Neurosecretory Dysfunction Research Articles

Response to growth hormone treatment in patients with sufficient secretion

BackgroundThere are situations of short stature, with a normal stimulus test for GH, but decreased nocturnal secretion in which there could be a benefit with GH treatment. ObjetivesTo assess adult height and height gain in patients with neurosecretory dysfunction diagnosis treated with growth hormone. Material y methodsLongitudinal, retrospective and observational study including 61 patients treated with growth hormone after diagnosis of neurosecretory dysfunction who have already reached adult height. Variables such as adult height gain, growth rate, growth prognosis variation and IGF-I and IGFBP-3 were evaluated. Variables related to a good response in the first year have also been calculated, using the Index of responsiveness (IoR). ResultsGH treatment produces an improvement in growth rate and height, observing an increase in adult height with respect to initial height of 1.15±0.60 SD, height with respect to genetic height of -0.015±0.62 SD and adult height with respect to the initial growth prognosis 0,74±1,13 DE. The IoR in the first year is associated with a greater increase in height in the first year (p=0.000), with a greater adult height (p=0.000) and with a greater gain in adult height compared to its initial height (p=0.039). ConclusionsPatients with growth delay due to neurosecretory dysfunction of GH show a good response to treatment with rhGH, observing a significant height gain in their genetic size and improving their initial growth prognosis.

Respuesta al tratamiento con hormona del crecimiento en pacientes con secreción suficiente

BackgroundThere are situations of short stature, with a normal stimulus test for GH, but decreased nocturnal secretion in which there could be a benefit with GH treatment. ObjetivesTo assess adult height and height gain in patients with neurosecretory dysfunction diagnosis treated with growth hormone. Material y methodsLongitudinal, retrospective and observational study including 61 patients treated with growth hormone after diagnosis of neurosecretory dysfunction who have already reached adult height. Variables such as adult height gain, growth rate, growth prognosis variation and IGF-1 and IGFBP-3 were evaluated. Variables related to a good response in the first year have also been calculated, using the index of responsiveness. ResultsGH treatment produces an improvement in growth rate and height, observing an increase in adult height with respect to initial height of 1.15±0.60 SD, height with respect to genetic height of −0.015±0.62 SD and adult height with respect to the initial growth prognosis 0,74±1,13 DE. The index of responsiveness in the first year is associated with a greater increase in height in the first year (P<0.001), with a greater adult height (P<0.001) and with a greater gain in adult height compared to its initial height (P=0.039). ConclusionsPatients with growth delay due to neurosecretory dysfunction of GH show a good response to treatment with rhGH, observing a significant height gain in their genetic size and improving their initial growth prognosis.

Inclusion and Withdrawal Criteria for Growth Hormone (GH) Therapy in Children with Idiopathic GH Deficiency—Towards Following the Evidence but Still with Unresolved Problems

According to current guidelines, growth hormone (GH) therapy is strongly recommended in children and adolescents with GH deficiency (GHD) in order to accelerate growth rate and attain normal adult height. The diagnosis of GHD requires demonstration of decreased GH secretion in stimulation tests, below the established threshold value. Currently, GHD in children is classified as secondary insulin-like growth factor-1 (IGF-1) deficiency. Most children diagnosed with isolated GHD present with normal GH secretion at the attainment of near-final height or even in mid-puberty. The most important clinical problems, related to the diagnosis of isolated GHD in children and to optimal duration of rhGH therapy include: arbitrary definition of subnormal GH peak in stimulation tests, disregarding factors influencing GH secretion, insufficient diagnostic accuracy and poor reproducibility of GH stimulation tests, discrepancies between spontaneous and stimulated GH secretion, clinical entity of neurosecretory dysfunction, discrepancies between IGF-1 concentrations and results of GH stimulation tests, significance of IGF-1 deficiency for the diagnosis of GHD, and a need for validation IGF-1 reference ranges. Many of these issues have remained unresolved for 25 years or even longer. It seems that finding solutions to them should optimize diagnostics and therapy of children with short stature.

Adult height after treatment of neurosecretory dysfunction and comparison to idiopathic GHD.

Neurosecretory dysfunction (NSD) causes growth hormone deficiency (GHD). Data on adult height after recombinant human growth hormone (rhGH) treatment are lacking. We collected treatment data of all patients with NSD seen between 1990 and 2017 at our outpatient department (tertiary centre) and measured adult height. For comparison, patients with idiopathic GHD were used. Diagnoses were based on short stature (<-2 standard deviation score [SDS]), continuously low height velocity (<25th percentile), delayed bone age (by >1 SD) and low serum IGF-1 concentration (<-2 SDS). NSD was defined by normal GH challenge results, but subnormal spontaneous GH secretion. Exclusion criteria were no information on adult height, underweight and other short stature disorders. Out of 67 patients diagnosed with NSD, six were still growing, 31 had test results exceeding validated GH cut-offs and three had other disorders causing short stature. Out of the 25 eligible patients with NSD, 21 could be recruited. These patients reached an adult height of -0.85 SDS (mean); 0.34 SDS below midparental height. Height gain during treatment was 2.01 SDS. This outcome was not different to 32 patients with idiopathic GHD. Long-term results suggest the viability of the diagnosis of NSD and the efficacy of rhGH treatment.

Influence of biochemical diagnosis of growth hormone deficiency on replacement therapy response and retesting results at adult height

Isolated growth hormone deficiency (IGHD) is the most frequent endocrinological disorder in children with short stature, however the diagnosis is still controversial due to the scarcity of reliable diagnostic criteria and pre-treatment predictive factors of long term-response. To evaluate recombinant growth hormone (rGH) long-term response and retesting results in three different groups of children divided in accordance with the biochemical criteria of initial diagnosis. Height gain (∆HT) at adult height (AH) and retesting results were evaluated in 57 rGH treated children (M = 34, 59.6%) divided into 3 groups according to initial diagnosis: Group A (n = 25) with max GH peak at stimulation test < 8 µg/L, Group B (n = 19) between 8 and 10 µg/L and Group C (n = 13) with mean overnight GH < 3 µg/L (neurosecretory dysfunction, NSD). Retesting was carried out in all patients after at least one month off therapy upon reaching the AH. 40/57 (70.2%) patients were pre-pubertal at diagnosis and showed ∆HT of 1.37 ± 1.00 SDS, with no significant differences between groups (P = 0.08). Nonetheless, 46% patients in Group B showed ∆HT < 1SDS (vs 13% and 12% in Group A and C, respectively) and 25% children failed to reach mid-parental height (vs 6% and 0% in Group A and C, respectively). At AH attainment, IGHD was reconfirmed in 28% (7/25) and 10% (2/19) in Group A and B, respectively. A reduction of diagnostic cut-off at GH stimulation tests could better discriminate between “good” and “poor responders” and predict the persistence of IGHD through transition. Group C response and the predictive value of baseline IGF-I SDS bring back to light NSD: should we consider an underlying hypothalamic derangement when the clinical presentation is strongly consistent with IGHD but pharmacological stimulation test is normal?

BÜYÜME HORMONU TEDAVİSİ ALAN ÇOCUKLARIN KLİNİK ÖZELLİKLERİ: TEK MERKEZ DENEYİMİ

Objective: In this study, we aimed to investigate the clinical features of children who received growth hormone (GH) treatment with a diagnosis of GH deficiency (GHD). Material and Methods: The clinical features of children treated with GH treatment between 01.06.2013-31.12.2018 in a tertiary healthcare service were retrospectively analyzed. Children with isolated GHD and children with panhipopituitarism were compared. Results: In total, 70 boys 118 children were included in the study. 78 (66.3%) of patients were treated with GH due to isoleted GHD, 14 (11.9%) due to bio-inactive GH syndrome, 9 (7.6%) due to panhypopituitarism, 6 (5.1%) due to GH neurosecretory dysfunction, 6 (5.1%) due to Turner syndrome and 5 (4.2%) due to off-label reasons.There were no significant diffrence between groups of isoleted GHD and panhipopituitarism regarding gender, age of diagnosis and oxological features at diagnosis. Serum IGF-1 SDS, IGFBP-3 SDS, TSH and pik GH response to klonidine test were lower in panhipopituitarism group (p=0.026, p=0.002, p=0.009 ve p=0.005, respectively). Significantly higher growth rates in the first 2 years in the patient with panhypopituitarism were determined (p<0.001 and p=0.005, respectively). A correlation was found between the growth rate in the first year and age of diagnosis, GH stimulation test responses, serum IGFBP-3 SDS and difference between chronologic age and bone age. Conclusion: Patients with panhypopituitarism had more significant laboratory findings for GHD at admission and better GH treatment responses in follow-up compared to patients with isolated GHD.

Pathogenesis of Growth Failure in Rasopathies.

The RASopathies are a group of developmental genetic syndromes that are caused by germline mutations in genes encoding proteins of the Ras-Mitogen-Activated Protein kinase (RAS-MAPK) pathway. RASopathies include Noonan Syndrome (NS), Neurofibromatosis Type 1 (NF1), Noonan syndrome with multiple lentigines (NSML/LEOPARD), Costello syndrome (CS), Cardio-facio-cutaneous syndrome (CFC), capillary malformation-arteriovenous malformation syndrome (CM-AVM) and Legius Syndrome. These syndromes have many overlapping features; however, the most persistent feature common to all is the postnatal growth failure. The mechanism of growth failure in Rasopathies is highly complex and there are many proposed hypotheses including partial growth hormone insensitivity, growth hormone deficiency, neurosecretory dysfunction of growth hormone secretion, delayed puberty, poor feeding and skeletal abnormalities. Amongst these causes, the most widely accepted is partial growth hormone insensitivity due to a post-receptor signaling defect. Growth hormone therapy seems to be effective in improving height velocity in these syndromes, although the long-term effects on final height remain unproven. However, it is important to consider the potential risk of tumors and cardiomyopathy before and during growth hormone therapy.

Biological Significance of Anti-GH Antibodies in Children Treated with rhGH

Background: The occurrence of antidrug antibodies is common in children treated with recombinant human growth hormone (rhGH). However, their clinical significance is unclear. Objective: This study aimed to examine the clinical significance of anti-GH antibodies by analyzing the phenotype of patients who tested positive in relation to the quantity of anti-GH antibodies. Method: In this laboratory-based retrospective study encompassing a time span of 6 years, all positive samples were identified, and senders were contacted. Anti-GH antibodies were measured using a radioprecipitation assay; positive samples underwent a confirmatory assay. Results: Out of a total of 104 samples from 66 patients, positive test results were found in 28 samples from 13 patients. Clinical data were available from all but one. The group with positive test results comprised 6 patients with a normal response to GH provocative tests (group A) and 6 with an insufficient response or with isolated GH deficiency (IGHD) type 1A (group B). Diagnoses in group A were neurosecretory dysfunction, bioinactive GH syndrome and constitutional delay of growth and puberty. Diagnoses in group B were IGHD type 1A, septo-optic dysplasia, and cerebral midline defect with multiple pituitary hormone deficiency. Insufficient growth response to rhGH was absent except in one sibling pair with IGHD type 1A and a patient with cerebral midline defect. These patients had the highest concentrations of anti-GH antibodies. Conclusions: The biological significance of anti-GH antibodies seems to be limited to patients with high concentrations of anti-GH antibodies. For all other patients, we recommend a careful “wait and see” strategy and monitoring antibody titers.

Growth hormone therapy in patients with Noonan syndrome.

Noonan syndrome (NS) is an autosomal dominant disorder that involves multiple organ systems, with short stature as the most common presentation (>70%). Possible mechanisms of short stature in NS include growth hormone (GH) deficiency, neurosecretory dysfunction, and GH resistance. Accordingly, GH therapy has been carried out for NS patients over the last three decades, and multiple studies have reported acceleration of growth velocity (GV) and increase of height standard deviation score (SDS) in both prepubertal and pubertal NS patients upon GH therapy. One year of GH therapy resulted in almost doubling of GV compared with baseline; afterwards, the increase in GV gradually decreased in the following years, showing that the effect of GH therapy wanes over time. After four years of GH therapy, ~70% of NS patients reached normal height considering their age and sex. Early initiation, long duration of GH therapy, and higher height SDS at the onset of puberty were associated with improved final height, whereas gender, dosage of GH, and the clinical severity did not show significant association with final height. Studies have reported no significant adverse events of GH therapy regarding progression of hypertrophic cardiomyopathy, alteration of metabolism, and tumor development. Therefore, GH therapy is effective for improving height and GV of NS patients; nevertheless, concerns on possible malignancy remains, which necessitates continuous monitoring of NS patients receiving GH therapy.

Basal characteristics and first year responses to human growth hormone (GH) vary according to diagnostic criteria in children with non-acquired GH deficiency (naGHD): observations from a single center over a period of five decades.

Background Children with non-acquired (na) growth hormone deficiency (GHD) diagnosed over decades in one center may provide perspective insight. Methods naGHD is divided into idiopathic GHD (IGHD), GHD of known cause (cGHD) and GHD neurosecretory dysfunction (NSD); time periods: <1988 (I); 1988-1997 (II); 1998-2007 (III); 2008-2015 (IV). Descriptive analyses were performed at diagnosis and during first year GH treatment. Results Patients (periods, N): I, 87; II, 141; III, 356; IV, 51. In cGHD (all), age, maximum GH, insulin-like growth factor-I (IGF-I), and insulin-like growth factor-binding protein-3 (IGFBP-3) (5.1 years, 3.6 μg/L, -5.3 standard deviation score [SDS], -3.7 SDS) were lower than in IGHD (all) (6.8 years 5.8 μg/L, -2.5 SDS, -1.0 SDS), but not height (-3.1 vs. -3.2 SDS). Characteristics of NSD were similar to that of IGHD. Patients with IGHD - not cGHD - diagnosed during 2008-2015 (IV) were the youngest with most severe GHD (maxGH, IGF-I, IGFBP-3), and first year height velocity (HV) and ∆ IGF-I (10.5 cm/year, 4.0 SDS) but not ∆ height SDS were the highest on recombinant human growth hormone (rhGH) (27 μg/kg/day). Conclusions Although during 1988-2007 patient characteristics were similar, the recently (>2008) stipulated more stringent diagnostic criteria - HV before testing, sex steroid priming, lower GH cut-off - have restricted diagnoses to more severe cases as they were observed before the rhGH era.

Growth hormone neurosecretory dysfunction as part of the spectrum of growth hormone deficiency disorders which benefit from growth hormone treatment

Growth hormone neurosecretory dysfunction as part of the spectrum of growth hormone deficiency disorders which benefit from growth hormone treatment

GENETIC FORMS OF GROWTH HORMONE INSUFFICIENCY, PECULIARITIES OF CLINIC AND DIAGNOSTIC

The article considers genetic forms of growth hormone insufficiency in children. Analysis of genes, defects of which can lead to severe growth retardation due to somatotropic insufficiency or syndromal disorders, is important not only to improve the diagnosis, but also for choosing of adequate therapy and prediction of final height. Choice of analyzed gene is determined by a combination of clinical data and features of hormone secretion.Are discussed primary IGF-1 deficiency (disturbance of synthesis and secretion of growth hormone (neurosecretory dysfunction), biologically inactive growth hormone (GH1 gene mutation), and partial insensitivity to growth hormone as a result of its receptor defects (GHR gene mutations).The article details the principles of diagnostic search in the genetic forms of growth hormone insufficiency, was analyzed molecular-genetic defects in genes of the growth axis system: growth hormone - insulin-like growth factor 1.

Evaluation of Prepubertal Patients with Suspected Neurosecretory Dysfunction of Growth Hormone Secretion: Diagnostic Steps and Treatment Response

Background and Aims.Existence and diagnostic procedures of neurosecretory dysfunction of growth hormone (NSD) are still a matter of debate. The aim of our study was (a) to find out if prediagnostic auxological and laboratory data could serve as an indicator for pathologic and normal spontaneous GH-secretion and (b) to evaluate the response to GH-therapy in NSD-patients.Methods.Of 90 children (unicentric study) with normal response to GH-stimulation tests, in whom 12-hour night profiles for GH-secretion were performed, 49 were diagnosed with NSD (NSD group). Their auxologic data, IGF-I/IGFBP3-levels as well as the night profiles, were analysed and compared to those of the non-NSD group. Additionally, follow-up auxological data of the GH-treated NSD-patients were collected.Results.Prediagnostic auxologic and laboratory data did not differ between the two groups. Instead, for all analysed criteria of spontaneous GH-secretion (number of peaks, maximal and mean secretion) a significant difference was found. Children with NSD showed a good response to GH-treatment after 1 (ΔH-SDS +0,77 ± 0,48) as well as 4 years (+1,51 ± 0,75).Conclusion.According to our results, analysing spontaneous GH-secretion remains the only method to identify NSD. Yet, as response to GH-treatment is comparable to results in idiopathic GHD, it is worth to consider this diagnosis.

Growth hormone deficiency after childhood bone marrow transplantation with total body irradiation: interaction with adiposity and age

Bone marrow transplantation with total body irradiation (BMT/TBI) has adverse effects on growth, growth hormone status and adiposity. We investigated the GH-IGF-I axis in relation to adiposity. Cross-sectional case control study. BMT/TBI survivors (n = 22) and short stature control participants (n = 19), all GH-naïve or off GH treatment >3 months. Auxology, DEXA scans and GH-IGF-I axis investigation: (i) 12-h overnight GH profiles; (ii) insulin tolerance test (ITT); and (iii) IGF-I generation test. auto-deconvolution of GH profile data and comparison of quantitative parameters using ANOVA. Eighty-two percent of BMT/TBI survivors had growth hormone deficiency (GHD) using ITT. GH profile area-under-the-curve (GH-AUC) was reduced in BMT/TBI survivors vs short stature control participants [geometric mean (range) 209 (21-825) vs 428 (64-1400) mcg/l/12 h, respectively, P = 0·007]. GHD was more marked in those who had additional cranial irradiation (CRT) [ITT peak 1·4 (0·2-3·0) vs TBI only 4·1 (1·1-14·8) mcg/l, P = 0·036]. GHD was more marked at the end of growth in BMT/TBI survivors vs short stature control participants (GH-AUC 551 (64-2474) vs 1369 (192-4197) mcg/l/12 h, respectively, P = 0·011) and more prevalent (9/11 vs 1/9, respectively, P = 0·005). GH profile data were consistent with ITT results in 80% of participants. IGF-I generation tests were normal. BMT/TBI survivors still demonstrated lower GH levels after adjustment for adiposity (fat-adjusted mean difference for GH-AUC 90·9 mcg/l/12 h, P = 0·025). GHD was more prevalent in BMT/TBI survivors than expected for the CRT dose in TBI, worsened with time and persisted into adulthood. GHD could not be explained by adiposity. There was no evidence of GH neurosecretory dysfunction or resistance after BMT/TBI.

Quality of life of young adults after a growth hormone therapy with childhood onset

Little is known about the health-related quality of life of young adults with childhood onset idiopathic growth hormone deficiency or neurosecretory dysfunction of growth hormone secretion, who have been treated with recombinant human growth hormone (GH). Patients were diagnosed and treated with human growth hormone at the University Children´s Hospital in Erlangen (n=85). The data of both groups were merged for analysis, because no difference between idiopathic growth hormone deficiency and neurosecretory dysfunction of growth hormone secretion in auxological. Data were found. Health-related quality of life was cross- sectionally assessed after the end of growth hormone therapy with the Short Form-36 Health Survey and the Nottingham Health Profiles for which population based norm data are available. At the time of the survey, the patients (53 m, 32 f) were 23.5 ± 4.6 years old. At start of GH therapy, age was 10.5 ± 2.8 and at the end 16.3 ± 1,4 years. At start, height SDS was -3.20 ± 1.06. GH dose was 0,026 ± 0,012 mg/kg/d (daily s. c.-injections). The increase in height SDS after the end of GH therapy was 1.69 ± 1.22. Compared to the reference population, patients reported significantly lower scores on the scales energy level, vitality, social functioning, indicating a greater social isolation, a stronger emotional reaction, an increased loss of mobility and a worse psychological state. Young adults report specific impairments after completion of GH therapy.

Validation of the KIGS growth prediction models in an independent cohort of a tertiary growth centre

Background: Prediction models derived from growth data of patients documented in the Kabi International Growth Study (KIGS) need to be validated in independent cohorts to confirm applicability in clinical practice. Objectives: Retrospective comparison of predicted and observed first year growth response in children treated with recombinant human growth hormone of different brands. Patients and Methods: 597 children treated in the Hormone Centre for Children and Adolescents, University Hospital of Schleswig-Holstein, Kiel, Germany, were considered. 230 patients met the requirements for use of prediction models. The model for Growth Hormone Deficiency (GHD) was validated in 141 patients (classical idiopathic growth hormone deficiency (IGHD): n = 39, neurosecretory dysfunction (NSD): n = 102), that for Ullrich-Turner-Syndrome (UTS) in 46 patients and that for Small for Gestational Age (SGA) in 43 patients. NSD and IGHD as well as the six various brands were also analysed separately. Results: Low mean absolute Studentized Residuals (SRs) indicate that differences between predicted and observed growth responses are small for all diagnoses (IGHD: 0.96 ± 0.75, NSD: 0.64 ± 0.61, UTS: 0.84 ± 0.60, SGA: 0.87 ± 0.73) and for the different brands (A: 0.93 ± 0.77, B: 0.68 ± 0.48, C: 0.92 ± 0.82, D: 0.57 ± 0.44, E: 0.67 ± 0.69, F: 0.86 ± 0.61). Positive correlations between predicted and observed height velocity reflect their causal connection (IGHD: r = 0.72, NSD: r = 0.36, UTS: r = 0.43, SGA: r = 0.43). Conclusion: KIGS prediction models for GHD, UTS and SGA are applicable in an independent cohort. Prediction works regardless of the applied brand of recombinant human growth hormone.

Long-term auxological and endocrinological evaluation of patients with 9p trisomy: a focus on the growth hormone-insulin-like growth factor-I axis

BackgroundTrisomy 9p is an uncommon anomaly characterised by mental retardation, head and facial abnormalities, congenital heart defects, kidney abnormalities, and skeletal malformations. Affected children may also show growth and puberty retardation with delayed bone age. Auxological and endocrinological data are lacking for this syndrome.MethodsWe describe three girls and one boy with 9p trisomy showing substantial growth failure, and we evaluate the main causes of their short stature.ResultsThe target height was normal in all families, ranging from 0.1 and -1.2 standard deviation scores (SDS). The patients had a low birth-weight (from -1.2 to -2.4 SDS), birth length (from -1.1 to -3.2 SDS), and head circumference (from -0.5 to -1.6 SDS). All patients presented with substantial growth (height) retardation at the time of 9p trisomy diagnosis (from -3.0 to -3.8 SDS).The growth hormone stimulation test revealed a classic growth hormone (GH) deficiency (GHD) in patients 1, 3, and 4. In contrast, patient 2 was determined to have a GH neurosecretory dysfunction (GHNSD). The plasma concentrations of IGF-I and IGFBP-3 were low in all patients for their ages and sexes (from -2.0 to -3.4 SDS, and from -1.9 to -2.8 SDS, respectively).The auxological follow-up showed that those patients who underwent rhGH treatment exhibited a very good response to the GH therapy, whereas patients 3 and 4, whose families chose not to use rhGH treatment, did not experience any significant catch-up growth.ConclusionsGH deficiency appears to be a possible feature of patients with 9p trisomy syndrome. These patients, particularly those with growth delays, should be evaluated for GH secretion.

How safe is growth hormone therapy? SAGhE and beyond

Although short term health on growth hormone treatment has been extensively studied, little is known of the long-term health of subjects treated with growth hormone in childhood. Approximately 40 000 children are treated with growth hormone in the European Union and several hundred thousands in the world and it is essential to address this important question. SAGhE is an European consortium aimed at addressing this question as well as to gain further insight in the long term effect of growth hormone both in terms of height and of significance on quality of life. Eight countries participate in SAGhE: Belgium, France, Germany, Italy, Netherlands, Sweden, Switzerland, United Kingdom and have recruited approximately 25 000 patients who were treated for the most part in the late 80's and 90's and who are currently adults. The results of the SAGhE study as a whole are expected to be available to the investigators at the end of 2012 and will be disseminated in 2013. However, the study did not start synchronously in all countries and results from France and from 3 other countries have been made disseminated in late 2010 and published in early 2012. In the report from France, 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 were followed on vital status up to September 2009 for 94.7% of the patients. In this population of patients, all-cause mortality was increased with a standardized mortality ratio (SMR) of 1.33. 95% CI 1.08–1.64). In multivariate analysis adjusted for height, the use of GH doses >50 µg/kg/day was associated with mortality rates using external and internal references (SMR 2.94, 95%CI 1.22–7.07, HR 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), subarachnoid or intracerebral hemorrhage (SMR 6.66, 95%CI 1.79–17.05) was observed. Mortality rates were therefore increased in this population of adults treated as children with recombinant GH, particularly in those who had received the highest doses. In a parallel report, 3 additional countries (Belgium, Netherlands, Sweden) the cause of death from a cohort of 2543 patients could be identified and no cancer- or cardiovascular disease-related deaths were found. These results highlight the need for additional studies of long-term mortality and morbidity after GH treatment in childhood but do not change the risk benefit balance of growth hormone treatments, after careful evaluation by Medicine Agencies. Consolidated results of the SAGhE study are expected to be available at the end of 2012 and to be disseminated during 2013.

Update in Mortality in GH-Treated Patients

During GH therapy for 2.3-9.6 years, male adult-onset GH-deficient patients with a diagnosis of a nonfunctioning adenoma have no increased all-cause mortality. However, women with adult-onset GH deficiency (GHD) are still at slightly higher risk. This general improvement in mortality is due to a more contemporary regimen of cardiovascular drugs, a refinement of surgical procedures, besides the introduction of GH therapy improved hormone replacement regimens with lowered glucocorticoid replacement, updated approaches of sex steroids for women, and less use of cranial radiotherapy. The underlying disease is the most important predictor for mortality: eg, a craniopharyngioma, malignant causes of hypopituitarism, previous Cushing's disease, and the presence of diabetes insipidus/aggressive tumors. The main cause of increased mortality was cerebrovascular diseases and infectious/respiratory diseases in ACTH-deficient patients. Furthermore, there was a significant impact of young age at disease onset and of death from secondary brain tumors, with a higher risk after cranial radiotherapy. Reports on four cohorts of GH-treated childhood-onset GHD patients have been published. Two of them included only patients with idiopathic isolated GHD, neurosecretory dysfunction, idiopathic short stature, or being born short for gestational age. Increased mortality in circulatory disorders, ill-defined diseases, and bone cancer were recorded in one study, but not in the other smaller study, where suicide and accidents caused the majority of deaths. A third childhood-onset GHD cohort included patients with a background of malignant tumors, craniopharyngioma, pituitary adenomas, pituitary aplasia/hypoplasia, and trauma. An increase of all-cause mortality was recorded in both males and females. The fourth cohort included isolated GHD and idiopathic short stature (60%), but also diagnosis of chronic renal failure and Turner's syndrome. In these latter studies, an underlying serious condition was the most important factor for death, with central nervous system tumors (recurrent or new tumor) being the leading cause of mortality.

Magnetic resonance imaging of CNS in 15 043 children with GH deficiency in KIGS (Pfizer International Growth Database)

Neuroimaging has become an essential part of the diagnostic process in children with GH deficiency (GHD). The aim of the study was to document the frequency of neuroanatomical abnormalities in a very large cohort of children with GHD and to relate these findings to patient clinical characteristics. Results of magnetic resonance imaging (MRI) were reported in 15,043 of 43,725 children with non-acquired GHD (idiopathic, neurosecretory dysfunction (NSD) and known congenital cause) who were enrolled in KIGS (Pfizer International Growth Database) between 1987 and 2011. Clinical characteristics of patients before GH treatment with normal MRI (idiopathic GHD (IGHD) and NSD) were compared with those of patients with abnormal pituitaries (hypoplasia, empty sella (ES), HME (hypoplastic anterior pituitary, missing pituitary stalk and ectopic posterior pituitary)). Abnormal MRIs were found in 4032 (26.8%) children, within which ES (N=1178 (7.8%)) and HME (N=1019 (6.8%)) were the most frequent findings. In 2361 children diagnosed as IGHD or NSD before MRI examination, anatomical abnormalities ((pituitary hypoplasia: n=974); (HME: n=459)) were documented. Patients with anatomical abnormalities had more severe characteristics of GHD: normal MRI < pituitary hypoplasia < ES < HME. GHD is associated with a great variety of neuroanatomical abnormalities as identified by MRI. The investigation and evaluation of MRI need to be conducted in a structured mode. There is an association between anatomical and functional abnormalities of the pituitary.