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1.
Lancet Diabetes Endocrinol ; 8(8): 683-692, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32707116

RESUMO

BACKGROUND: Recombinant human growth hormone has been used for more than 30 years and its indications have increased worldwide. There is concern that this treatment might increase mortality, but published data are scarce. We present data from the entire dataset of all eight countries of the Safety and Appropriateness of Growth hormone treatments in Europe (SAGhE) consortium, with the aim of studying long-term overall and cause-specific mortality in young adult patients treated with recombinant human growth hormone during childhood and relating this to the underlying diagnosis. METHODS: This cohort study was done in eight European countries (Belgium, France, Germany, Italy, The Netherlands, Sweden, Switzerland, and the UK). Patients were classified a priori based on pre-treatment perceived mortality risk from their underlying disease and followed up for cause-specific mortality. Person-years at risk of mortality and expected rates from general population data were used to calculate standardised mortality ratios (SMRs). FINDINGS: The cohort comprised 24 232 patients treated with recombinant human growth hormone during childhood, with more than 400 000 patient-years of follow-up. In low-risk patients with isolated growth hormone deficiency or idiopathic short stature, all-cause mortality was not significantly increased (SMR 1·1, 95% CI 0·9-1·3). In children born small for gestational age, all-cause mortality was significantly increased when analysed for all countries (SMR 1·5, CI 1·1-1·9), but this result was driven by the French subcohort. In patients at moderate or high risk, mortality was increased (SMR 3·8, 3·3-4·4; and 17·1, 15·6-18·7, respectively). Mortality was not associated with mean daily or cumulative doses of recombinant human growth hormone for any of the risk groups. Cause-specific mortality from diseases of the circulatory and haematological systems was increased in all risk groups. INTERPRETATION: In this cohort, the largest, to our knowledge, with long-term follow-up of patients treated with recombinant human growth hormone during childhood, all-cause mortality was associated with underlying diagnosis. In patients with isolated growth hormone deficiency or idiopathic short stature, recombinant human growth hormone treatment was not associated with increased all-cause mortality. However, mortality from certain causes was increased, emphasising the need for further long-term surveillance. FUNDING: European Union.


Assuntos
Nanismo Hipofisário/tratamento farmacológico , Nanismo Hipofisário/mortalidade , Hormônio do Crescimento Humano/administração & dosagem , Hormônio do Crescimento Humano/efeitos adversos , Adolescente , Adulto , Criança , Pré-Escolar , Estudos de Coortes , Europa (Continente)/epidemiologia , Feminino , Seguimentos , Humanos , Lactente , Recém-Nascido , Masculino , Mortalidade/tendências , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/efeitos adversos , Fatores de Tempo , Adulto Jovem
2.
Curr Opin Endocrinol Diabetes Obes ; 27(1): 82-86, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31789832

RESUMO

PURPOSE OF REVIEW: To discuss treatments used to enhance growth in pediatric patients with short stature. RECENT FINDINGS: New data confirm the known efficacy of recombinant human growth hormone (rhGH) in growth hormone deficiency (GHD) and idiopathic short stature. The latest data from the Safety and Appropriateness of Growth hormone Treatment in Europe cohort did not indicate a long-term risk of malignancy in those treated for isolated GHD, but possibly increased risk in those with other diagnoses. Recombinant human insulin-like growth factor 1 is effective in treating patients with pregnancy-associated plasma protein A2 deficiency. Gonadotropin-releasing hormone agonists or aromatase inhibitor treatment to delay puberty remains controversial. They are more likely to augment adult height if combined with rhGH treatment in children already receiving rhGH. Preliminary data indicate that recombinant C-type natriuretic peptide (CNP) is safe in children and increases growth velocity upon 42 months of treatment in achondroplasia. SUMMARY: Recent data confirms previous data on rhGH efficacy and safety. Therapies to delay growth plate closure have greatest efficacy to augment height if combined with GH in select diagnoses. Recombinant CNP holds promise as a medical treatment for short stature associated with achondroplasia.


Assuntos
Endocrinologia , Transtornos do Crescimento/prevenção & controle , Transtornos do Crescimento/terapia , Hormônio do Crescimento Humano/deficiência , Adulto , Estatura/efeitos dos fármacos , Criança , Nanismo Hipofisário/tratamento farmacológico , Nanismo Hipofisário/epidemiologia , Endocrinologia/métodos , Endocrinologia/tendências , Europa (Continente)/epidemiologia , Transtornos do Crescimento/epidemiologia , Terapia de Reposição Hormonal/métodos , Terapia de Reposição Hormonal/tendências , Hormônio do Crescimento Humano/uso terapêutico , Humanos , Fator de Crescimento Insulin-Like I/uso terapêutico , Puberdade/efeitos dos fármacos , Puberdade/fisiologia , Proteínas Recombinantes/uso terapêutico
3.
Clin Pharmacol Ther ; 107(4): 988-993, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31628764

RESUMO

Manufacturing process changes may alter the characteristics of a protein therapeutic. In 2009, somatropin (version 1.0), a recombinant human growth hormone therapeutic, underwent a manufacturing update (version 1.1). The immunogenicity of somatropin version 1.1 as a daily subcutaneous injection was evaluated in 2014 in a prospective, open-label, single-arm clinical study of treatment-naive pediatric patients with idiopathic human growth hormone deficiency for 1 year. The primary end point was the proportion of patients who developed antidrug antibodies (ADAs) after treatment. Eighty-two patients were enrolled. The mean (SD) treatment duration was 347 (53) days. The incidence of ADAs was 3.7%. No neutralizing antibodies were observed in the three patients with ADA-positive samples. Two patients (2.6%) had growth attenuation, but they were not ADA positive. The manufacturing changes for somatropin version 1.1 resulted in a similar safety and efficacy profile compared with somatropin version 1.0 and a different immunogenicity profile with a lower incidence of ADAs.


Assuntos
Terapia Biológica/métodos , Química Farmacêutica/métodos , Hormônio do Crescimento Humano/síntese química , Hormônio do Crescimento Humano/uso terapêutico , Fenômenos Imunogenéticos/efeitos dos fármacos , Terapia Biológica/normas , Química Farmacêutica/normas , Criança , Nanismo Hipofisário/tratamento farmacológico , Nanismo Hipofisário/genética , Nanismo Hipofisário/imunologia , Feminino , Hormônio do Crescimento Humano/imunologia , Humanos , Fenômenos Imunogenéticos/fisiologia , Masculino , Estudos Prospectivos
4.
J Endocrinol Invest ; 43(2): 209-217, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31452114

RESUMO

PURPOSE: Growth hormone deficiency (GHD) is the most prevalent hypothalamic-pituitary (HP) disorder found in childhood cancer survivors (CCS). The published studies assessing GHD in CCS concluded that recombinant human GH (rhGH) does not restore final height (FH) to that predicted from mid-parental height (MPH). Thus, wider analyses on final height outcomes after rhGH in CCS are needed. METHODS: Retrospective study on final height (FH) in 87 CCS treated with rhGH. Patients were divided into: Group A (n =48) who underwent cranial radiotherapy or had non-irradiated tumours of HP area, and B (n =39) who were treated with craniospinal or total body irradiation (TBI). 19/87 patients with central precocious/early puberty also received GnRH analogues. RESULTS: Height (HT) gain after 1 and 2 years of rhGH was 0.38 ± 0.35 SDS and 0.18 ± 0.30 SDS, respectively (P < 0.0001); mean FH was in the normal range (- 0.85 ± 1.34 SDS), though not significantly different from HT SDS at baseline. 67% overall failed to reach MPH especially in Group B (P < 0.0001). However, height loss (HT SDS-MPH SDS) at FH improved or remained stable compared to baseline in 26/45 patients (58%). On stepwise regression analysis, major determinants of FH were HT at baseline (P < 0.0001) and delay before start of rhGH (P = 0.012). There was no significant difference in FH when GnRHa was added to rhGH. CONCLUSION: rhGH and GnRH analogues therapy, when indicated, though failing to induce catch-up growth, prevented further height loss leading to a FH within the normal range but still below MPH, this latter being statistically significant in children who received craniospinal and TBI.


Assuntos
Estatura/efeitos dos fármacos , Sobreviventes de Câncer , Nanismo Hipofisário/tratamento farmacológico , Hormônio do Crescimento Humano/uso terapêutico , Maturidade Sexual/efeitos dos fármacos , Adolescente , Estatura/fisiologia , Criança , Pré-Escolar , Nanismo Hipofisário/epidemiologia , Feminino , Hormônio do Crescimento Humano/farmacologia , Humanos , Lactente , Masculino , Estudos Retrospectivos , Maturidade Sexual/fisiologia , Adulto Jovem
5.
Expert Rev Endocrinol Metab ; 14(6): 419-436, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31721610

RESUMO

Introduction: There have been significant clinical advances in the understanding of the diagnosis and benefits of long-term recombinant human growth hormone (rhGH) replacement in adults with GH deficiency (GHD) since its approval in 1996 by the United States Food and Drug Administration.Areas covered: We searched PubMed, Medline, CINAHL, EMBASE and PsychInfo databases between January 2000 and June 2019 for published studies evaluating adults with GHD. We reviewed the data of the oral macimorelin test compared to the GHRH plus arginine and the insulin tolerance tests that led to its approval by the United States FDA and European Medicines Agency for adult diagnostic testing. We summarize the clinical advances of long-term benefits of rhGH therapy and the potential effects of GH receptor polymorphisms on individual treatment responsiveness. We identify that non-adherence and discontinuation rates are high and recommend strategies to support patients to improve adherence. We also provide an overview of several long-acting GH (LAGH) preparations currently under development and their potential role in improving treatment adherence.Expert opinion: This article summarizes recent clinical advances in rhGH replacement therapy, the biological and molecular aspects that may influence rhGH action, and offers practical strategies to enhance adherence in adults with GHD.


Assuntos
Nanismo Hipofisário/tratamento farmacológico , Terapia de Reposição Hormonal/métodos , Hormônio do Crescimento Humano/deficiência , Adesão à Medicação , Adulto , Nanismo Hipofisário/diagnóstico , Nanismo Hipofisário/fisiopatologia , Hormônio Liberador de Hormônio do Crescimento/efeitos adversos , Terapia de Reposição Hormonal/instrumentação , Hormônio do Crescimento Humano/uso terapêutico , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto
6.
Horm Res Paediatr ; 92(2): 115-123, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31715605

RESUMO

BACKGROUND: Floating-Harbor syndrome (FHS) is a rare condition characterized by dysmorphic facial features, short stature, and expressive language delay. OBJECTIVE: The aim of this study was to describe a cohort of patients with FHS and review the literature about the response to recombinant human growth hormone (rhGH) therapy. METHODS: Anthropometric and laboratory data from 7 patients with FHS were described. The molecular diagnosis was established by multigene analysis. Moreover, we reviewed the literature concerning patients with FHS treated with rhGH. RESULTS: All 7 patients were born small for gestational age. At first evaluation, 6 patients had a height standard deviation score (SDS) ≤-2 and 1 had short stature in relation to their target height. Bone age was usually delayed, which rapidly advanced during puberty. Nonspecific skeletal abnormalities were frequently noticed, and normal to elevated plasma IGF-I levels were observed in all except 1 patient with growth hormone deficiency. Information about 20 patients with FHS treated with rhGH was analyzed (4 from our cohort and 16 from the literature). The median height changes during the treatment period (approx. 2.9 years) were 1.1 SDS (range from -0.4 to 3.1). Nontreated patients had an adult height SDS of -4.1 ± 1.2 (n = 10) versus -2.6 ± 0.8 SDS (n = 7, p 0.012) for treated patients. CONCLUSION: We observed a laboratory profile compatible with IGF-1 insensitivity in some patients with FHS. Nevertheless, our study suggests that children with FHS may be considered as candidates for rhGH therapy. Further studies are necessary to establish the real benefit and safety of rhGH therapy in these patients.


Assuntos
Anormalidades Múltiplas , Desenvolvimento do Adolescente/efeitos dos fármacos , Desenvolvimento Infantil/efeitos dos fármacos , Anormalidades Craniofaciais , Nanismo Hipofisário , Transtornos do Crescimento , Comunicação Interventricular , Hormônio do Crescimento Humano/uso terapêutico , Puberdade/efeitos dos fármacos , Anormalidades Múltiplas/tratamento farmacológico , Anormalidades Múltiplas/metabolismo , Anormalidades Múltiplas/patologia , Anormalidades Múltiplas/fisiopatologia , Adolescente , Estatura/efeitos dos fármacos , Criança , Pré-Escolar , Anormalidades Craniofaciais/tratamento farmacológico , Anormalidades Craniofaciais/metabolismo , Anormalidades Craniofaciais/patologia , Anormalidades Craniofaciais/fisiopatologia , Nanismo Hipofisário/tratamento farmacológico , Nanismo Hipofisário/metabolismo , Nanismo Hipofisário/patologia , Nanismo Hipofisário/fisiopatologia , Feminino , Transtornos do Crescimento/tratamento farmacológico , Transtornos do Crescimento/metabolismo , Transtornos do Crescimento/patologia , Transtornos do Crescimento/fisiopatologia , Comunicação Interventricular/tratamento farmacológico , Comunicação Interventricular/metabolismo , Comunicação Interventricular/patologia , Comunicação Interventricular/fisiopatologia , Humanos , Fator de Crescimento Insulin-Like I/metabolismo , Masculino
7.
Pediatr Endocrinol Rev ; 17(1): 41-46, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31599135

RESUMO

The somatotropic axis is intricately involved in normal sleep, as evidenced by the fact that hypothalamic growth hormone-releasing hormone (GHRH) has sleep promoting effects and pituitary growth hormone (GH) release is strongly associated with slow-wave sleep (SWS). Abnormalities in the somatotropic axis, such as GH deficiency of hypothalamic or pituitary origin, result in an alteration of normal sleep patterns which may explain the fatigue reported in these individuals. Sleep disorders such as narcolepsy, in which individuals abnormally enter rapid eye movement (REM) sleep at sleep onset are also associated with an altered GHRH circadian rhythm and abnormal GH secretion. While few studies are available, this review explores what is known about sleep abnormalities in GH deficiency, the effect of treatment on sleep in patients with GH deficiency, and GH secretion in narcolepsy. Emerging evidence suggests a hypothalamic link between narcolepsy and GH secretion. We also describe the unique constellation of isolated idiopathic GH deficiency and severe excessive sleepiness in adopted Nicaraguan siblings, one of which has narcolepsy and the other idiopathic hypersomnia.


Assuntos
Hormônio do Crescimento Humano , Sonolência , Criança , Nanismo Hipofisário/tratamento farmacológico , Hormônio Liberador de Hormônio do Crescimento/metabolismo , Hormônio do Crescimento Humano/efeitos adversos , Hormônio do Crescimento Humano/metabolismo , Hormônio do Crescimento Humano/uso terapêutico , Humanos , Narcolepsia/fisiopatologia
8.
Eur J Endocrinol ; 181(6): 629-638, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31590143

RESUMO

Objective: Clinical observations over time of adults with growth hormone (GH) deficiency (GHD) have indicated a shift in patient characteristics at diagnosis. The objective of this study was to compare baseline characteristics of patients diagnosed with adult-onset GHD naive to GH replacement during three study periods (1994-1999 (P1), 2000-2004 (P2), and 2005-2012 (P3)) using the KIMS (Pfizer's International Metabolic) database. Methods: Data were retrieved for a total of 6069 patients with adult-onset GHD from six countries (Belgium, Germany, Netherlands, Spain, Sweden, and UK): P1 (n = 1705), P2 (n = 2397), and P3 (n = 1967). Results: The proportions of patients with pituitary/hypothalamic tumors and patients with multiple pituitary hormone deficiencies decreased per entry year period, while the proportions with hypertension and diabetes increased. The lag time from diagnosis of pituitary disease to start of GH treatment decreased by 2.9 years over the entry year periods. IGF-1 increased by 0.1 standard deviation score per entry year period. Maximum GH following various stimulation tests, BMI, and waist circumference increased. The use of radiotherapy, glucocorticoid replacement doses, and the proportion of women >50 years on estrogen replacement therapy decreased. The effects of 1 year of GH replacement were similar over the entry year periods despite changes in the patients' baseline characteristics. An expected increase in fasting blood glucose was seen after 1 year of GH treatment. Conclusions: The degree of confirmed GHD became less pronounced and more patients with co-morbidities and diabetes were considered for GH replacement therapy, possibly reflecting increased knowledge and confidence in GH therapy gained with time.


Assuntos
Nanismo Hipofisário/tratamento farmacológico , Nanismo Hipofisário/epidemiologia , Nanismo Hipofisário/patologia , Hormônio do Crescimento/uso terapêutico , Adulto , Bélgica/epidemiologia , Feminino , Alemanha/epidemiologia , Glucocorticoides/uso terapêutico , Terapia de Reposição Hormonal , Humanos , Masculino , Pessoa de Meia-Idade , Países Baixos/epidemiologia , Espanha/epidemiologia , Suécia/epidemiologia , Reino Unido/epidemiologia
9.
Acta Biomed ; 90(8-S): 43-51, 2019 09 23.
Artigo em Inglês | MEDLINE | ID: mdl-31544806

RESUMO

BACKGROUND: Variability still exist about the growth response to growth hormone (GH) therapy in children with idiopathic short stature (ISS). We describe the growth response to rhGH therapy for >2 years in 20 prepubertal children with idiopathic short stature (ISS) and 18 children with GH deficiency (GHD) and compared them with 15 children with ISS who did not receive rhGH therapy. PATIENTS AND METHODS: Our study included 35 prepubertal and peripubertal (Tanner 1 and 2) children with short stature (Ht-SDS <-2) and/or Ht-SDS >1SD below their mid parental height SD (MP-Ht-SDS) with slow growth velocity (<-1 SD), with normal peak GH response to provocation tests (15.5±6.5 ng/dl), normal IGF-I SDS (-0.9±0.6), and no bone age delay (± 1 year from chronological age) (ISS). 20 children were treated for 2.5±1.5 years with rhGH 0.05 mg/kg/day and 15 children were not treated with rhGH. 18 children with diagnosis of GHD, diagnosed in the same period, receiving rhGH therapy served as controls. We assessed the linear growth and IGF-I levels of all children for an average of 2 years. RESULTS: Children with ISS on rhGH therapy had a height gain of 0.77 SD in 2 years versus 1.05 SD in GHD children, with significant increase in IGF-I and normal progression of bone age and puberty. Children with ISS who did not receive rhGH had no gain in the changes of Ht-SDS inspite of normal progression of bone age and puberty. The difference between children Ht-SDS and mid-parental height SDS (MP-Ht-SDS) changed significantly from -1.1±3 to -0.3±0.5 in the ISS group and from -1.35±0.5 to -0.3±0.25 in the GHD group, after an average of 2 years of treatment. In the treated ISS group, the Ht-SDS gain was correlated positively with the duration of rhGH therapy (r = 0.82, p<0.0001), negatively with the age at the start of treatment (r = -0.544, p = 0.01), and positively with the bone age (r =-0.44, p = 0.04). DISCUSSION: The Ht-SDS of children with ISS on rhGH treatment closely approached their MP-Ht-SDS after 2 years of rhGH therapy while those who did not receive rhGH kept the same distance from their MP-Ht-SDS after 2 years. Analysis of possible factors affecting linear growth in children with ISS on rhGH therapy showed that children below 9 years with Ht-SDS <-2.5 SD and those with Ht-SDS >1SD below MP-Ht-SDS grew better on rhGH therapy compared to older children and those with Ht-SDS >-2.5 and were less than 1SD from their MP-HT-SD. Higher doses of rhGH (to keep IGF-I in high normal levels) and longer duration of therapy improved the Ht-SDS gain of these children. CONCLUSION: We report significant gain in Ht-SDS in prepubertal children with ISS on rhGH therapy and better response in younger children and in those with Ht-SDS > 1 SD below their MP-Ht-SDS.


Assuntos
Estatura/efeitos dos fármacos , Nanismo Hipofisário/tratamento farmacológico , Transtornos do Crescimento/tratamento farmacológico , Hormônio do Crescimento Humano/sangue , Hormônio do Crescimento Humano/uso terapêutico , Adolescente , Determinação da Idade pelo Esqueleto , Fatores Etários , Criança , Pré-Escolar , Estudos de Coortes , Países em Desenvolvimento , Nanismo Hipofisário/diagnóstico , Feminino , Transtornos do Crescimento/sangue , Humanos , Masculino , Catar , Estudos Retrospectivos , Medição de Risco , Fatores Sexuais , Maturidade Sexual/efeitos dos fármacos , Resultado do Tratamento
10.
Horm Res Paediatr ; 92(1): 36-44, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31461713

RESUMO

BACKGROUND/AIMS: Studies are lacking regarding the timing of peak growth hormone (PGH) response. We aim to elucidate the timing of PGH response to arginine and levodopa (A-LD) and evaluate the influence of body mass index (BMI) and other metabolic parameters on PGH. METHODS: During growth hormone (GH) stimulation testing (ST) with A-LD, serum GH was measured at baseline and every 30 min up to 180 min. The PGH cut-off was defined as &#x3c;10 ng/mL. IGF-1, IGF BP3, BMI, and metabolic parameters were obtained in a fasting state at baseline. RESULTS: In the 315 tested children, stimulated PGH levels occurred at or before 120 min in 97.8% and at 180 min in 2.2%. GH area under the curve (AUC) positively correlated with PGH in all patients and with IGF-1 in pubertal males and females. BMI negatively correlated with PGH in all subjects. GH AUC negatively correlated with HOMA-IR and total cholesterol. CONCLUSION: We propose termination of the GH ST with A-LD at 120 min since omission of GH measurement at 180 min did not alter the diagnosis of GH deficiency based on a cut-off of &#x3c; 10 ng/mL. BMI should be considered in the interpretation of GH ST with A-LD. The relationships between GH AUC and metabolic parameters need further study.


Assuntos
Índice de Massa Corporal , Nanismo Hipofisário , Hormônio do Crescimento Humano , Fator de Crescimento Insulin-Like I/metabolismo , Puberdade/sangue , Adolescente , Criança , Nanismo Hipofisário/sangue , Nanismo Hipofisário/tratamento farmacológico , Feminino , Hormônio do Crescimento Humano/administração & dosagem , Hormônio do Crescimento Humano/sangue , Hormônio do Crescimento Humano/deficiência , Humanos , Masculino
11.
Endocrine ; 66(3): 614-621, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31423546

RESUMO

PURPOSE: The definition of growth response in growth hormone (GH)-treated children is controversial. This study aims at: (1) evaluating short-term and long-term efficacy of GH treatment in a cohort of short children with GH deficiency (GHD); (2) assessing and compare various poor response criteria; (3) identifying predictive factors of growth response. METHODS: Our study included 94 children, affected by isolated GHD and treated with GH until they reached final height. Criteria used for calculating the proportion of poor responders to GH for the first year were gain in height (ΔHt) SDS < 0.5 ("Bang criterion"), <0.3 or <0.4 SDS for less-severe and severe GHD, respectively ("Ranke criterion"), height velocity (HV) < mean -1 SDS ("Bakker criterion"); for adult height "Cianfarani criterion" was total ΔHt < 1 SDS. RESULTS: After 1 year of treatment we defined "poor responders" 55.3% of patients according to Bang criterion, 40.9% according to Bakker criterion and 23.4% according to Ranke criterion. At the end of the treatment, poor responders according to Cianfarani criterion were 22.34%; almost everyone in our population (97.9%) achieved mMid-parental height (MPH). Median final Ht was -1.11 SDS. Our analysis revealed a significant negative association between ΔHt and age at diagnosis. CONCLUSIONS: Bang criterion generated the highest number of poor responders, but had a low negative predictive value (67.5%); Ranke and Cianfarani criteria displayed similar rate of poor response. There is no reliable predictive factor of growth hormone response. However, almost all children treated reached MPH, suggesting good treatment efficacy.


Assuntos
Hormônio do Crescimento/deficiência , Terapia de Reposição Hormonal , Avaliação de Resultados em Cuidados de Saúde , Adolescente , Criança , Pré-Escolar , Nanismo Hipofisário/tratamento farmacológico , Feminino , Hormônio do Crescimento/uso terapêutico , Humanos , Estudos Longitudinais , Masculino , Estudos Retrospectivos
12.
J Clin Endocrinol Metab ; 104(10): 4730-4742, 2019 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-31305924

RESUMO

CONTEXT: Understanding real-world prescribing of GH may help improve treatment of eligible patients. OBJECTIVE: Overall: to assess real-world effectiveness and safety of GH (Norditropin). This analysis: to compare clinical characteristics of GH-treated children in the United States and Europe. DESIGN: The American Norditropin Studies: Web-Enabled Research Program (ANSWER; 2002 to 2016, United States) and the NordiNet International Outcome Study (NordiNet IOS; 2006 to 2016, Europe) were multicenter longitudinal observational cohort studies. SETTING: Data were recorded in 207 (United States) and 469 (Europe) clinics. PARTICIPANTS: Patients with GH deficiency, Turner syndrome, Noonan syndrome, idiopathic short stature, Prader-Willi syndrome, or born small for gestational age, who commenced GH treatment aged <1 year. INTERVENTION: GH was prescribed by treating physicians according to local practice. MAIN OUTCOMES MEASURES: Baseline data and drug doses were recorded. Data on effectiveness and safety were collected. RESULTS: ANSWER had 19,847 patients in the full analysis set (FAS; patients with birthdate information and one or more GH prescription) and 12,660 in the effectiveness analysis set (EAS; GH-naive patients with valid baseline information). NordiNet IOS had 17,711 (FAS) and 11,967 (EAS). Boys accounted for 69% (ANSWER) and 57% (NordiNet IOS). Treatment start occurred later than optimal to improve growth. The proportion of boys treated was generally larger, children were older at treatment start, and GH doses were higher in the United States vs Europe. No new safety signals of concern were noted. CONCLUSIONS: In most indications, more boys than girls were treated, and treatment started late. Earlier diagnosis of GH-related disorders is needed. The data support a favorable benefit-risk profile of GH therapy in children.


Assuntos
Transtornos do Crescimento/tratamento farmacológico , Transtornos do Crescimento/epidemiologia , Hormônio do Crescimento Humano/uso terapêutico , Adolescente , Criança , Pré-Escolar , Nanismo Hipofisário/tratamento farmacológico , Nanismo Hipofisário/epidemiologia , Europa (Continente)/epidemiologia , Feminino , Seguimentos , Humanos , Recém-Nascido Pequeno para a Idade Gestacional/crescimento & desenvolvimento , Estudos Longitudinais , Masculino , Síndrome de Prader-Willi/tratamento farmacológico , Síndrome de Prader-Willi/epidemiologia , Síndrome de Turner/tratamento farmacológico , Síndrome de Turner/epidemiologia , Estados Unidos/epidemiologia
13.
Adv Ther ; 36(9): 2374-2383, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31301056

RESUMO

INTRODUCTION: This study aims to explore the safety and efficacy of growth hormone (GH) therapy by retrospectively analyzing the changes of insulin-like growth factor-1 (IGF-1) Z-scores in children with short stature after treatment with GH. METHODS: The etiology of 104 children with short stature was classified according to the GH stimulation test and IGF-1 levels: (1) growth hormone deficiency (GHD); (2) mild growth hormone deficiency (M-GHD); (3) idiopathic short stature (ISS); (4) GH insensitivity syndrome (GHIS). In addition, all patients were treated with recombinant human growth hormone (rhGH) for 12 months, and the growth rate (Gv), height, body mass, bone age, height standard deviation scores (HtSDS), IGF-1 and adverse reactions were compared among these three groups before and after treatment. RESULTS: The height, body mass, Gv and HtSDS were significantly higher in each group compared with those before treatment. Furthermore, the Z-score of IGF-1 significantly increased after 1 month of GH treatment and was positively correlated with the dosage of GH. Moreover, the difference in standard deviation score was significantly positively correlated with the increase in standard deviation score of IGF-1. CONCLUSION: The detection of the GH-IGF-1 axis function can be carried out for the etiologic diagnosis of short stature. IGF-1 increased after rhGH treatment, and IGF-1 level was correlated to the time of therapy and dosage of GH. IGF-1-based GH dosing targeted to age- and gender-adjusted means may save medical costs and offer a more dose-sparing and potentially safer mode of therapy compared with traditional weight-based dosing.


Assuntos
Transtornos do Crescimento/tratamento farmacológico , Hormônio do Crescimento Humano/uso terapêutico , Proteína 3 de Ligação a Fator de Crescimento Semelhante à Insulina/sangue , Estatura/efeitos dos fármacos , Desenvolvimento Ósseo/efeitos dos fármacos , Criança , Pré-Escolar , Relação Dose-Resposta a Droga , Nanismo Hipofisário/tratamento farmacológico , Feminino , Transtornos do Crescimento/sangue , Humanos , Fator de Crescimento Insulin-Like I/análise , Masculino , Proteínas Recombinantes/uso terapêutico , Estudos Retrospectivos
14.
Horm Res Paediatr ; 91(4): 241-251, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31185471

RESUMO

BACKGROUND/OBJECTIVES: Growth hormone (GH) treatment of idiopathic short stature (ISS) received US Food and Drug Administration approval in 2003. We assessed height gain and safety in 2,450 children with ISS treated with GH in US clinical practice. METHODS: Short-term height gain, near-adult height (NAH), and safety outcomes were investigated using Genetics and Neuroendocrinology of Short Stature International Study data. RESULTS: Compared to children with isolated idiopathic GH deficiency (IGHD), those with ISS were shorter at baseline but had similar age and GH dose. Mean ± SD height SD score (SDS) increase was similar for ISS and IGHD, with 0.6 ± 0.3 (first), 0.4 ± 0.3 (second), 0.3 ± 0.3 (third), and 0.1 ± 0.3 (fourth year) for ISS. Girls with ISS (27% of subjects) were younger and shorter than boys but had similar height gain over time. At NAH in the ISS group (n = 467), mean ± SD age, GH duration, and height SDS were 17.3 ± 2.3 years, 4.6 ± 2.7 years, and -1.2 ± 0.9, respectively. Height gain from baseline was 1.1 ± 1.0 SDS and was greater for boys than girls (1.2 ± 1.0 vs. 0.9 ± 0.9), but boys were treated longer (5.1 ± 2.8 vs. 3.6 ± 2.5 years). Adverse events were reported for 24% with ISS versus 20% with IGHD - most were common childhood conditions or previously reported in GH-treated patients. CONCLUSIONS: GH-treated children with ISS achieved substantial height gain, similar to patients with IGHD. Fewer GH-treated girls were enrolled than boys, but with similar height SDS gain over time. No ISS-specific safety issues were identified. Thus, GH treatment of ISS appears to have a safety/effectiveness profile similar to that of IGHD.


Assuntos
Estatura/efeitos dos fármacos , Nanismo Hipofisário/tratamento farmacológico , Transtornos do Crescimento/tratamento farmacológico , Hormônio do Crescimento Humano/administração & dosagem , Adolescente , Criança , Nanismo Hipofisário/fisiopatologia , Feminino , Transtornos do Crescimento/fisiopatologia , Humanos , Masculino , Estudos Prospectivos
15.
J Clin Endocrinol Metab ; 104(11): 5263-5273, 2019 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-31215990

RESUMO

BACKGROUND: GH deficiency (GHD) is characterized by a cluster of cardiovascular risk factors and subtle inflammation. We aimed to demonstrate, through a proteomic approach, molecules directly modulated by GHD and involved in the inflammatory state. METHODS: Ten children with isolated GHD were studied before and after 1 year of treatment with rhGH and compared with 14 matched controls. A two-dimensional electrophoresis plasma proteomics analysis was performed at baseline and after GH treatment to identify the top molecules modulated by GH. In vitro studies on human hepatoma (HepG2) cells were performed to validate the data. RESULTS: Twelve of 20 proteomic spots were predicted to be isoforms α and ß of haptoglobin (Hp) and confirmed by liquid chromatography tandem mass spectrometry and Western immunoblot analyses. Hp levels were higher in patients with GHD than controls at baseline (P < 0.001) and were reduced following GH treatment (P < 0.01). In HepG2 cells, both GH and IGF-1 were able to downregulate IL-6-induced Hp secretion. Moreover, Hp secretion was restored in pegvisomant-treated HepG2 cells. CONCLUSIONS: Hp is a molecule acting in the inflammatory state of GHD and a possible biomarker for GH treatment. Nevertheless, the contribution of other factors and the molecular pathways involved in the GH downregulation of Hp remain to be clearly defined.


Assuntos
Nanismo Hipofisário/sangue , Nanismo Hipofisário/tratamento farmacológico , Haptoglobinas/metabolismo , Hormônio do Crescimento Humano/uso terapêutico , Inflamação/sangue , Inflamação/tratamento farmacológico , Biomarcadores/sangue , Linhagem Celular Tumoral , Criança , Regulação para Baixo , Nanismo Hipofisário/complicações , Feminino , Humanos , Inflamação/complicações , Fator de Crescimento Insulin-Like I/metabolismo , Interleucina-6/sangue , Masculino , Proteômica
17.
Clin Endocrinol (Oxf) ; 91(2): 304-313, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31077606

RESUMO

BACKGROUND: Health-related quality of life (HRQOL) may improve as an additional benefit of the growth hormone treatment (GHT) in children with short stature, but this effect has not been conclusively proven. OBJECTIVES: To explore the direct effect of GHT on HRQOL in children starting GHT due to isolated or multiple GH deficiency (IGHD), acquired GH deficiency (AGHD) and Turner syndrome (TS), in comparison with untreated short stature controls in 18 UK centres. METHODS: We used recognized measures of HRQOL, the PedsQL, the Strengths and Difficulties Questionnaire and Youth Life Optimism Test scales to investigate the effect of GHT at 0, 6 and 12 months in children and adolescents 6-16 years with IGHD (n = 73) and AGHD (n = 45), and 22 girls with TS. 49 children with non-GHD short stature served as the controls. RESULTS: Children rated their HRQOL better than their parents. Those with IGHD and TS rated their overall HRQOL lower than the controls at baseline, psychosocial scores significantly lower in IGHD. After 12 months, the control and TS groups scored higher than UK norms. Those with AGHD had lowest HRQOL scores at all time points, due to poorer physical functioning. The controls showed the greatest improvement in the strength and difficulties scale. All measures evaluated, whether from child, parent or teacher showed an equal improvement over the year of GHT with no discernible direct treatment effect, despite reduced numbers in some patient groups. CONCLUSIONS: Children with short stature resulting from GHD have lower functioning than controls but HRQOL appears to improve with GHT, most likely on account of greater attention and as a result of the retest phenomenon. We were not able to demonstrate an absolute and independent effect of GHT in itself. HRQOL should not be used as a primary measure, as in adults, to determine whether children should receive GHT.


Assuntos
Nanismo Hipofisário/tratamento farmacológico , Transtornos do Crescimento/tratamento farmacológico , Nível de Saúde , Hormônio do Crescimento Humano/uso terapêutico , Qualidade de Vida , Síndrome de Turner/tratamento farmacológico , Adolescente , Adulto , Estatura/efeitos dos fármacos , Estatura/fisiologia , Criança , Nanismo Hipofisário/fisiopatologia , Nanismo Hipofisário/psicologia , Feminino , Transtornos do Crescimento/fisiopatologia , Transtornos do Crescimento/psicologia , Humanos , Masculino , Estudos Prospectivos , Inquéritos e Questionários , Síndrome de Turner/fisiopatologia , Síndrome de Turner/psicologia
18.
An. pediatr. (2003. Ed. impr.) ; 90(5): 285-292, mayo 2019. tab, graf
Artigo em Espanhol | IBECS | ID: ibc-186660

RESUMO

Introducción: El crecimiento en pacientes con déficit aislado de hormona del crecimiento (GH) es heterogéneo a pesar del tratamiento, debido a la baja especificidad de las pruebas diagnósticas, por lo que es necesario definir las variables de eficacia. Objetivos: Evaluar la eficacia de la terapia de reemplazo hormonal en niños con déficit aislado de GH. Métodos: Estudio observacional-ambispectivo de pacientes tratados en nuestro servicio en los últimos 14 años por déficit aislado de GH, definido como GH inferior a 7,4 mg/dl en 2 pruebas de estímulo, en pacientes con talla < -2DE y velocidad de crecimiento disminuida. Resultados: Se estudiaron 97 pacientes. El 69% eran varones. Con el tratamiento hubo una ganancia de talla de 1,17DE. El 79,31% alcanzaron la talla diana. El 71,13% fueron reevaluados en la edad adulta, de los cuales el 39,4% mantuvo el déficit. La talla diana, el pronóstico de talla adulta y la ganancia puberal total se correlacionaron positivamente con la talla adulta, mientras que la relación edad ósea/edad cronológica y factor de crecimiento insulínico tipo 1 inicial mostraron una correlación negativa. Ninguno tuvo efectos secundarios. Conclusiones: La mayoría de los pacientes alcanzaron la talla diana, aunque no todos mostraron permanencia del déficit en edad adulta. La talla diana, el pronóstico de talla adulta y las variables de pubertad están directamente relacionados con la talla adulta; mientras que la edad ósea/edad cronológica y factor de crecimiento insulínico tipo 1 están inversamente relacionadas, pudiendo utilizarse estas como variables de eficacia. No se han observado efectos adversos en la muestra con las dosis utilizadas


Introduction: Growth in patients with isolated growth hormone (GH) deficiency is heterogeneous despite treatment due to the low specificity of diagnostic tests, making it necessary to define efficacy variables. Aims: To evaluate efficacy of hormone replacement therapy in children with isolated GH deficiency. Methods: Observational-ambispective study of patients treated in our department in the last 14 years for isolated GH deficiency. This was defined as a GH level less than 7.4 mg/dl in response to 2 stimulation tests in patients with height < 2SD and a decreased growth rate. Results: The study included a total 97 patients, of whom 69% were boys. The large majority (89.58%) achieved final height. None of them had side effects. The median dose of GH used was 0.028 mg/kg/day (0.03-0.025). There was a gain of 1.17 SD in final height. Around three-quarters (71.13%) of the patients were reassessed in adulthood, of whom 39.4% maintained the deficiency, and 79.31% achieved target range height. Target height, estimated height, and the total pubertal gain were positively correlated with final height, while the bone age/chronological age ratio and the initial insulin-like growth factor-1 showed a negative correlation. Conclusions: A majority of patients reached target size, although only a few of them maintained the deficiency in adulthood. Target size, estimated adult height, and pubertal variables are directly related to adult height, while bone age/chronological age and insulin-like growth factor-1 were inversely related, and these can be used as efficacy variables. No adverse effects were observed in the sample with the doses used for the treatment


Assuntos
Humanos , Masculino , Feminino , Pré-Escolar , Criança , Adolescente , Nanismo Hipofisário/tratamento farmacológico , Terapia de Reposição Hormonal/métodos , Hormônio do Crescimento Humano/administração & dosagem , Fator de Crescimento Insulin-Like I/metabolismo , Fatores Etários , Estatura/efeitos dos fármacos , Relação Dose-Resposta a Droga , Hormônio do Crescimento Humano/efeitos adversos , Estudos Prospectivos , Estudos Retrospectivos
19.
J Endocrinol Invest ; 42(10): 1241-1244, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30968283

RESUMO

BACKGROUND: With the use of non-objective measurement, adherence to growth hormone (GH) therapy has been reported suboptimal in a large proportion of patients, and poor adherence has been shown to affect short-term growth response in patients receiving GH treatment. OBJECTIVE: The Easypod™ electronic device allows objective measurement of adherence. In this study, we report 3-year prospective adherence data of the Italian cohort of naïve GH deficient (GHD) children extrapolated from the Easypod Connect Observational Study (ECOS) database. PATIENTS AND METHODS: Seventy-three GHD children naïve to GH treatment were included in the analysis. 22 Italian centers participated in the study. RESULTS: Mean adherence rate was consistently above 85% across the 3-year observation period. Particularly, mean adherence was 88.5%, 86.6%, and 85.7% after 1, 2 and 3 years, respectively. Mean (± SD) height-SDS increase after the first year was 0.41 (± 0.38). CONCLUSIONS: The majority of naïve GHD children starting GH treatment with Easypod maintained an adherence rate > 85% up to 3 years. Easypod is a useful tool to follow-up patients' adherence allowing timely intervention to improve optimal treatment for these patients.


Assuntos
Transtornos do Crescimento/tratamento farmacológico , Hormônio do Crescimento Humano/uso terapêutico , Sistemas Computadorizados de Registros Médicos , Adesão à Medicação/estatística & dados numéricos , Dispositivos Eletrônicos Vestíveis , Adolescente , Criança , Estudos de Coortes , Bases de Dados Factuais , Nanismo Hipofisário/tratamento farmacológico , Nanismo Hipofisário/epidemiologia , Feminino , Transtornos do Crescimento/epidemiologia , Hormônio do Crescimento Humano/deficiência , Humanos , Itália/epidemiologia , Masculino , Sistemas Computadorizados de Registros Médicos/instrumentação , Sistemas Computadorizados de Registros Médicos/normas , Sistemas Computadorizados de Registros Médicos/estatística & dados numéricos , Telemedicina/instrumentação , Telemedicina/estatística & dados numéricos , Dispositivos Eletrônicos Vestíveis/estatística & dados numéricos
20.
Horm Res Paediatr ; 91(1): 17-24, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30947197

RESUMO

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.


Assuntos
Anticorpos/sangue , Nanismo Hipofisário/sangue , Nanismo Hipofisário/tratamento farmacológico , Hormônio do Crescimento Humano/administração & dosagem , Anticorpos/imunologia , Criança , Pré-Escolar , Nanismo Hipofisário/imunologia , Feminino , Seguimentos , Hormônio do Crescimento Humano/imunologia , Humanos , Lactente , Masculino , Estudos Retrospectivos
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