness of Growth hormone treatments in Europe (SAGhE) study raised concerns regarding the safety of recombinant human GH, suggesting that GH may increase mortality and incidence of stroke in patients treated during childhood for GH deficiency or short stature. We evaluated published safety data, focusing on mortality, neoplasms, cerebrovascular events and diabetes across a number of large-scale pharmaceutical company GH registries., Design: A literature review was conducted using PubMed, EMBASE and Google Scholar to identify all relevant safety data from manufacturers' GH registries published between 1988 and April 2016. Results were hand-sorted to exclude nonrelevant publications; bibliographic references from retrieved articles were evaluated for any additional references., Results: The published data do not support an increased risk of mortality in children or adults treated with GH. There was no evidence of an increased risk of stroke, new malignancy, leukaemia, nonleukaemic extracranial tumours or recurrence of intracranial malignancy in patients without risk factors. The risk of a second neoplasm is increased, particularly if patients have received radiation therapy for a central nervous system tumour. There may be an increased risk of type 2 diabetes in GH-treated patients, but this appears to be confined to those with pre-existing risk factors., Conclusions: Patients with risk factors for malignancy or type 2 diabetes should be treated with caution and monitored during follow-up, but current published data provide reassurance on the long-term safety profile of GH in patients receiving GH treatment., (© 2017 John Wiley & Sons Ltd.)

Hormones with anabolic properties such as growth hormone (GH), insulin-like growth factor-1 (IGF-I), and insulin are commonly abused among professional and recreational athletes to enhance physical ability. Performance enhancing drugs (PEDs) such as these are also commonly used by recreational athletes to improve body aesthetics. The perception of increased muscle mass due to supraphysiologic hormone supplementation, or doping, is widespread among PED users despite a paucity of evidence-based data in humans. Even still, athletes will continue to abuse PEDs in hopes of replicating anecdotal results. It is important to educate the general public and potential treating physicians of the risks of PED use, including the dangers of polypharmacy and substance dependence. It will also be important for the research community to address the common challenges associated with studying PED use such as the ethical considerations of PED administration, the general reticence of the PED-using community to volunteer information, and the constant need to improve or create new detection methods as athletes continually attempt to circumvent current methods. This review highlights the anabolic mechanisms and suggestive data implicating GH, IGF-I, and insulin for use as PEDs, the specific detection methods with cutoff ranges that may be utilized to diagnose abuse of each substance, and their respective side effects., (Published by Elsevier B.V.)

The known interactions between the somatotropic and hypothalamic-pituitary-gonadal (HPG) axes have not been well delineated in older individuals. Aging-associated decline in insulin like growth factor-1 (IGF-1) levels has been proposed to play a role in reproductive senescence in animals. However, the effects of GH on LH secretion are unknown in older individuals. Our objective was to determine whether GH modulates LH secretion or levels of sex steroids (SS) in healthy older (ages 65-88 years) men ( n  = 24) and women ( n  = 24) with low-normal plasma IGF-1 levels. In a double-masked, placebo-controlled ( n  = 24), randomized study, we evaluated the effects of GH ( n  = 24, 20  μ g/kg sc 3×/week) for 26 weeks on nocturnal LH secretory dynamics [(8 pm to 8 am, Q20) min sampling and analyzed by multiparameter deconvolution algorithm]. Indices of LH secretion [frequency, mass per burst, pulsatile production rate, and approximate entropy (ApEn)] and fasting serum IGF-1, SHBG, and SS (TT, fT, or E2) were measured. At baseline, all indices of LH secretion (frequency, mass per burst, pulsatile production rate) were inversely ( P  < 0.05) related to IGF-1, but not to mean nocturnal serum GH concentrations. GH administration for 26 weeks increased serum IGF-1, but exerted no significant effects on LH secretory dynamics, or concentrations of SSs (TT, fT, or E2) or SHBG in older women or men. These data suggest that GH-mediated increases in IGF-1 do not modulate the HPG axis in older individuals., (Published 2017. This article has been contributed to by US Government employees and their work is in the public domain in the USA.)

Background: Recombinant human growth hormone (rhGH) treatment in children is usually prescribed using actual body weight. This may result in inappropriately high doses in obese children., Methods: Retrospective audit of all paediatric patients treated with rhGH 2010-14 at a tertiary paediatric hospital in the UK. Change in height SDS and IGF-I SDS during the first year of treatment was stratified by initial BMI SDS in a mixed cohort, and a subgroup of GH deficient (GHD) patients. Alternative doses for those BMI SDS ≥2.0 (Obese) were calculated using BSA, IBW and LBW., Results: 354 patients (133 female) received rhGH, including 213 (60.2%) with GHD. Obesity was present in 40 patients (11.3%) of the unselected cohort, and 32 (15.0%) of the GHD cohort. For GHD patients, gain in height SDS was directly related to BMI SDS, except in obese patients (p<0.05). For both the entire cohort, and GHD patients only, IGF-1 SDS was significantly higher in obese patients (p<0.0001 for both groups). Cross sectional data identified 265 children receiving rhGH, 81 (30.5%) with a BMI-SDS ≥1.75. Alternate prescribing strategies for rhGH prescribing in obese patients suggest a saving of 27% - 38% annually., Conclusions: Gain in IGF-I SDS is greater in obese children, and is likely to be related to relatively higher doses of rhGH. Additional gain in height was not achieved at the higher doses administered to obese children. Alternative dosing strategies in the obese patient population should be examined in rigorous clinical trials.

Introduction: Ataxia telangiectasia (A-T) is a devastating autosomal recessive disorder with chromosomal instability and growth failure. Low levels of growth hormone (GH) and growth factors may be related to advanced neurological deterioration, wasting syndrome and more pronounced immunodeficiency., Objective: The objective of this study is to study safety and effectiveness of GH therapy in patients with A-T and evaluate the effect of GH on ataxia and lymphocyte subsets., Methods: Three patients with classical A-T were treated with GH (0.3 mg/kg/d) for 1 year. Growth rate, ataxia score and lymphocyte subsets were monitored., Results: GH treatment was well tolerated. All patients showed a significant increase of height SDS of +1.3 (mean height SDS -1.994), a mean increase of 8 (6-11) cm/12 months. Lymphocytes subsets and ataxia were not altered before and after GH treatment., Conclusions: Treatment with GH is feasible and effective in A-T patients with severe growth arrest, but no effect on ataxia and lymphocytes could be recorded.

For nearly 100 years, growth hormone (GH) has been known to affect insulin sensitivity and risk of diabetes. However, the tissue governing the effects of GH signaling on insulin and glucose homeostasis remains unknown. Excess GH reduces fat mass and insulin sensitivity. Conversely, GH insensitivity (GHI) is associated with increased adiposity, augmented insulin sensitivity, and protection from diabetes. Here, we induce adipocyte-specific GHI through conditional deletion of Jak2 (JAK2A), an obligate transducer of GH signaling. Similar to whole-body GHI, JAK2A mice had increased adiposity and extreme insulin sensitivity. Loss of adipocyte Jak2 augmented hepatic insulin sensitivity and conferred resistance to diet-induced metabolic stress without overt changes in circulating fatty acids. While GH injections induced hepatic insulin resistance in control mice, the diabetogenic action was absent in JAK2A mice. Adipocyte GH signaling directly impinged on both adipose and hepatic insulin signal transduction. Collectively, our results show that adipose tissue governs the effects of GH on insulin and glucose homeostasis. Further, we show that JAK2 mediates liver insulin sensitivity via an extrahepatic, adipose tissue-dependent mechanism., Competing Interests: The authors have declared that no conflict of interest exists.

To assess the long-term safety of administering growth hormone (GH) in patients with GH deficiency due to treatment for childhood medulloblastoma and primitive neuroectodermal tumor (PNET). Data were retrospectively retrieved on children receiving GH supplementation, assessing their disease-free and overall survival outcomes and risk of secondary malignancies using Kaplan-Meier and Cox models. Overall 65 children were consecutively collected from May 1981 to April 2013. All patients had undergone craniospinal irradiation (total dose 18-39 Gy), and subsequently received GH for a median (interquartile range, IQR) of 81 (50.6-114.9) months. At a median (IQR) of 122.4 months (74.4-149.5) after the end of their adjuvant cancer treatment, two patients (3 %) experienced recurrent disease and 8 (12.3 %) developed secondary malignancies, all but one of them (an osteosarcoma) related to radiation exposure and occurring within the radiation fields. There was no apparent correlation between the administration of GH replacement therapy (or its duration) and primary tumor relapse or the onset of secondary malignancies [HR: 1.01 (95 % CI: 0.98, 1.03) for every additional 12 months of GH supplementation; p = 0.36). At univariate analysis, the large cell or anaplastic medulloblastoma subtype, metastases and myeloablative chemotherapy correlated with a higher risk of secondary malignancies (p < 0.1), but multivariate analysis failed to identify any factors independently associated with this risk. Our data supports once more the safety of long-term GH replacement therapy in children treated for medulloblastoma/PNET, previously reported in larger data sets. The neurooncology community now need to warrant large-scale meta-analyses or international prospective trials in order to consolidate our knowledge of factors other than GH, such as genetic predisposition, high-grade/metastatic disease, high-dose chemotherapy and era of treatment, in promoting the occurrence of secondary malignancies.

Context: Growth of short children in puberty is limited by the effect of estrogen on epiphyseal fusion., Objectives: To compare: 1) the efficacy and safety of aromatase inhibitors (AIs) vs GH vs AI/GH on increasing adult height potential in pubertal boys with severe idiopathic short stature (ISS); and 2) differences in body composition among groups., Design: Randomized three-arm open-label comparator., Setting: Outpatient clinical research., Patients: Seventy-six pubertal boys [mean (SE) age, 14.1 (0.1) years] with ISS [height SD score (SDS), -2.3 (0.0)]., Intervention: Daily AIs (anastrozole or letrozole), GH, or AI/GH for 24-36 months., Outcomes: Anthropometry, bone ages, dual x-ray absorptiometry, spine x-rays, hormones, safety labs., Results: Height gain [mean (SE)] at 24 months was: AI, +14.0 (0.8) cm; GH, +17.1 (0.9) cm; AI/GH, +18.9 (0.8) cm (P < .0006, analysis of covariance). Height SDS was: AI, -1.73 (0.12); GH, -1.43 (0.14); AI/GH, -1.25 (0.12) (P < .0012). Those treated through 36 months grew more. Regardless of treatment duration, height SDS at near-final height [n = 71; age, 17.4 (0.2) years; bone age, 15.3 (0.1) years; height achieved, ∼97.6%] was: AI, -1.4 (0.1); GH, -1.4 (0.2); AI/GH, -1.0 (0.1) (P = .06). Absolute height change was: AI, +18.2 (1.6) cm; GH, +20.6 (1.5) cm; AI/GH, +22.5 (1.4) cm (P = .01) (expected height gain at -2.0 height SDS, +13.0 cm). AI/GH had higher fat free mass accrual. Measures of bone health, safety labs, and adverse events were similar in all groups. Letrozole caused higher T and lower estradiol than anastrozole., Conclusions: Combination therapy with AI/GH increases height potential in pubertal boys with ISS more than GH and AI alone treated for 24-36 months with a strong safety profile.

Previous studies have shown that GH and IGF-I may enhance tumorigenesis, metastasis, and cell proliferation in humans and animals. Evidence supporting this notion is derived from animal model studies, epidemiological studies, experience from patients with acromegaly, molecular therapeutic manipulation of GH and IGF-I actions, and individuals with GH receptor and congenital IGF-I deficiencies. Prior exposure to radiation therapy, aging, family history of cancer, and individual susceptibility may also contribute to increase this risk. Therefore, the use of GH replacement in patients with a history of cancer raises hypothetical safety concerns for patients, caregivers, and providers. Studies of GH therapy in GH-deficient adults with hypopituitarism and childhood cancer survivors have not convincingly demonstrated an increased cancer risk. Conversely, the risk of occurrence of a second neoplasm (SN) in childhood cancer survivors may be increased, with meningiomas being the most common tumor; however, this risk appears to decline over time. In light of these findings, if GH replacement is to be considered in patients with a previous history of cancer, we propose this consideration to be based on each individual circumstance and that such therapy should only be initiated at least 2 years after cancer remission is achieved with the understanding that in some patients (particularly those with childhood cancers), GH may potentially increase the risk of SNs. In addition, close surveillance should be undertaken working closely with the patient's oncologist. More long-term data are thus needed to determine if GH replacement in GH-deficient adults with a history of cancer is associated with the development of de novo tumors and tumor recurrence.

Context: Long-term safety of growth hormone (GH) treatment is an area of much debate. Studies including children treated with GH not only due to GHD, but also due to non-GHD causes like idiopathic short stature or like short stature in children born small for gestational age have suggested that GH treatment is associated with increased mortality or stroke., Objective: To study the impact of GH replacement on overall and cause-specific mortality in childhood-onset GHD (CO GHD) patients., Design: A nationwide population-based registry study on patients with CO GHD and general population controls matched on age and gender. Mortality hazard ratios (HRs) were computed comparing patients and controls, and comparing GH-replaced patients and non-GH-replaced patients, using Cox regression. Comparing GH- and non-GH-replaced patients HRs were adjusted for birth year, year of diagnosis, gender, irradiation, ACTH insufficiency and primary disease., Patients and Controls: A total of 494 patients with CO GHD each matched with 100 general population controls were included., Results: Mortality was substantially increased comparing patients with CO GHD and general population controls, HR = 7·51 (95% CI = 6·06-9·31). Comparing GH-replaced patients with non-GH-replaced patients mortality was significantly decreased in total (HR = 0·27, CI = 0·17-0·43) and due to malignancy (HR = 0·14, CI = 0·07-0·28) in GH-replaced patients. Adjusting for relevant confounders, this decrease remained significant both in total (HR = 0·56, CI = 0·32-0·96) and due to malignancy (HR = 0·33, CI = 0·16-0·69). Overall and cause-specific mortality was increased in both GH-replaced and non-GH-replaced patients compared to general population controls, but mortality was generally highest in non-GH-replaced patients., Conclusion: The present data from a national cohort of patients with CO GHD do not support the suggestion that GH replacement is associated with increased mortality., (© 2015 John Wiley & Sons Ltd.)

Performance-enhancing drugs (PEDs) gained wide popularity not only among sportsmen but also among specific subsets of population, such as adolescents. Apart from their claimed effects on athletic performance, they are very appealing due to the body shaping effect exerted on fat mass and fat-free mass. Besides the "underestimated" massive misuse of PEDs, the short- as well as long-term consequences of such habits remain largely unrecognized. They have been strictly associated with serious adverse effects, but molecular mechanisms are yet to be elucidated. Here, we analyze the current understanding of the molecular effects of supraphysiological doses of doping agents in healthy biological systems, at genomic and proteomic levels, in order to define the molecular sensors of organ/tissue impairment, determined by their misuse. The focus is put on the anabolic androgenic steroids (AASs), specifically testosterone (T) and its most potent derivative dihydrotestosterone (DHT), and on the peptide hormones, specifically the growth hormone (GH) and the insulin-like growth factor-1 (IGF-1). A map of molecular targets is defined and the risk incidence for human health is taken into account.

"Bovine spongiform encephalopathy", "scrapie", as well as Creutzfeldt-Jakob disease and kuru belong to a group of related neurological conditions termed "transmissible spongiform encephalopathies". These diseases are based on the LD50 measurement whereby saline brain homogenates are injected into experimental animals and when 50% of them develop symptoms, this is considered as transmission of the disease, but the gold standard for diagnosis is autopsy examination. However, an untenable assumption is being made in that saline brain homogenates do not cause tissue damage but it is known since the time of Pasteur, that they give rise to "post-rabies vaccination allergic encephalomyelitis". This is the fundamental flaw in the diagnosis of these diseases. A way forward, however, is to examine infectious agents, such as Acinetobacter which show molecular mimicry with myelin and elevated levels of antibodies to this microbe are found in multiple sclerosis patients and animals affected by "bovine spongiform encephalopathy"., (Copyright © 2014. Published by Elsevier Ltd.)

Objective: The potential involvement of growth hormone therapy in tumor promotion and progression has been of concern for several decades. Our aim was to assess systematically the association between growth hormone therapy and all-cause, cancer and cardiovascular mortality, cancer morbidity and risk of second neoplasm mainly in patients treated during childhood and adolescence., Design: A systematic review of all articles published until September 2013 was carried out. The primary efficacy outcome measures were the all-cause, cancer and cardiovascular standardized mortality ratios (SMR). The secondary efficacy outcome measures were the standardized incidence ratio (SIR) for cancer and the relative risk (RR) for second neoplasms. The global effect size was calculated by pooling the data. When the effect size was significant in a fixed model we repeated the analyses using a random model., Results: The overall all-cause SMR was 1.19 (95% CI 1.08-1.32, p<0.001). Malignancy and cardiovascular SMRs were not significantly increased. Both the overall cancer SIR 2.74 (95% CI 1.18-5.41), and RR for second neoplasms 1.99 (95% CI 1.28-3.08, p=0.002), were significantly increased., Conclusion: The results of this meta-analysis may raise concern on the long-term safety of GH treatment. However, several confounders and biases may affect the analysis. Independent, long-term, well-designed studies are needed to properly address the issue of GH therapy safety., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Context and Objective: Titrating the dosage of growth hormone (GH) to serum levels of insulin-like growth factor-I (IGF-I) is a feasible treatment strategy in children with GH deficiency (GHD) and idiopathic short stature (ISS). The objective was to assess the dose-sparing effect and theoretical safety of IGF-I-based GH therapy., Design, Setting and Patients: This was a post hoc analysis of a previously described 2-year, multicenter, open-label, randomized, outpatient, controlled clinical trial in 172 prepubertal short children [age 7·5 ± 2·4 years; height standard deviation score (HSDS) -2·64 ± 0·61] classified by baseline peak GH levels as GHD (<7 ng/ml) or ISS (≥7 ng/ml)., Intervention: Conventional weight-based dosing of GH (0·04 mg/kg/day) (n = 34) or GH dosing titrated to an IGF-I target of 0 SDS (IGF0T; n = 70) or an IGF-I target of +2 SDS (IGF2T; n = 68)., Main Outcome Measures: Change in HSDS per GH mg/kg/day dose (∆HSDS/GH dose ratio) and proportion of IGF-I levels above +2 SDS at the end of 2 years., Results: GH dosing titrated to an IGF-I target of 0 SDS was the most dose-sparing treatment regimen for GHD or ISS children (mean±SE ∆HSDS/GH dose ratios 48·1 ± 4·4 and 32·5 ± 2·8, respectively) compared with conventional dosing (30·3 ± 6·6 and 21·3 ± 3·5, respectively; P = 0·02, P = 0·005) and IGF2T (32·7 ± 4·8 and 16·3 ± 2·8, respectively; P = 0·02, P < 0·0001). IGF0T also resulted in the fewest IGF-I excursions above +2 SDS (6·8% vs 30·0% for conventional dosing; P < 0·01)., Conclusions: IGF-I-based GH dosing, targeted to age- and gender-adjusted means, may offer a more dose-sparing and potentially safer mode of therapy than traditional weight-based dosing., (© 2014 John Wiley & Sons Ltd.)

Purpose: The administration of recombinant human growth hormone in adults with growth hormone deficiency has been known to improve metabolic impairment and quality of life. Patients, however, have to tolerate daily injections of growth hormone. The efficacy, safety, and compliance of weekly administered sustained-release recombinant human growth hormone (SR-rhGH, Declage™) supplement in patients with growth hormone deficiency were evaluated., Materials and Methods: This trial is 12-week prospective, single-arm, open-label trial. Men and women aged ≥20 years with diagnosed growth hormone deficiency (caused by pituitary tumor, trauma and other pituitary diseases) were eligible for this study. Each subject was given 2 mg (6 IU) of SR-rhGH once a week, subcutaneously for 12 weeks. Efficacy and safety at baseline and within 30 days after the 12th injection were assessed and compared. Score of Assessment of Growth Hormone Deficiency in Adults (AGHDA score) for quality of life and serum IGF-1 level., Results: The IGF-1 level of 108.67±74.03 ng/mL was increased to 129.01±68.37 ng/mL (p=0.0111) and the AGHDA QoL score was decreased from 9.80±6.51 to 7.55±5.76 (p<0.0001) at week 12 compared with those at baseline. Adverse events included pain, swelling, erythema, and warmth sensation at the administration site, but many adverse events gradually disappeared during the investigation., Conclusion: Weekly administered SR-rhGH for 12 weeks effectively increased IGF-1 level and improved the quality of life in patients with GH deficiency without serious adverse events.

Importance: Approximately 2% of children are defined as having short stature. Deciding when to pursue recombinant human growth hormone therapy to increase adult height is controversial., Objective: To review the management of children with idiopathic short stature, including diagnostic evaluation and therapeutic options., Evidence Review: Systematic literature search of PubMed, Embase, and the Cochrane Library databases. For height outcome, articles were limited to studies reporting adult height and to systematic reviews., Findings: Recombinant human growth hormone therapy of children with idiopathic short stature increases height in some children. The estimated mean gain in adult height is 5.2 cm (2 in). The cost-benefit ratio is controversial. Treatment with growth hormone appears safe in the short term, while data on long-term effects are limited because studies of long-term efficacy were not powered to determine safety., Conclusions and Relevance: Growth hormone treatment may be considered in some children with idiopathic short stature.

Acanthosis nigricans is a skin lesion characterized by the presence of a hyperpigmented, velvety cutaneous thickening that usually appears in flexural areas. Less frequently, it can occur in other locations, such as the dorsum of hands and feet. In this case it is called acral acanthosis nigricans. It is a dermatological manifestation of systemic disease. It is often associated with insulin resistance-mediated endocrine diseases. A case is presented on a patient with acanthosis nigricans secondary to the use of growth hormone., (Copyright © 2013 Sociedad Española de Médicos de Atención Primaria (SEMERGEN). Publicado por Elsevier España. All rights reserved.)

The 20 yr of commercial use of recombinant bovine somatotropin (rbST) in the United States provide the backdrop for reviewing the outcome of use on human health issues by the upcoming 78th meeting of the Joint Food and Agriculture Organization of the United Nations (FAO)/World Health Organization (WHO) Expert Committee on Food Additives. These results and further advancements in scientific knowledge indicate there are no new human health issues related to the use of rbST by the dairy industry. Use of rbST has no effect on the micro- and macrocomposition of milk. Also, no evidence exists that rbST use has increased human exposure to antibiotic residues in milk. Concerns that IGF-I present in milk could have biological effects on humans have been allayed by studies showing that oral consumption of IGF-I by humans has little or no biological activity. Additionally, concentrations of IGF-I in digestive tract fluids of humans far exceed any IGF-I consumed when drinking milk. Furthermore, chronic supplementation of cows with rbST does not increase concentrations of milk IGF-I outside the range typically observed for effects of farm, parity, or stage of lactation. Use of rbST has not affected expression of retroviruses in cattle or posed an increased risk to human health from retroviruses in cattle. Furthermore, risk for development of type 1 or type 2 diabetes has not increased in children or adults consuming milk and dairy products from rbST-supplemented cows. Overall, milk and dairy products provide essential nutrients and related benefits in health maintenance and the prevention of chronic diseases.

Background/aims: Growth hormone (GH) treatment regimens do not account for the pubertal increase in endogenous GH secretion. This study assessed whether increasing the GH dose and/or frequency of administration improves pubertal height gain and adult height (AH) in children with low GH secretion during stimulation tests, i.e. idiopathic isolated GH deficiency., Methods: A multicenter, randomized, clinical trial (No. 88-177) followed 111 children (96 boys) at study start from onset of puberty to AH who had received GH 33 µg/kg/day for ≥1 year. They were randomized to receive 67 µg/kg/day (GH(67)) given as one (GH(67×1); n = 35) or two daily injections (GH(33×2); n = 36), or to remain on a single 33 µg/kg/day dose (GH(33×1); n = 40). Growth was assessed as heightSDSgain for prepubertal, pubertal and total periods, as well as AHSDS versus the population and the midparental height., Results: Pubertal heightSDSgain was greater for patients receiving a high dose (GH(67), 0.73) than a low dose (GH(33×1), 0.41, p < 0.05). AHSDS was greater on GH(67) (GH(67×1), -0.84; GH(33×2), -0.83) than GH(33) (-1.25, p < 0.05), and heightSDSgain was greater on GH(67) than GH(33) (2.04 and 1.56, respectively; p < 0.01). All groups reached their target heightSDS., Conclusion: Pubertal heightSDSgain and AHSDS were dose dependent, with greater growth being observed for the GH(67) than the GH(33) randomization group; however, there were no differences between the once- and twice-daily GH(67) regimens. © 2014 S. Karger AG, Basel.

The weekly sustained-release recombinant human GH formulation LB03002, showed beneficial effects in GH-deficient (GHD) adults in a previous 26-week double-blind study. Prior studies of long-acting GH preparations in adults have only been conducted for 6 or 8 months, so the effects of longer-term use are unknown; this is important to address, as replacement is given for many years in GHD adults. This open-label, 26-week study extension evaluated longer-term safety and efficacy of LB03002 over 52 weeks in adults with GHD who had previously been randomized to GH, and provides additional safety and efficacy data over 26 weeks in the cohort who had previously been randomized to placebo. Of 147 adults with GHD who completed a preceding study, 136 patients continued in this open-label study to receive LB03002 over an additional 26 weeks. This represented a continuation of long-acting GH for 26 weeks in the cohort who took this medication in the prior study (LB03002 Throughout group), and describes the first use of long-acting GH in the cohort that was randomized to placebo in the prior study (Switched to LB03002 group). The LB03002 dose was adjusted according to serum insulin-like growth factor-I (IGF-I) levels. LB03002 treatment demonstrated mean significant decreases from baseline in fat mass (FM) for both 26 (Switched group, P = 0.001) and 52 weeks (Throughout group, P = 0.002) of 1.11 (1.95) kg and 1.06 (3.16) kg, respectively. Prolonged GH treatment was effective in sustaining the increase in lean body mass (LBM), serum IGF-I and IGFBP-3 levels achieved during the first 26 weeks. Long-term treatment with the sustained-release weekly GH preparation over both 26 and 52 weeks in adults with GHD demonstrated a sustained reduction of FM with a favorable safety profile. This study extends prior knowledge about long-acting GH because it reports the most prolonged treatment of adults with any long-acting GH preparation, thereby confirming the value and safety of such agents for long-term GH replacement.

In 2010, new data about the safety of recombinant human growth hormone (rhGH) resulted in warnings and subsequent pronouncements by the US Food and Drug Administration (FDA) and its European counterpart [the European Medicines Agency (EMA)] regarding its use in children and adolescents as an elective treatment for short stature. However, opinions about these new data are divergent: the FDA did not change the label of the drug and experts have argued for further research on the safety of rhGH. In this situation of an evolving scientific controversy, it is unclear how questions about benefit and risk are communicated to patients and their parents. Social biases and misperceptions about the deleterious effects of short stature and the benefits of added height influence decisions to prescribe rhGH and may affect discussions of the warnings by regulators. Fully supporting a model of shared decision-making involving children and adolescents requires sharing risk-benefit information, including evolving information from drug regulators, with patients and parents., (Copyright © 2013 S. Karger AG, Basel.)

The hormonal abuse in physical exercise practioners is very common. Many pleople believe these substances can promote skeletal muscle hyperthrophy and improve physical fitness without health damaging effects. However, this is another myth that science unmasked. This article updates information regarding abuse of insulin, growth hormone, thyroid hormones, and erythropoitin. The peptide hormone abuse can cause motor paralysis, skeletal muscle damage and loss, diabetes mellitus, hypothyroidism, arterial hypertension, sweating, headaches, vomiting and enhances the risk for atherosclerosis, thrombosis, osteoporosis, and cancer.

This review provides an overview of the safety of growth hormone replacement therapy in individuals previously treated for cancer. The review focuses on the risk of disease recurrence and second neoplasm occurrence with special attention to data on childhood cancer survivors., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Objective: To report a case of slipped capital femoral epiphysis in a young patient with Turner syndrome (TS) receiving growth hormone therapy and to emphasize the importance of keeping this orthopedic condition in mind during management of this patient group., Methods: Clinical, laboratory, and radiographic findings are presented, and risk factors for slipped capital femoral epiphysis are discussed., Results: A child with TS presented for medical assessment because of a limp but with no history of trauma or febrile illness. Growth hormone therapy had been administered for 1 year because of her short stature. Physical examination and pelvic radiography of the patient showed the presence of bilateral slipped capital femoral epiphysis. She underwent bilateral pinning in situ, and growth hormone therapy was terminated. At follow-up after more than 2 years, no sequelae were noted., Conclusion: Patients with TS are at high risk for developing certain orthopedic conditions, such as slipped capital femoral epiphysis. Furthermore, slipped capital femoral epiphysis is a known complication of growth hormone therapy in growing children. A limp, hip pain, knee pain, or thigh pain might be a symptom of slipped capital femoral epiphysis in patients with TS, especially those receiving growth hormone therapy. Prompt recognition and treatment of this condition are important for prevention of sequelae.

Growth hormone (GH) exerts its effects through insulin-like growth factor-1, and although ubiquitous in human tissues, it has a significant role in cardiovascular function. In recent years, there has been a great deal of interest in GH as an etiologic factor in many cardiovascular disease states. Acromegaly, a state of endogenous GH excess, results in myocardial hypertrophy and decreased cardiac performance with increased cardiovascular mortality. Additional insight into the role of excess GH on the cardiovascular system has been gained from data collected in athletes doping with GH. Likewise, GH deficiency is associated with increased mortality, possibly from the associated increase in atherosclerosis, lipid abnormalities, and endothelial dysfunction. However, further research is required to clarify the benefit of GH treatment in both deficient states and in heart failure patients.

Context: Little is known about the long-term health of subjects treated with GH in childhood, and Safety and Appropriateness of Growth hormone treatments in Europe (SAGhE) is a study addressing this question., Objective: The objective of the study was to evaluate the long-term mortality of patients treated with recombinant GH in childhood in France., Design: This was a population-based cohort study., Setting: The setting of the study was a French population-based register., Participants: A total of 6928 children with idiopathic isolated GH deficiency (n = 5162), neurosecretory dysfunction (n = 534), idiopathic short stature (n = 871), or born short for gestational age (n = 335) who started treatment between 1985 and 1996 participated in the study. Follow-up data on vital status were available in September 2009 for 94.7% of the patients., Main Outcome Measures: All-cause and cause-specific mortality was measured in the study., Results: All-cause mortality was increased in treated subjects [standardized mortality ratio (SMR) 1.33, 95% confidence interval (CI) 1.08-1.64]. In a multivariate analysis adjusted for height, the use of GH doses greater than 50 μg/kg · d was associated with mortality rates using external and internal references (SMR 2.94, 95% CI 1.22-7.07, hazard ratio 2.79, 95% CI 1.14-6.82). All type cancer-related mortality was not increased. Bone tumor-related mortality was increased (SMR 5.00, 95% CI 1.01-14.63). An increase in mortality due to diseases of the circulatory system (SMR 3.07, 95% CI 1.40-5.83) or subarachnoid or intracerebral hemorrhage (SMR 6.66, 95% CI 1.79-17.05) was observed., Conclusions: Mortality rates were increased in this population of adults treated as children with recombinant GH, particularly in those who had received the highest doses. Specific effects were detected in terms of death due to bone tumors or cerebral hemorrhage but not for all cancers. These results highlight the need for additional studies of long-term mortality and morbidity after GH treatment in childhood.

We report a case of Moyamoya syndrome developing in association with growth hormone-secreting pituitary adenoma. A 31-year-old female presented with acromegalic features. Magnetic resonance imaging revealed a 1 × 2 cm tumor in the sella turcica and MR angiography demonstrated unremarkable findings. Blood growth hormone and insulin-like growth factor I levels were elevated to 74.1 ng/ml and over 1 575 ng/ml, respectively. The diagnosis was growth hormone-secreting pituitary adenoma, and the tumor was removed through a transsphenoidal approach. Four years after surgery, she visited the outpatient department due to left side weakness for 2 months. Magnetic resonance images showed acute and old infarcted lesions in the basal ganglia and subcortical area and residual small pituitary adenoma in the sellar area. MR angiography demonstrated stenosis of the bilateral distal internal carotid arteries with basal collateral vessels. Conventional cerebral angiography showed complete obstruction in the right internal carotid artery and severe stenosis of the left internal carotid artery, middle cerebral artery, and anterior cerebral artery with basal collateral vessels. Her blood growth hormone and insulin-like growth factor I levels were 15.3 ng/ml and 1 055 ng/ml, respectively. We believe that excess systemic exposures of growth hormone and insulin-like growth factor I may participate in the development of Moyamoya syndrome.