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.

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

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.

Eje somatotrópico y marcadores moleculares del metabolismo mineral en niños en diálisis / Somatotropic axis and molecular markers of mineral metabolism in children undergoing chronic peritoneal dialysis

El retraso del crecimiento de los niños con enfermedad renal crónica es de origen multifactorial, incluyendo la resistencia a hormona de crecimiento (GH) y alteraciones en el metabolismo mineral óseo. Objetivos: 1) Caracterizar marcadores del metabolismo mineral: FGF23-Klotho y del eje somatotrópico: IGF1, IGFBP3 y GHBP, en niños en diálisis peritoneal (DP); 2) Evaluar la evolución de la talla en aquellos pacientes tratados con rhGH. Pacientes y Método: Niños prepuberales en DP seguidos durante 12 meses. Criterios exclusión fueron Tanner > 1, síndrome nefrótico activo, tratamiento esteroidal, malabsorción gastrointestinal, enfermedades endocrinas, síndromes genéticos, uso de rhGH al ingreso del estudio. Se evaluaron variables demográficas, antropométricas: Z talla/edad, (ZT/E), velocidad de crecimiento (VC), bioquímicas (calcio, fósforo, PTH), marcadores del metabolismo mineral (25OHvitD, 1,25OHvitD, FGF23, Klotho), y de crecimiento (IGF-1, IGFBP-3, GHBP). Resultados: Quince pacientes, 7 varones, edad 6,9 ± 3,0 años, tiempo en DP 14,33 ± 12,26 meses. Puntaje ZT/E al mes 1= -1,69 ± 1,03. FGF23: 131,7 ± 279,4 y Klotho: 125,9 ± 24,2 pg/ml. Durante los 12 meses de seguimiento no hubo diferencia significativa en el promedio de las variables. El uso de rhGH en 8 pacientes no mostró mejoría significativa del ZT/E ni la VC. El análisis bivariado mostró correlación positiva entre niveles de Klotho y delta ZT/E, y entre GHBP y VC (p < 0,05). Conclusiones: Los valores de FGF23 se encuentran elevados y los de Klotho disminuidos en niños con enfermedad renal crónica en DP en comparación con niños sanos. Las variables de eje somatotrópico, se encuentran normales o elevadas. rhGH tiende a mejorar la talla y GHBP se correlaciona positivamente con VC en estos niños.

Growth failure is one of the most relevant complications in children with chronic kidney disease (CKD). Among others, growth hormone (GH) resistance and bone mineral disorders have been identified as the most important causes of growth retardation. Objectives: 1. To characterize bone mineral metabolism and growth hormone bio-markers in CKD children treated with chronic peritoneal dialysis (PD). 2. To evaluate height change with rhGH treatment. Patients and Method: A longitudinal 12-month follow-up in prepuberal PD children. Exclusion criteria: Tanner stage >1, nephrotic syndrome, genetic disorders, steroids, intestinal absorption disorders, endocrine disturbances, treatment with GH to the entry of the study. Demographic and anthropometric data were registered. FGF23, Klotho, VitD, IGF-1, IGFBP3, and GHBP were measured to evaluate mineral and growth metabolism. Results: 15 patients, 7 male, age 6.9 ± 3.0 y were included. Time on PD was 14.33 ± 12.26 months. Height/age Z score at month 1 was -1.69 ± 1.03. FGF23 and Klotho: 131.7 ± 279.4 y 125.9 ± 24.2 pg/ml, respectively. 8 patients were treated with GH during 6-12 months, showing a non-significant increase in height/age Z-score during the treatment period. Bivariate analysis showed a positive correlation between Klotho and delta ZT/E, and between GHBP vs growth velocity index (p < .05). Conclusions: FGF23 values were high and Klotho values were reduced in children with CKD in PD, comparing to healthy children. Somatotropic axis variables were normal or elevated. rhGH tends to improve height and there is a positive correlation of GHBP and growth velocity in these children.

Children with isolated growth hormone deficiency: Empty sella versus normal sella.

BACKGROUND: Empty sella (ES) may be associated with variable clinical conditions ranging from the occasional discovery of a clinically asymptomatic pouch within the sella turcica to severe intracranial hypertension and rhinorrhea. The need for replacement hormone therapy in ES, as in other syndromes that may cause hypopituitarism, must be assessed for every single hormone, including growth hormone (GH). AIM: To determine whether or not the presence of ES could allow some changes in the GH responses of the isolated growth hormone deficiency (GHD) patients. MATERIALS AND METHODS: We included a cohort of 59 short stature children and adolescents with isolated GHD. According to computed tomography finding, they were classified into 2 groups: Group 1 included 40 children with normal sella and 19 children with ES in Group 2. All patients received recombinant human growth hormone (rhGH) with a standard dose of 20 IU/m2/week. RESULTS: The baseline results were not significantly different for all variables except weight standard deviation was smaller with statistical significant difference (P = 0.02). We identified no significant differences when comparing both groups, except for height standard deviation (HTSD) after the first year of therapy which revealed significant difference in favor of group 1. When comparing pre- and the two post-treatments HTSD results of the studied cases, all showed significant changes after GH therapy. The results of related variables pre-and post-treatment in both the groups showed significant improvement in all variables of the two groups of the study. CONCLUSION: Our study showed a similar stature outcome in the two treatment groups.

Somatic growth effects of intramuscular injection of growth hormone in androgen-treated juvenile Nile tilapia, Oreochromis niloticus (Perciformes: Cichlidae)

Little is known about the effects of the interaction of growth hormone (GH) with 17 a-methyltestosterone (17-MT) during fish growth. We evaluated this in the present study to assess the effect on fish growth. Fish in two batches of juvenile tilapia (Oreochromis niloticus) (approximately 5.0cm in length) were randomly assigned in triplicate to three treatments and a control group, distributed among 12 fiberglass tanks of 1 000L capacity (50 fish per tank) in an experiment covering a period of six weeks. The experimental groups were: a) fish treated with 17-MT and GH in mineral oil (RGH); b) fish treated with 17-MT and mineral oil without the addition of GH (R); c) fish treated with GH in mineral oil but not 17-MT (NGH); and d) fish of the control group, which were treated with mineral oil but not 17-MT or GH (N). The GH was injected into the fish at a rate of 0.625mg/g body weight. Morphometric data were recorded at the beginning of the experiment (T) and at 15, 30 and 45 days (T, T and T), and various indicators of growth were assessed: condition factor (K); survival percentage (S), feed conversion rate (FCR), percentage weight gain (WG) and (v) daily weight gain. The optimum dietary level was calculated assuming 5% food conversion to total weight in each group. During the experiment, the fish were provided with a commercial food containing 45% protein. The data showed that GH injection resulted in a greater weight gain in fish treated with 17-MT (the RGH treatment group), being particularly significant increase in weight during T and T (p<0.05). High values of K were found in the R and RGH treatments during the initial days of the experiment, which may have been a consequence of the better nutritional status affecting both weight gain and growth in body length, as a result of the additive effects of 17-MT and GH. The fish in groups not treated with 17-MT and treated with 17-MT and added GH showed greater increases in WG per day, higher K values and lower FCRs than fish in the other groups, which suggests that greater feed efficiency occurred in the hormone-treated fish. Fish in the RGH treatment showed the most growth, suggesting a possible interaction between 17-MT and injected GH.

Actualmente, durante el crecimiento de los peces existe poco conocimiento sobre los efectos de la interacción de la hormona del crecimiento (HC) con 17 α-metiltestosterona (17-MT). En el presente estudio los peces en dos lotes de tilapia (Oreochromis niloticus) (5.0cm de longitud), fueron asignados al azar por triplicado a tres tratamientos y un grupo control, distribuidos en 12 tanques de fibra de vidrio de 1 000 litros (50 peces por tanque), en un período de seis semanas. Los tratamientos fueron: a) peces tratados con 17-MT+HC en aceite mineral (RGH), b) peces tratados con 17-MT+aceite mineral sin la adición de HC (R), c) los peces que no fueron tratados con 17-MT-tratado+HC en aceite mineral (NGH), y d) los peces que no fueron tratados con 17-MT+aceite mineral (N). La hormona de crecimiento humano recombinante (Humatrope, Eli Lilly & Co., Windlesham, Inglaterra), se inyectó en el pez con una dosis de 0.625mg por gramo de peso corporal. Los datos morfométricos se registraron al comienzo del experimento (T) y en los días 15, 30 y 45 (T, T y T), Se registraron diversos indicadores de crecimiento: factor de condición (K), porcentaje de supervivencia (S), la tasa de conversión alimenticia (FCR), porcentaje de ganancia de peso (GP) y el aumento de peso al día. El nivel óptimo dietético fue calculado suponiendo 5% de conversión de alimentos al peso total de cada grupo. Durante el experimento fue usada una dieta comercial con el 45% de proteína. De los resultados presentados, es evidente que la inyección de HC dio lugar a una mayor ganancia de peso en el 17-MT-los peces tratados (el grupo de tratamiento RGH), y la diferencia fue significativa, tanto en T y T (p<0.05) para ambas comparaciones. De manera similar, los altos valores de K se presentaron en los tratamientos R y RGH durante los primeros días de cultivo. Esto puede haber sido asociado con un mejor estado nutricional que afectó tanto el desarrollo de peso y la longitud del cuerpo del pez, como resultado del efecto aditivo de 17-MT y GH. Los tratamientos no andrógenos y los grupos tratados con andrógenos y con HC mostraron un mayor incremento en la ganancia de peso por día, los mayores valores de K y menores tasas de conversión del alimento, lo que sugiere una mayor eficiencia de la alimentación en los peces tratados con hormonas. Peces en el tratamiento RGH mostraron el mayor crecimiento, lo que sugiere una posible interacción entre el 17 de α-metiltestosterona (17-MT) y hormona de crecimiento inyectada.

Growth response of Egyptian children with idiopathic short stature during four years of growth hormone therapy.

BACKGROUND: Multiple factors affect the growth response to recombinant human growth hormone (rhGH) in children with idiopathic short stature (ISS). AIM: To evaluate the growth responses of children with ISS treated with rhGH, aiming to identify the predictors of growth response. MATERIALS AND METHODS: We studied 120 cases, 90 males (75%), with a mean age of 13.8±2.7 years and 30 females (25%), with a mean age of 12.3±2.5 years. All patients received rhGH with a standard dose of 20 IU/m2/week. The calculated dose per week was divided into six days and given subcutaneous at night. RESULTS: A significant positive trend was detected in the delta changes of all anthropometric data. For the first year, the growth response was positively correlated to CA and BA delay and negatively correlated to height, weight and IGF-1 SDSs. For the second year, the growth response was correlated positively to first year growth velocity, BA, triceps skin fold thickness SDS and deviation from target height, and negatively correlated to weight, IGFBP3 SDS and target height SDS. For the third year, the growth response was positively correlated to five variables namely target height, 2nd year growth velocity, IGF-1 SDS, weight SDS and triceps skin fold thickness SDS. For the fourth year, growth response was positively correlated to 2nd and 3rd year growth velocity, BA, deviation from target height and weight/ height SDS. CONCLUSION: Our study showed multiplicity of predictors that is responsible for response in ISS children treated with rhGH, and BA was an important predictor.

Deficiencia de hormona de crecimiento en el adulto ¿debe tratarse? / Growth Hormone Deficiency (GHD) in Adults: To Treat or Not To Treat?

Over the last decade, different guidelines have been published for the diagnosis, treatment and monitoring of adult growth hormone deficiency (AGHD). Themes and recommendations common to the guidelines offer a pragmatic approach to the management of AGHD. Nevertheless, there is a need for more research in some key areas in which recommendations in the guidelines are supported by moderate evidence, at best. Recent meta-analysis and long-term follow-up studies have contributed with valuable information on the efficacy and safety of GH therapy in adults. This review brings a historical perspective of the AGHD, with an emphasis on the following aspects: (I) who are the appropriate candidates for GH therapy in adult life? (II) how to make the diagnosis (III) the impact of GH therapy; (IV) which therapeutic approach should be used? (V) how to follow and monitor the patients; and (VI) special aspects on mortality and longevity related to the GH-IGF-1 axis.

Bone age is the best predictor of growth response to recombinant human growth hormone in Turner’s syndrome.

BACKGROUND AND OBJECTIVES: Recombinant human growth hormone (rhGH) is approved for use in children with Turner’s syndrome (TS) in most industrialized countries and is recommended in the recently issued guidelines. We determined the growth responses of girls who are treated with rhGH for TS, with an aim to identify the predictors of growth response. MATERIALS AND METHODS: Fifty-six prepubertal girls with TS, documented by peripheral blood karyotype, were enrolled. All the patients received biosynthetic growth hormone therapy with a standard dose of 30 IU/m2/week. The calculated dose per week was divided for 6 days and given subcutaneously at night. RESULTS: This study showed that rhGH therapy provides satisfactory auxological results. Bone age delay is to be considered as a predictive factor which may negatively influence the effect of rhGH therapy on final height. The growth velocity in the preceding year is the most important predictor of rhGH therapy response. CONCLUSION: These observations help us to guide rhGH prescription, to reduce the risks and costs.

Additive Effects of Intra-articular Injection of Growth Hormone and Hyaluronic Acid in Rabbit Model of Collagenase-induced Osteoarthritis

In a rabbit model of collagenase-induced osteoarthritis, the additive effects of intra-articular recombinant human growth hormone (GH) administration to hyaluronic acid (HA) were evaluated. After intra-articular collagenase injection, mature New Zealand white rabbits (n=30) were divided into 3 groups. Group 1 (control rabbits) received once weekly intra-articular saline injections for 4 weeks. Group 2 rabbits received 6 mg HA injections, and group 3 rabbits were injected with 6 mg HA and 3 mg recombinant human GH. These injections were initiated 4 weeks after collagenase injections. Lameness was observed for 9 weeks after collagenase injections. Macroscopic and histopathological knee joint findings were also evaluated at the end of 9 weeks after collagenase injections. Although all animals had lameness after collagenase injections, the duration and severity of lameness were significantly shorter and less severe in group 3 than group 1 and 2 (P<0.01). Macroscopic scores showed that femoral condyles of group 3 rabbits received significantly less cartilage damage than those of groups 1 and 2 rabbits (P<0.01). Histopathological score was also the lowest in group 3 (P<0.01). These results suggest that co-injection of intra-articular HA and recombinant human GH is more effective than HA injections alone in an osteoarthritis model.

Adult height in Turner syndrome girls after long-term growth hormone treatment / Talla adulta en pacientes con síndrome de Turner tratadas con hormona de crecimiento a largo plazo

We studied the adult height (AH) outcome, and factors likely to influence it, in Turner Syndrome (TS) girls treated with growth hormone (GH). A total of 25 TS girls treated with GH were compared with 10 TS girls not treated with GH. The percentage of girls who achieved normal third percentile was determined. Projected AH (PAH) was calculated according to height standard deviation score (HSDS) at the beginning of the treatment. Gain in height was determined as: AH - pretreatment PAH. The percentage of girls who achieved target range (midparental height±2 SD) was determined. Multiple linear regression models were fitted on baseline variables- chronological age (CA), midparental height (MPH) and HSDS; and treatment variablesduration of oestrogen-free GH therapy and duration of GH therapy+oestrogens. As for baseline data: median CA was 13.0 years (5.6-15.8). Mean HSDS was 0.25±1.1 SDS. PAH was 139.2±5.6 cm. MPH was 160.0±5.0 cm. As for follow up data: Median CA at onset oestrogens was 15.1 years (13.2-16.6). Median duration of GH therapy was 3.8 years (2.1-10.3). Median oestrogen-free GH period was 2.0 years (0.7-7.8), and median GH+oestrogens period, 1.8 years (1.0-3.2). Adult height: Mean AH was 150.4±7.0 cm in treated patients and 140.8±7.2 cm in the group not treated with GH (p=0.001). Fourteen (56%) girls achieved normal third percentile compared with an initially predicted 1 (4%). Gain in height was 11.2±3.7 cm. Thirteen (59%) girls reached an AH within target range. HSDS at the beginning of the treatment was the variable most strongly related to AH and duration of oestrogen-free GH period was the variable most strongly related to gain in height.

Se estudió la talla adulta (TA) y los factores que pudieran influenciarla en niñas con síndrome de Turner (ST) tratadas con hormona de crecimiento (HC). Se compararon 25 pacientes con ST tratadas con HC y 10 niñas no tratadas. Se determinó: el porcentaje de niñas que alcanzó el tercer percentilo de la curva de normalidad, la talla adulta proyectada (TAP) de acuerdo al score de desvío estándar de talla (SDST) al inicio del tratamiento, la ganancia en talla (TA - TAP pretratamiento) y el porcentaje de niñas que alcanzó el rango genético (talla media parental ± 2 DS). Se ajustaron modelos de regresión múltiple sobre variables basalesedad cronológica (EC), talla media parental y SDST; y variables durante el tratamiento- duración del tratamiento con GH sin estrógenos y con GH+estrógenos. Resultados: datos basales: la EC mediana fue 13.0 años (5.6- 15.8), el SDST 0.25 ± 1.1 SDS, la TAP 139.2 ± 5.6 cm y la talla media parental 160.0 ± 5.0 cm. Datos en el seguimiento: la EC mediana al inicio del estrógeno fue 15.1 años (13.2-16.6), la duración mediana del tratamiento con GH 3.8 años (2.1-10.3), del tratamiento con GH y sin estrógenos 2.0 años (0.7-7.8), y del tratamiento con GH + estrógenos 1.8 años (1.0-3.2). Talla adulta: la TA media fue 150.4 ± 7.0 cm en pacientes tratadas y 140.8 ± 7.2 cm en el grupo no tratado (p = 0.001). 14 niñas (56%) alcanzaron el tercer percentilo comparado con la predicción inicial de una niña (4%). La ganancia en talla fue 11.2 ± 3.7 cm. 13 niñas (59%) alcanzaron una TA dentro del rango genético. La variable que más se relacionó con la TA fue el SDST al inicio del tratamiento y con la ganancia en talla, la duración del tratamiento con GH libre de estrógenos.

Comparative Study of the Effects of Different Growth Hormone Doses on Growth and Spatial Performance of Hypophysectomized Rats

This study was designed to examine the effects of recombinant human growth hormone replacement on somatic growth and cognitive function in hypophysectomized (HYPOX) female Sprague-Dawley rats. Rats (5 per group) were randomized by weight to 3 experimental groups: group 1, administered 200 microgram/kg of GH once daily for 9 days; group 2, administered 200 microgram/kg of GH twice daily; and group 3, administered saline daily. Somatic growth was evaluated by measurement of body weight daily and of the width of the proximal tibial growth plate of the HYPOX rats. Cognitive function was evaluated using the Morris water maze (MWM) test. The results indicated that GH replacement therapy in HYPOX rats promoted an increase in the body weight and the width of the tibial growth plate in a dose-dependent manner. On the third day of the MWM test, the escape latency in the GH-treated groups 1 and 2 was significantly shorter than that in the control rats (P<0.001 and P=0.032, respectively), suggesting that rhGH improved spatial memory acquisition in the MWM test. Therefore it is concluded that rhGH replacement therapy in HYPOX rats stimulates an increase in somatic growth in a dose-dependent manner and also has beneficial effects on cognitive functions.

Anormalidades metabólicas en la deficiencia de la hormona de crecimiento / Metabolic Abnormalities in growth hormone deficiency

Increased cardiovascular morbidity and mortality has been reported in adult subjects with growth hormone deficiency (GHD). Long term follow up of a large cohort of patients with adult onset GHD, suggests that GH therapy may contribute to a reduced risk of nonfatal stroke, particularly in women and in a decline in nonfatal cardiac events in GHD men(1,2). Adult hypopituitary patients with untreated growth hormone deficiency have been shown to have a cluster of cardiovascular risk factors such as increased visceral adiposity, disturbances in lipoprotein metabolism, premature atherosclerosis, impaired fibrinolytic activity, increased peripheral insulin resistance, abnormal cardiac structure, impaired cardiac performance and endothelial dysfunction (3,4). Several of these risk factors have now been confirmed in double blind, randomized, placebo controlled trials (5,6). Metabolic changes in GH deficient children and adolescents have been evaluated only quite recently and superficially. In this article we will discuss these metabolic abnormalities and their underlying mechanism in untreated GHD subjects and we will review the beneficial effect of growth hormone therapy in adults, adolescents and children with GHD.

Se ha reportado un aumento en la morbilidad y mortalidad de pacientes adultos con deficiencia de la hormona de crecimiento (DHC). El seguimiento a largo plazo de una cohorte de pacientes con DHC sugiere que la administracion de hormona de crecimiento puede contribuir a una reducción en el número de los accidentes cerebrovasculares no fatales, particularmente en mujeres y de eventos cardíacos en hombres(1,2). Pacientes adultos con hipopituitarismo y una DHC cursan con un acúmulo de factores de riesgo cardiovascular tales como un aumento en la adiposidad visceral, alteraciones en el metabolismo lipoproteico, ateroesclerosis prematura, actividad fibrinolítica alterada, resistencia a la insulina, masa y función cardíaca alterada y disfunción endotelial (3,4). Varios de estos factores de riesgo han sido comprobados en estudios doble ciego, randomizados con placebo (5,6). Las alteraciones metabólicas en niños y adolescentes deficientes de hormona de crecimiento han sido evaluadas sólo recientemente y de manera aún superficial. En este manuscrito discutiremos estas anormalidades y los mecanismos etilógicos subyacentes en sujetos DHC no tratados y revisaremos el efecto beneficioso de la terapia con hormona de crecimiento en niños, adolescentes y adultos.

Eficácia, segurança e aderência ao tratamento de longo prazo com hormônio de crescimento (GH) em adultos com deficiência de GH / Efficacy, safety and compliance of long-term growth hormone (GH) replacement therapy in adults with GH deficiency

OBJETIVO: Avaliar a eficácia, a segurança e a aderência de quatro anos de tratamento com GH em 18 adultos [12 mulheres, 6 homens, com idade média de 50,5 anos (25-66 anos)] com deficiência grave de GH (DGH). MÉTODOS: Avaliações clínica, laboratorial e de composição corporal (DXA) realizadas antes e anualmente após o início do GH, e ecocardiografia realizada antes e após quatro anos de tratamento. Dose de 0,2 mg GH/dia mantida fixa no primeiro ano, com posteriores ajustes para normalizar IGF-1. RESULTADOS: Redução significativa da gordura corporal total (média 2,8 kg) e da gordura truncal (média 1,9 kg), associadas com aumento da massa magra (média 0,8 kg) e aumento da densidade mineral óssea (DMO) em coluna lombar e fêmur, particularmente nos sítios com T-escore menor que 1,0 na avaliação basal. Houve piora dos níveis de insulina e HOMA no primeiro ano de terapia, mas ao final do quarto ano os valores de glicose, insulina, HOMA e hemoglobina glicosilada não eram diferentes dos basais. Desenvolveram diabetes tipo 2 no seguimento dois pacientes com intolerância à glicose pré-tratamento. O colesterol total e o LDL colesterol reduziram significativamente, e as mudanças foram proporcionais aos valores basais. Os parâmetros ecocardiográficos não se alteraram. Os efeitos colaterais foram leves e bem tolerados. Não foi observada recorrência tumoral. Baixa adesão ao tratamento (estimada por níveis baixos de IGF-1) ocorreu em quatro (22 por cento), dois (11 por cento) e seis (30 por cento) pacientes ao final do segundo, terceiro e quarto ano, respectivamente. CONCLUSÕES: Quatro anos de tratamento com GH em adultos com DGH teve impacto positivo sobre a composição corporal, a DMO e o perfil lipídico, e nenhum efeito sobre sensibilidade insulínica e o coração. A intolerância à glicose deve ser cuidadosamente monitorada no tratamento de longo prazo.

AIM: To study efficacy, safety and compliance of GH therapy for 4 years in 18 GH deficient (GHD) adults [12 women; mean age 50.5 yrs (25-66 yrs)]. METHODS: Clinical, biochemical and body composition (DXA) measurements were performed before and every year after GH therapy. Ecocardiography was performed at baseline and after 4 years. Dose of GH was 0.2 mg/day during the first year with subsequent titration to attain normal IGF-1 levels. RESULTS: There was a significant reduction of total body fat (mean 2.8 kg), truncal fat (mean 1.9 kg) and an increase of lean body mass (mean 0.8 kg) and bone mineral density (BMD) on lumbar spine and femur, particularly in sites with T-score < -1,0 at baseline. Insulin levels and HOMA index worsened in the first year, but at the end no changes were noted on glucose, insulin, HOMA index and glycosylated hemoglobin. Two patients with altered glucose tolerance at baseline developed type 2 diabetes during follow-up. Total and LDL-cholesterol were significantly lower after therapy, with changes directly associated with baseline values. Cardiac parameters did not change. Side effects were mild and disappeared spontaneously. Tumor recurrence was not observed. Low compliance (estimated by low IGF-1 levels) was observed in 4 (22 percent), 2 (11 percent) and 6 (33 percent) patients at the end of second, third and fourth year, respectively. CONCLUSIONS: Four years of GH therapy in GHD adults had a positive impact on body composition, BMD and lipid profile, with no effects on insulin sensitivity and heart. Glucose tolerance should be monitored carefully during long-term GH therapy.

Effects of 4 Weeks Recombinant Human Growth Hormone Administration on Insulin Resistance of Skeletal Muscle in Rats

PURPOSE: Effect of recombinant human growth hormone (rhGH) administration on lipid storage, and its subsequent effect on insulin sensitivity have not yet been adequately examined. Thus, we investigated the effects of rhGH treatment on muscle triglyceride (TG) and ceramide content, and insulin sensitivity after 4 weeks of rhGH administration in rats. MATERIALS AND METHODS: Fourteen rats were randomly assigned to two groups: rhGH injection group (GH, n = 7) and saline injection group (CON, n = 7). GH received rhGH by subcutaneous injections (130microgram/kg(-1)/day(-1), 6 days/week(-1)) for 4 weeks, while CON received saline injections that were equivalent in volume to GH group. Intramuscular TG and ceramide content and hepatic TG content were measured. To determine insulin sesitivity, oral glucose tolerance test (OGTT) and muscle incubation for glucose transport rate were performed in rats, and used as indicators of insulin sensitivity. We also examined plasm lipid profiles. RESULTS: After 4 weeks of rhGH treatment, the GH group had higher muscle and liver TG contents than the CON (p < 0.05). Ceramide content in GH was significantly greater than that in CON (p < 0.05). GH also had higher plasma levels of FFA (p < 0.05), glucose and insulin responses during OGTT (p < 0.05), and lower glucose transport rates in submaximal insulin concentration (p < 0.05) as compared with CON. Results indicate that rhGH treatment is associated with insulin resistance in rats. CONCLUSION: rhGH treatment elevated muscle TG and ceramide content, and hepatic TG content. Thus, elevation of these compounde by rhGH treatment could contribute to the development of insulin resistance in rats.