GH Treatment in Children of Normal Height.

The increased availability of recombinant human GH (rhGH), albeit at a relatively high cost, has increased a demand for treatment of children and adolescents of normal height to increase their adult stature. There are no scientific reports on the efficacy and safety of rhGH therapy in this condition; therefore, the authors comment on the possible causes and consequences based on their personal opinion and experience. As in gigantism, when GH action and end-organ are normal, enough GH is expected to result in increased growth velocity. Short-term adverse effects related to rhGH therapy for approved indications of short stature in children have been very rare. Data on long-term adverse effects are still scarce. A small increase in height might be statistically significant but not functionally or socially relevant. Considering that an increase in height represents more a desire than a need, physicians should emphasize the normality and qualities of these children, discuss with families the alternatives, such as counseling, and refrain from supporting the concept that taller is better.

The growzen™ buddy smartphone app to improve adherence in patients receiving recombinant human growth hormone therapy: a retrospective observational study in Argentina.

Introduction: This study in Argentina evaluated the impact of the growzen™ buddy smartphone app on adherence to recombinant human growth hormone (r-hGH) treatment. Methods: The adherence data, invitation dates with a link to the app, app activation dates, and height measurements entered were extracted from the growzen™ digital health ecosystem. Patients with 12 months of adherence data, aged ≥2 years at treatment start, and aged <19 years were selected both before and after app implementation. Mean adherence was classified as optimal (≥85%) versus suboptimal (<85%). Adherence before and after implementation and the pre-post effect on adherence were assessed. Results: Data for 830 patients were available. Prior to app implementation, the proportion of patients with optimal adherence was 68% (n = 348/515). Following the app implementation, out of 315 patients, 302 (96%) received an invitation with a link to the app, 225 (71%) activated their account, and 127 (40%) entered height data in the first year. There was a significant early increase in the proportion of patients with optimal adherence following implementation: 82% (n = 258/315), p < 0.001. After implementation, the proportion of patients with optimal adherence included 80% (n = 78/98) of those with an active account who did not enter height measurements and 89% (n = 113/127) of those who did. There was a significant and positive pre-post app effect on adherence (p < 0.01) in patients with an active account. Discussion: Our results show that using the growzen™ buddy app has a rapid and positive impact on adherence to r-hGH treatment, and patients who were more engaged with the app demonstrated better adherence.

Síndrome de Turner / Turner's Syndrome / Sindrome de Turner

Introducción: el síndrome de Turner es una enfermedad genética caracterizada por la pérdida total o parcial de un cromosoma X, siendo sus características fundamentales la talla baja, la disgenesia gonadal y hallazgos fenotípicos característicos. Tiene una amplia variabilidad en su forma de presentación. Grandes estudios epidemiológicos muestran que la morbilidad aumenta en mujeres con este síndrome, debido a una amplia gama de enfermedades asociadas, sobre todo cardiovasculares, que eleva la mortalidad de manera significativa. Objetivo: realizar una revisión de la literatura, en base a la presentación de un caso clínico, para recabar información sobre las ultimas pautas de manejo y presentar los nuevos objetivos de tratamiento. Conclusiones: el diagnóstico temprano es fundamental, y tiene características propias y criterios de sospecha según la etapa en la que se efectúa, el reto actual en el manejo de estas pacientes consiste en la formación de un equipo médico multidisciplinario, conformado por una amplia gama de especialistas para el adecuado seguimiento, con el fin de disminuir las complicaciones y ayudar a que la paciente alcance sus objetivos para una vida plena. Se presenta el caso de una paciente con síndrome de Turner vista por el equipo médico en el Hospital Pediátrico del Centro Hospitalario Pereira Rossell, Montevideo-Uruguay.

Introduction: Turner's syndrome is a genetic disease characterized by total or partial loss of an X chromosome, its main features being low height, gonadal dysgenesis and characteristic phenotypic findings. It has a wide variability in its form of presentation. Large epidemiological studies show that morbidity increases in women with this syndrome, due to a wide range of associated diseases, especially cardiovascular disease, which significantly raises mortality. Objectives: to carry out a review of the literature, based on a clinical case in order to gather information regarding the latest treatment guidelines and present the new treatment goals. Conclusions: early diagnosis is essential, and has its own characteristics and suspicion criteria according to the stage in which it is carried out. The present challenge regarding the management of these patients consists of the training of a multidisciplinary medical team made up of a wide range of specialists able to carry out proper follow-up, in order to reduce complications and help the patient live a full life. We present a case of a patient with Turner's syndrome assisted at the Pereira Rossell Hospital Center in Montevideo-Uruguay.

Introdução: a síndrome de Turner é uma doença genética caracterizada pela perda total ou parcial de um cromossomo X, sendo suas características fundamentais de baixa estatura, disgenesia gonadal e achados fenotípicos característicos. Tem uma ampla variabilidade em sua forma de apresentação. Consideráveis (grandes, amplos, extensos) estudos epidemiológicos mostram que a morbidade aumenta em mulheres com essa síndrome, devido a uma ampla gama de doenças associadas, especialmente cardiovasculares, o que aumenta significativamente a mortalidade. Objetivos: realizar uma revisão da literatura, a partir da apresentação de um caso clínico, reunir informações sobre as últimas diretrizes de tratamento e apresentar os novos objetivos do tratamento. Conclusões: o diagnóstico precoce é fundamental, e possui características próprias e critérios de suspeita de acordo com a etapa em que é realizado, o desafio atual na gestão desses pacientes consiste na formação de uma equipe médica multidisciplinar, formada por uma ampla gama de especialistas para o acompanhamento adequado, a fim de reduzir complicações e ajudar a paciente a alcançar uma vida plena. Apresentamos o caso de uma paciente com síndrome de Turner atendido pela equipe médica do Hospital Pediátrico do Centro Hospitalar Pereira Rossell, Montevidéu-Uruguai.

Adult Height in 299 Patients with Turner Syndrome with or without Growth Hormone Therapy: Results and Literature Review.

CONTEXT: Treatment with growth hormone (GH) is considered effective in improving adult height (AH) in Turner syndrome (TS). However, there are few studies comparing AH between treated patients and a concurrent untreated group. OBJECTIVE: To assess the efficacy of GH treatment in improving AH in TS and to review previous published studies with treated and untreated groups. PARTICIPANTS AND METHODS: We retrospectively analyzed clinical data and AH of a large cohort of GH-treated (n = 168) and untreated (n = 131) patients with TS. Data are shown as median and interquartile range (IQR). We assessed pretreatment variables related with AH and compared our results with 16 studies that also included an untreated group. RESULTS: The GH-treated group was 6.2 cm taller than the untreated group (AH = 149 cm [IQR 144.5-152.5 cm] vs. 142.8 cm [IQR 139-148 cm], p < 0.001) after 4.9 years of GH treatment with a dose of 0.35 mg/kg/week. AH SDS corrected for target height (TH) was 7.2 cm higher in GH-treated patients. AH SDS ≥-2 was more frequent in GH-treated patients (43%) than in untreated patients (16%, p < 0.001). AH SDS was also more frequently within the TH range in the GH-treated group (52%) than in the untreated group (15%, p < 0.001). Height SDS at start of GH therapy and TH SDS were positively correlated with AH (p < 0.001; R2 = 0.375). Considering the current result together with previous similar publications, a mean AH gain of 5.7 cm was observed in GH-treated (n = 696) versus untreated (n = 633) patients. CONCLUSIONS: Our study strengthens the evidence for efficacy of GH therapy in patients with TS from different populations.

Insulin resistant diabetes mellitus in SHORT syndrome: case report and literature review.

SHORT syndrome is a rare developmental disorder frequently associated with growth failure and insulin resistant diabetes mellitus (IRDM). Since GH has a diabetogenic effect, GH therapy has been regarded as a contraindication. We observed a Brazilian girl with SHORT syndrome who received GH therapy from 4 6/12 years of age for SGA short stature. GH dosage was increased from 0.23 to 0.36 mg/kg/week, but statural response to GH therapy remained poor. Her blood HbA1c level, though it remained 5.5-6.0% in childhood, began to elevate with puberty and increased to 9.2% at 10 6/12 years of age, despite the discontinuation of GH therapy at 9 11/12 years of age. Laboratory studies indicated antibody-negative IRDM. She was treated with metformin and canagliflozin (a sodium glucose co-transporter 2 (SGLT2) inhibitor), which ameliorated overt diurnal hyperglycemia and mild nocturnal hypoglycemia and reduced her blood HbA1c around 7%. Whole exome sequencing revealed a de novo heterozygous pathogenic variant (c.1945C>T:p.(Arg649Trp)) in PIK3R1 known as the sole causative gene for SHORT syndrome. Subsequent literature review for patients with molecularly confirmed SHORT syndrome revealed the development of IRDM in 10 of 15 GH-untreated patients aged ≥12 years but in none of three GH-treated and six GH-untreated patients aged ≤10 years. These findings imply a critical role of pubertal development and/or advanced age rather than GH therapy in the development of IRDM, and a usefulness of SGLT2 inhibitor in the treatment of IRDM.

Near-Adult Height After Growth Hormone Treatment in Children Born Prematurely-Data From KIGS.

CONTEXT: Children born prematurely have been treated with growth hormone (GH), and a significant improvement in height during the first years of treatment has been described. OBJECTIVE: To evaluate the influence of prematurity on near-adult height (NAH) after GH treatment. DESIGN: KIGS (Pfizer International Growth Database) was queried for children born preterm treated with GH. SETTING: KIGS database. PATIENTS: A total of 586 children short in stature born preterm with various GH status and with available gestational age (GA), birth weight, and NAH, all treated with GH. INTERVENTION: GH treatment. MAIN OUTCOME MEASURE: NAH. RESULTS: Values were expressed as median. From the 586 children included, 482 born appropriate for GA (AGA; median age 8.26 years) and 104 born small for gestational age (SGA) (median age 8.54 years); 66.6% of preterm AGA had GH peak < 7 µg/L during a provocation test, whereas only 8.6% of preterm SGA. Change in height standard deviation scores (SDS) from GH start to NAH after 8.04 years of GH treatment was 1.82 in preterm AGA. Respective values were 7.08 years and 1.08 SDS for preterm SGA (P < 0.001); 57% of the variability of the growth response to NAH could be explained, and the distance to parental height was the strongest predictor. No significant changes in height SDS were observed from puberty start to NAH. No correlation was found with GA. GH treatment was well tolerated. CONCLUSION: GH treatment resulted in significant improvement in height in children born preterm, particularly during prepubertal years and for those with GH deficiency. The degree of prematurity did not influence the growth response.

Potential applications for rhIGF-I: Bone disease and IGFI.

Growth hormone (GH) and insulin like growth factor-I (IGFI) are key bone trophic hormones, whose rising levels during puberty are critical for pubertal bone accrual. Conditions of GH deficiency and genetic resistance impact cortical and trabecular bone deleteriously with reduced estimates of bone strength. In humans, conditions of undernutrition (as in anorexia nervosa (AN), or subsequent to chronic illnesses) are associated with low IGF-I levels, which correlate with disease severity, and also with lower bone mineral density (BMD), impaired bone structure and lower strength estimates. In adolescents and adults with AN, studies have demonstrated a nutritionally acquired GH resistance with low IGF-I levels despite high concentrations of GH. IGF-I levels go up with increasing body weight, and are associated with rising levels of bone turnover markers. In short-term studies lasting 6-10 days, recombinant human IGF-I (rhIGF-I) administration in physiologic replacement doses normalized IGF-I levels and increased levels of bone formation markers in both adults and adolescents with AN. In a randomized controlled trial in adults with AN in which participants were randomized to one of four arms: (i) rhIGF-I with oral estrogen-progesterone (EP), (ii) rhIGF-I alone, (iii) EP alone, or (iv) neither for 9 months, a significant increase in bone formation markers was noted in the groups that received rhIGF-I, and a significant decrease in bone resorption markers in the groups that received EP. The group that received both rhIGF-I and EP had a significant increase in bone density at the spine and hip compared to the group that received neither. Side effects were minimal, with no documented fingerstick glucose of <50 mg/dl. These data thus suggest a potential role for rhIGF-I administration in optimizing bone accrual in states of undernutrition associated with low IGF-I.

Eficacia y seguridad de somatropina administrada con dispositivo electrónico, en comparación con somatropina administrada sin dispositivo electrónico, en el tratamiento de pacientes pediatricos con deficit de hormona de crecimiento / Efficacy and safety of somatropin administered with an electronic device, compared with somatropin administered without an electronic device, in the treatment of pediatric patients with growth hormone deficiency

INTRODUCCIÓN: El presente dictamen expone la evaluación de tecnología de la eficacia y seguridad de somatropina administrada con dispositivo electrónico, en comparación con somatropina administrada sin dispositivo electrónico, en el tratamiento de pacientes pediátricos con déficit de hormona del crecimiento. Una falla específica en la glándula pituitaria genera una deficiencia de hormona del crecimiento (DHC), que es la causa endocrina más común de baja estatura. Se estima que la incidencia de baja estatura asociada a DHC se encuentra alrededor de 1:4000 a 1:10000 en niños. Así, el tratamiento estándar para la población pediátrica con falla en el crecimiento por DHC es la terapia hormonal de reemplazo con hormona de crecimiento (HC) sintética, llamada somatropina. En la actualidad EsSalud cuenta con somatropina en polvo liofilizado para solución inyectable para el tratamiento de pacientes pediátricos con baja estatura asociada a DHC. La concentración de somatropina disponible en la institución corresponde a un vial de 10 UI, en una presentación sin dispositivo electrónico para aplicación. El procedimiento actual para la aplicación de las dosis requeridas (i.e., 0.025-0.035 mg/kg/día), es que los padres o cuidadores del paciente preparen las ampollas e inyecten el medicamento utilizando una jeringa común. No obstante, algunos especialistas de la institución manifiestan dos preocupaciones con respecto a este procedimiento. Por un lado, mencionan que la dificultad en la preparación y aplicación asociadas a este proceso puede impactar sobre la precisión en las dosis inyectadas, lo que podría llevar a la aplicación de dosis sub-optimas; y, por otro lado, el uso de una jeringa común puede afectarla adherencia al tratamiento ya que el dolor luego de la inyección dificultaría sus siguientes aplicaciones. METODOLOGIA: Se llevó a cabo una búsqueda de la literatura con respecto a la eficacia y seguridad de somatropina administrada con dispositivo electrónico, en comparación con somatropina administrada sin dispositivo electrónico, en pacientes pediátricos con déficit de hormona del crecimiento en las bases de datos de PubMed, TRIPDATABASE y www.clinicaltrials.gov. Adicionalmente, se realizó una búsqueda de evaluaciones de tecnologías y guías de práctica clínica en las páginas web de grupos dedicados a la investigación y educación en salud en general como The National Institute for Health and Care Excellence (NICE), Canadian Agency for Drugs and Technologies in Health (CADTH), Scottish Medicines Consortium (SMC), Instituto de Evaluación de Efectividad Clínica y Sanitaria (IECS), Instituto de Evaluación de Tecnología en Salud (IETS); y en sitios especializados en endocrinología pediátrica como Pediatric Endocrine Society (PES), Endocrine Society of Australia (ESA), Japan Endocrine Society, European Society for Pediatric Endocrinology (ESPE). RESULTADOS: De acuerdo con la pregunta PICO, se llevó a cabo una búsqueda de evidencia científica relacionada al uso de somatropina administrada con dispositivo electrónico, en comparación con somatropina administrada sin dispositivo electrónico, en pacientes pediátricos con déficit de hormona del crecimiento. En la presente sinopsis se describe la evidencia disponible según el tipo de publicación, siguiendo lo indicado en los criterios de elegibilidad (GPC, ETS, RS, MA y ECA fase III). CONCLUSIONES: A la fecha no se han publicado estudios sobre la eficacia comparativa entre la aplicación de somatropina con un dispositivo electrónico y la aplicación con una ampolla común, en el tratamiento de pacientes pediátricos con falla de crecimiento por DHC. Se identificó uno que podría brindar información de relevancia pero no se encuentra disponible en texto completo, sino únicamente el resumen. La evidencia disponible en la actualidad en torno al uso de somatropina en dicha población corresponde a una guía de práctica clínica (GPC) del 2016 de La Sociedad de Endocrinología Pediátrica (PES, por sus siglas en inglés), y 4 evaluaciones de tecnología sanitaria (ETS) de National Institute for Health and Care Excellence (NICE) 2010, Scottish Medicines Consortium (SMC) 2006 y 2010, y Canadian Agency for Drugs and Technologies in Health (CADTH) 2013. En la GPC de PES, los elaboradores de la guía recomiendan el uso de somatropina en el tratamiento de pacientes pediátricos con DHC, pero no hacen mención a ningún aspecto relacionado a la administración del medicamento, ni a los factores involucrados en la adherencia al mismo. Con lo que se tiene que una GPC de buena calidad metodológica no plantea ninguna pregunta ni recomendación con respecto al uso de dispositivos para administración. De las ETS identificadas, dos (SMC 2010 y NICE 2010) mencionan aspectos relacionados a la administración de somatropina. En ambos contextos, (Reino Unido y Escocia) los respectivos sistemas de salud cuentan con diversas alternativas de presentaciones de somatropina que cuentan con dispositivo para aplicación, sobre los cuales se ha determinado que no hay diferencias en eficacia. Por lo que, por un lado, NICE recomienda que, para la elección de una presentación entre las disponibles, se considere la adherencia al tratamiento asociada a la administración del mismo, aunque la recomendación se basa únicamente en opinión de expertos. Por otro lado, SMC menciona que la elección del producto estaría sujeta a la preferencia del paciente en cuanto a la facilidad de uso del dispositivo. Sin embargo, si bien las ETS emiten recomendaciones en torno a los dispositivos de aplicación de somatropina, es posible que estas recomendaciones se refieran a elecciones entre los dispositivos disponibles y no entre el uso o no de un dispositivo, como lo requiere la pregunta PICO. Por lo que no queda claro si las recomendaciones responden a la pregunta PICO. Las dos ETS restantes consideradas en los resultados (SMC 2006 y CADTH 2010) no brindan información sobre el uso de dispositivos o la adherencia, sino que únicamente dan cuenta de las alternativas que están siendo evaluadas en los respectivos contextos, de las alternativas disponibles en dichos sistemas de salud y las opciones que se sopesan en las evaluaciones más recientes. Al considerar la evidencia disponible a la fecha, proveniente de una GPC y cuatro ETS, y la ausencia de estudios que comparen la eficacia y seguridad de somatropina con y sin dispositivo electrónico para su aplicación en el tratamiento de pacientes pediátricos con DHC, no es posible determinar el beneficio de la aplicación de somatropina con dispositivo electrónico por sobre la aplicación con jeringa común, ni en términos de eficacia ni de adherencia al tratamiento. El informe solicitado a la Dirección de Guías de práctica clínica, Farmacovilgilancia, y Tenocviglancia (DGPCFyT) del IETSI, menciona que durante el periodo de 2017 a 2019 no se ha recibido ninguna notificación de sospecha de reaccion adversa al medicamento ni de falta de efectividad. Así, no se cuenta con un registro que sustente las preocupaciones mencionadas por algunos de los especialistas. Por lo expuesto, el IETSI no aprueba el uso de somatropina con dispositivo electrónico en el tratamiento de pacientes pediátricos con falla en el crecimiento por DHC.

Personalized approach to growth hormone replacement in adults

ABSTRACT Growth hormone (GH) deficiency (GHD) in adults is well-characterized and includes abnormal body composition, reduced bone mass, an adverse cardiovascular risk profile, and impaired quality of life. In the early 1990s, it was also shown that patients with hypopituitarism without GH replacement therapy (GHRT) had excess mortality. Today, GHRT has been shown to decrease or reverse the negative effects of GHD. In addition, recent papers have shown that mortality and morbidity are approaching normal in hypopituitary patients with GHD who receive modern endocrine therapy including GHRT. Since the first dose-finding studies, it has been clear that efficacy and side effects differ substantially between patients. Many factors have been suggested as affecting responsiveness, such as sex, age, age at GHD onset, adherence, and GH receptor polymorphisms, with sex and sex steroid replacement having the greatest impact. Therefore, the individual tailoring of GH dose is of great importance to achieve sufficient efficacy without side effects. One group that stands out is women receiving oral estrogen replacement, who needs the highest dose. Serum insulin-like growth factor-1 (IGF-1) is still the most used biochemical biomarker for GH dose titration, although the best serum IGF-1 target is still debated. Patients with GHD due to acromegaly, Cushing's disease, or craniopharyngioma experience similar effects from GHRT as others. Arch Endocrinol Metab. 2019;63(6):592-600

The position of combined medical treatment in acromegaly

ABSTRACT Advances in combination medical treatment have offer new perspectives for acromegaly patients with persistent disease activity despite receiving the available medical monotherapies. The outcomes of combination medical treatment may reflect both additive and synergistic effects. This review focuses on combination medical treatment and its current position in acromegaly, based on clinical studies evaluating the efficacy and safety of combined medical treatment(s) and our own experiences with combination therapy. Arch Endocrinol Metab. 2019;63(6):646-52

Perspectives on long-acting growth hormone therapy in children and adults

ABSTRACT Growth hormone therapy with daily injections of recombinant human growth hormone has been available since 1985, and is shown to be safe and effective treatment for short stature in children and for adult growth hormone deficiency. In an effort to produce a product that would improve patient adherence, there has been a strong effort from industry to create a long acting form of growth hormone to ease the burden of use. Technologies used to increase half-life include depot formulations, PEGylated formulations, pro-drug formulations, non-covalent albumin binding growth hormone and growth hormone fusion proteins. At present, two long acting formulations are on the market in China and South Korea, and several more promising agents are under clinical investigation at various stages of development throughout the world. Arch Endocrinol Metab. 2019;63(6):601-7

The promise of growth hormone in sport: doped or duped

ABSTRACT Skeletal muscle is a target tissue of GH. Based on its anabolic properties, it is widely accepted that GH enhances muscle performance in sports. Athletic performance depends on muscle strength and the energy required to power muscle function. The energy required to power muscle function is derived from a continuum of anaerobic and aerobic sources. Molecular and functional studies provide evidence that in muscle GH stimulates the anaerobic and suppresses the aerobic energy system, in turn affecting power-based functional measures in a time-dependent manner. In recreational athletes, GH improves anaerobic capacity but has not been proven to significantly enhance muscle strength, power, or maximum rate of oxygen consumption. GH appears likely to selectively benefit sprint events and not physical performance that depends on strength and endurance. Arch Endocrinol Metab. 2019;63(6):576-81

Growth hormone effects on childrens height with achondroplasia and hypochondroplasia: a systematic review and metanalysis

Introduction: Achondroplasia (Ach) is the most frequent cause of dwarfism. The first therapeutic strategy offered to patients with Ach was. However, GH has played un important role in Ach and Hypochondroplasia (Hch), despite short-term and long-term effects. Purpose: The aim of this systematic review and meta-analysis was to assess the efficacy of GH in the height of patients with Ach and Hch in the short and long term. Methods: 12 studies were included selected from the Pubmed database (3 Randomized Clinical trials (RCTs) and 9 prospective studies) from 1993 to 2014. Comparing high and low doses of GH. The systematic review included 9 prospective studies and the high-dose GH arm of the 3 RCTs. Inclusion criteria was focused on paediatric patients with Ach and Hch treated with GH. Demographic variables were collected including age, gender, dose, height and follow-up. The height variables included height increase and height velocity. Finally, 363 patients with Ach and 41 patients with Hcb were included. A was performed with a follow-up from one to 3 years. Results: In patients with Ach the average height velocity at one, two and three years were 2.65, 1.07 and -0.87 cm/years respectively (p<0.05). The RCTs showed a significant increase in height velocity in patients treated with high dose of GH (MD= 1.38, 95% CI: 0.68-2.07, p=0.0001, I2=0%) . Height at one year increased 0.61 cm. The RCTs did not show significant differences (MD 0.11, 95% CI: 0.17-0.39, p=0.44, I2 = 0%). Finally, patients with Hch increased height velocity 4 cm/year at the first year (p<0.05). Conclusion: GH treatment is beneficial in the shor-term height of children with Ach and Hch. GH effect on different ages and subgroups is unknown, as well as its possible long--term consequences

Brazilian multicenter study on pegvisomant treatment in acromegaly.

OBJECTIVE: Investigate the therapeutic response of acromegaly patients to pegvisomant (PEGV) in a real-life, Brazilian multicenter study. SUBJECTS AND METHODS: Characteristics of acromegaly patients treated with PEGV were reviewed at diagnosis, just before and during treatment. All patients with at least two IGF-I measurements on PEGV were included. Efficacy was defined as any normal IGF-I measurement during treatment. Safety data were reviewed. Predictors of response were determined by comparing controlled versus uncontrolled patients. RESULTS: 109 patients [61 women; median age at diagnosis 34 years; 95.3% macroadenomas] from 10 Brazilian centers were studied. Previous treatment included surgery (89%), radiotherapy (34%), somatostatin receptor ligands (99%), and cabergoline (67%). Before PEGV, median levels of GH, IGF-I and IGF-I % of upper limit of normal were 4.3 µg/L, 613 ng/mL, and 209%, respectively. Pre-diabetes/diabetes was present in 48.6% and tumor remnant in 71% of patients. Initial dose was 10 mg/day in all except 4 cases, maximum dose was 30 mg/day, and median exposure time was 30.5 months. PEGV was used as monotherapy in 11% of cases. Normal IGF-I levels was obtained in 74.1% of patients. Glycemic control improved in 56.6% of patients with pre-diabetes/diabetes. Exposure time, pre-treatment GH and IGF-I levels were predictors of response. Tumor enlargement occurred in 6.5% and elevation of liver enzymes in 9.2%. PEGV was discontinued in 6 patients and 3 deaths unrelated to the drug were reported. CONCLUSIONS: In a real-life scenario, PEGV is a highly effective and safe treatment for acromegaly patients not controlled with other therapies.

Pegvisomant in acromegaly: a multicenter real-life study in Argentina.

OBJECTIVE: To describe the long term safety and efficacy of pegvisomant (PEGV), and the predictors of treatment response in patients with acromegaly in the real life setting. SUBJECTS AND METHODS: We retrospectively reviewed the clinical, hormonal and radiological data of acromegalic patients treated with PEGV in 17 Argentine centers. RESULTS: Seventy-five patients (age range 22-77, 51 females) with acromegaly have been treated with PEGV for up to 118 months (median 27 months). Before PEGV, 97.3% of patients had been treated with medical therapy, surgery and/or radiotherapy, two patients had no previous treatment. At that time, all patients had an IGF-1 above the upper normal limit (ULN) (mean 2.4 x ULN ± 0.98, range 1.25-7). At diagnosis of acromegaly 84% presented macroadenomas, prior to PEGV only 23,5% of patients remained with tumor remnant > 1 cm, the remaining showed normal or less than 1 cm images. Disease control (IGF-1 ≤ 1.2 x ULN) was achieved in 62.9% of patients with a mean dose of 11.8 mg/day. Thirty-four patients (45%) received PEGV monotherapy, while 41 (55%) received combined therapy with either somatostatin analogues and/or cabergoline. Adverse events related to PEGV were: local injection site reaction in 5.3%, elevated liver enzymes in 9.3%, and tumor size growth in 9.8%. Pre-PEGV IGF-I level was the only predictor of treatment response: 2.1 x ULN vs 2.8 x ULN in controlled and uncontrolled patients respectively (p < 0.001). CONCLUSION: this long term experience indicates PEGV treatment was highly effective and safe in our series of Argentine patients with acromegaly refractory to standard therapies. Arch Endocrinol Metab. 2019;63(4):320-7.

Pegvisomant in acromegaly: a multicenter real-life study in Argentina

ABSTRACT Objective To describe the long term safety and efficacy of pegvisomant (PEGV), and the predictors of treatment response in patients with acromegaly in the real life setting. Subjects and methods We retrospectively reviewed the clinical, hormonal and radiological data of acromegalic patients treated with PEGV in 17 Argentine centers. Results Seventy-five patients (age range 22-77, 51 females) with acromegaly have been treated with PEGV for up to 118 months (median 27 months). Before PEGV, 97.3% of patients had been treated with medical therapy, surgery and/or radiotherapy, two patients had no previous treatment. At that time, all patients had an IGF-1 above the upper normal limit (ULN) (mean 2.4 x ULN ± 0.98, range 1.25-7). At diagnosis of acromegaly 84% presented macroadenomas, prior to PEGV only 23,5% of patients remained with tumor remnant > 1 cm, the remaining showed normal or less than 1 cm images. Disease control (IGF-1 ≤ 1.2 x ULN) was achieved in 62.9% of patients with a mean dose of 11.8 mg/day. Thirty-four patients (45%) received PEGV monotherapy, while 41 (55%) received combined therapy with either somatostatin analogues and/or cabergoline. Adverse events related to PEGV were: local injection site reaction in 5.3%, elevated liver enzymes in 9.3%, and tumor size growth in 9.8%. Pre-PEGV IGF-I level was the only predictor of treatment response: 2.1 x ULN vs 2.8 x ULN in controlled and uncontrolled patients respectively (p < 0.001). Conclusion this long term experience indicates PEGV treatment was highly effective and safe in our series of Argentine patients with acromegaly refractory to standard therapies. Arch Endocrinol Metab. 2019;63(4):320-7

Resolution of fatty liver disease after growth hormone replacement in a pediatric survivor of thyroid cancer / Resolución de enfermedad hepática grasa posterior al reemplazo con hormona de crecimiento en un paciente pediátrico sobreviviente a cáncer de tiroides

Abstract Background A rare case of primary papillary thyroid cancer (PTC) and growth hormone (GH) deficiency in a pediatric patient is described. In addition, the patient developed fatty liver disease attributed to GH deficiency. Case report A 10-year-old male with a history of PTC with extension to the cervical nodes detected at 5 years of age was referred to the endocrinology consultation due to a low growth rate. On examination, GH deficiency was detected (height −3.51 standard deviations and low insulin-like growth factor-1 levels). This hormonal deficiency was not associated with thyroid cancer or treatment. Furthermore, elevated transaminases (~300 IU/ml), lipids, and fally liver disease by ultrasound were detected. These data suggested fatty liver disease, which was attributed to GH deficiency. Regardless of the risk of recurrence, somatotropin was administered due to liver dysfunction and very short stature of the patient. A considerable improvement in growth, transaminases, and lipid profile was observed. At present, at 14 years of age, resolution of hepatic steatosis and a considerable increase in his growth rate without recurrence of thyroid cancer 9 years after its diagnosis and 4 years after the initiation of GH treatment are confirmed. Conclusions GH therapy could be a good therapeutic option for pediatric cancer survivors to address impaired growth and fatty liver disease. However, additional medical evidence based on clinical trials is necessary to determine the benefits.

Resumen Introducción Se presenta el caso de un paciente pediátrico con una asociación de cáncer papilar de tiroides (CPT) y deficiencia de hormona de crecimiento (HC) que no ha sido descrita previamente. Además, presenta enfermedad hepática grasa atribuida a la deficiencia hormonal. Caso clínico Paciente de sexo masculino con antecedente de CPT con extensión a los ganglios cervicales diagnosticado a los 5 años de edad. Es referido a los 10 años por talla baja, sin datos de recurrencia del CPT. En el abordaje diagnóstico se detecta deficiencia de HC basándose en una estatura 3.51 desviaciones estándar por debajo de la media y niveles bajos de factor de crecimiento insulínico tipo 1. Adicionalmente, se detectó elevación de transaminasas (~300 IU/ml), dislipidemia y esteatosis hepática en el ultrasonido. Después de los estudios de extensión, la enfermedad hepática grasa se atribuyó a la deficiencia de HC. A pesar del riesgo de recurrencia del cáncer de tiroides, se decidió dar tratamiento con HC debido a la afectación hepática y de crecimiento. El paciente presentó una evolución satisfactoria y actualmente, a la edad de 14 años, la esteatosis hepática está resuelta, presenta una mejoría considerable en su estatura y no ha tenido recurrencia del cáncer de tiroides 9 años después del diagnóstico y 4 años después del inicio del tratamiento con HC. Conclusiones El tratamiento con HC puede ser una adecuada opción terapéutica para sobrevivientes de cáncer en la edad pediátrica con afectación en el crecimiento y esteatosis hepática. Sin embargo, se requieren estudios con mayor evidencia científica y seguimiento a largo plazo para apoyar esta afirmación.

Resolution of fatty liver disease after growth hormone replacement in a pediatric survivor of thyroid cancer.

Background: A rare case of primary papillary thyroid cancer (PTC) and growth hormone (GH) deficiency in a pediatric patient is described. In addition, the patient developed fatty liver disease attributed to GH deficiency. Case report: A 10-year-old male with a history of PTC with extension to the cervical nodes detected at 5 years of age was referred to the endocrinology consultation due to a low growth rate. On examination, GH deficiency was detected (height -3.51 standard deviations and low insulin-like growth factor-1 levels). This hormonal deficiency was not associated with thyroid cancer or treatment. Furthermore, elevated transaminases (~300 IU/ml), lipids, and fally liver disease by ultrasound were detected. These data suggested fatty liver disease, which was attributed to GH deficiency. Regardless of the risk of recurrence, somatotropin was administered due to liver dysfunction and very short stature of the patient. A considerable improvement in growth, transaminases, and lipid profile was observed. At present, at 14 years of age, resolution of hepatic steatosis and a considerable increase in his growth rate without recurrence of thyroid cancer 9 years after its diagnosis and 4 years after the initiation of GH treatment are confirmed. Conclusions: GH therapy could be a good therapeutic option for pediatric cancer survivors to address impaired growth and fatty liver disease. However, additional medical evidence based on clinical trials is necessary to determine the benefits.

Introducción: Se presenta el caso de un paciente pediátrico con una asociación de cáncer papilar de tiroides (CPT) y deficiencia de hormona de crecimiento (HC) que no ha sido descrita previamente. Además, presenta enfermedad hepática grasa atribuida a la deficiencia hormonal. Caso clínico: Paciente de sexo masculino con antecedente de CPT con extensión a los ganglios cervicales diagnosticado a los 5 años de edad. Es referido a los 10 años por talla baja, sin datos de recurrencia del CPT. En el abordaje diagnóstico se detecta deficiencia de HC basándose en una estatura 3.51 desviaciones estándar por debajo de la media y niveles bajos de factor de crecimiento insulínico tipo 1. Adicionalmente, se detectó elevación de transaminasas (~300 IU/ml), dislipidemia y esteatosis hepática en el ultrasonido. Después de los estudios de extensión, la enfermedad hepática grasa se atribuyó a la deficiencia de HC. A pesar del riesgo de recurrencia del cáncer de tiroides, se decidió dar tratamiento con HC debido a la afectación hepática y de crecimiento. El paciente presentó una evolución satisfactoria y actualmente, a la edad de 14 años, la esteatosis hepática está resuelta, presenta una mejoría considerable en su estatura y no ha tenido recurrencia del cáncer de tiroides 9 años después del diagnóstico y 4 años después del inicio del tratamiento con HC. Conclusiones: El tratamiento con HC puede ser una adecuada opción terapéutica para sobrevivientes de cáncer en la edad pediátrica con afectación en el crecimiento y esteatosis hepática. Sin embargo, se requieren estudios con mayor evidencia científica y seguimiento a largo plazo para apoyar esta afirmación.

The promise of growth hormone in sport: doped or duped.

Skeletal muscle is a target tissue of GH. Based on its anabolic properties, it is widely accepted that GH enhances muscle performance in sports. Athletic performance depends on muscle strength and the energy required to power muscle function. The energy required to power muscle function is derived from a continuum of anaerobic and aerobic sources. Molecular and functional studies provide evidence that in muscle GH stimulates the anaerobic and suppresses the aerobic energy system, in turn affecting power-based functional measures in a time-dependent manner. In recreational athletes, GH improves anaerobic capacity but has not been proven to significantly enhance muscle strength, power, or maximum rate of oxygen consumption. GH appears likely to selectively benefit sprint events and not physical performance that depends on strength and endurance. Arch Endocrinol Metab. 2019;63(6):576-81.

Personalized approach to growth hormone replacement in adults.

Growth hormone (GH) deficiency (GHD) in adults is well-characterized and includes abnormal body composition, reduced bone mass, an adverse cardiovascular risk profile, and impaired quality of life. In the early 1990s, it was also shown that patients with hypopituitarism without GH replacement therapy (GHRT) had excess mortality. Today, GHRT has been shown to decrease or reverse the negative effects of GHD. In addition, recent papers have shown that mortality and morbidity are approaching normal in hypopituitary patients with GHD who receive modern endocrine therapy including GHRT. Since the first dose-finding studies, it has been clear that efficacy and side effects differ substantially between patients. Many factors have been suggested as affecting responsiveness, such as sex, age, age at GHD onset, adherence, and GH receptor polymorphisms, with sex and sex steroid replacement having the greatest impact. Therefore, the individual tailoring of GH dose is of great importance to achieve sufficient efficacy without side effects. One group that stands out is women receiving oral estrogen replacement, who needs the highest dose. Serum insulin-like growth factor-1 (IGF-1) is still the most used biochemical biomarker for GH dose titration, although the best serum IGF-1 target is still debated. Patients with GHD due to acromegaly, Cushing's disease, or craniopharyngioma experience similar effects from GHRT as others. Arch Endocrinol Metab. 2019;63(6):592-600.