ABSTRACT
La talla baja idiopática (TBI) incluye a un grupo heterogéneo de pacientes con fallas en su crecimiento. Una causa probable de TBI puede ser la insensibilidad a la GH (IGH). La proteína de unión de GH de alta afinidad (GHBP) se genera por el clivaje proteolítico de la porción extracelular del receptor de GH (GHR) y su determinación se propone como un marcador periférico del nivel de GHR en los tejidos. El objetivo de este trabajo fue evaluar los niveles de GHBP circulantes y su asociación con factores de crecimiento y el polimorfismo del exón 3 del gen GHR en niños con TBI. Los niños con TBI presentaron talla, IMC, IGF-I, IGFBP-3, ALS y niveles de GHBP significativamente más bajos que un grupo de niños de edad comparable (p<0.001). El genotipo del exón 3 del GHR no fue un factor determinante de las diferencias observadas. La máxima respuesta de GH de los tests de estímulo de secreción correlacionó negativa y significativamente con los niveles de GHBP (r= -0.28, p= 0.012). Los perfiles de distribución de la concentración de GHBP, IGF-I, ALS y BP3 expresadas en score de desvío estándar (SDE) en la TBI, mostraron un sesgo hacia niveles bajos. En conclusión, los marcadores de acción de GH y los niveles de GHBP fueron bajos en la TBI, independientemente del genotipo del exón 3 del gen GHR. En un subgrupo de niños con TBI, niveles disminuidos de GHBP y de componentes del sistema de los IGFs, colaborarían en la evaluación de la IGH sugiriendo la búsqueda de defectos en el GHR.
Idiopathic Short Stature (ISS) includes a heterogeneous group of children with growth failure. One possible explanation for the growth failure is a reduced responsiveness to growth hormone (GH). Human circulating GH is partially bound to a highaffinity binding protein (GHBP) which is derived from proteolytical cleavage of the extracellular domain of the GH receptor. Many reports have demonstrated a close relationship between GHBP and liver GH receptor status in physiological conditions and diseases. Moreover, serum GHBP measurement has been proposed as an useful peripheral index of GH receptor abundance. Our objective was the evaluation of serum GHBP levels and its probable association with serum growth factors (IGF-I, IGFBP-3 and ALS) and the exon 3 polymorphism of the extracellular domain of the GHR gene in ISS children. Children with ISS presented significantly lower height SDS, BMI SDS, serum components of the IGFs system and GHBP concentration as compared to an age-matched control group of normal children (p<0.001). Interestingly, exon 3 genotype did not influence the differences observed in these parameters. The maximal GH response obtained after two GH provocative tests inversely and significantly correlated to GHBP serum levels (r= -0.28, p= 0.012). A frequency study showed a deviation to low SDS values of serum GHBP, IGF-I, IGFBP-3 and ALS. Conclusion: 1- in children with ISS the exon 3 genotype of the GHR gene is not a factor that could explain the lower levels observed in circulating GHBP concentration and components of the IGFs system; 2- low serum GHBP together with low IGF-I, IGFBP-3 or ALS levels would help pointing to GH insensitivity due to GH receptor gene abnormalities in ISS.
Subject(s)
Humans , Male , Female , Child, Preschool , Child , Adolescent , Human Growth Hormone/biosynthesis , Failure to Thrive/etiology , Biomarkers/metabolism , Human Growth Hormone/genetics , Intercellular Signaling Peptides and Proteins/geneticsABSTRACT
BACKGROUND: Growth hormone-producing pituitary tumours present with a wide variety of manifestations. The optimum diagnostic work up, management and follow up of such patients is complex and involves a multidisciplinary approach. There is paucity of data from India with regard to the clinical presentation and results of surgery for growth hormone-producing tumours. METHODS: We studied the first 50 patients presenting during 1989-94 with growth hormone-producing pituitary tumours to our centre. The work up included detailed endocrine and radiological assessment. The surgical outcome was analysed for 35 patients who were operated (trans-sphenoidal 29, transcranial 6) at our centre. RESULTS: All the patients had macroadenomas [mean (SD) diameter 3.12 (0.87) cm]. Seventy-five per cent of the patients had supra- and/or parasellar extension and 57% had visual field defects. Tumour size correlated with the preoperative basal (r = 0.57) and glucose-suppressed (r = 0.54) growth hormone levels. Thirty-three of the 35 patients operated at our centre (trans-sphenoidal 28, transcranial 5) were available for follow up (median duration 34 months). After trans-sphenoidal surgery alone, 12 of the 28 (43%) patients had normalization of growth hormone levels (post-glucose growth hormone < 5 ng/ml), and 9 of 11 (82%) showed improvement in visual fields. CONCLUSION: In India, growth hormone-producing pituitary tumours are usually large in size. The growth hormone levels correlate with the size of the tumour. These tumours can be effectively treated by trans-sphenoidal or transcranial surgery.