Melatonina y deficiencia de hormona de crecimiento: contribucin a la evaluacin de los desrdenes neuroendocrinos Translated title: Melatonin and growth hormone deficiency: a contribution to the evaluation of neuroendocrine disorders

Abstract

La melatonina constituye un integrante fundamental del denominado "reloj biolgico" y las alteraciones hormonales sueo-dependientes. Siendo la secrecin fisiolgica de GH, predominantemente nocturna, evaluamos en un grupo de nios y adultos deficitarios de GH (GHD) sin y con tratamiento sustitutivo, la secrecin nocturna de melatonina. Estudiamos 44 pacientes GHD: Grupo a (Ga): Nios sin tratamiento; Grupo b (Gb): Nios con tratamiento con GH (0.16 mg/Kg/semana, dosis estable por mnimo de 6 meses); Grupo c (Gc): Adultos sin tratamiento y Grupo d (Gd): Adultos con tratamiento con GH (0.1- 0.8 mg/da, para mantener IGF1 entre 0 y +2 SDS, dosis estable por mnimo de 6 meses). Todos los pacientes con dficits hormonales asociados estaban adecuadamente sustituidos. La produccin de melatonina fue evaluada a travs de la medicin de su principal metabolito urinario: 6-Sulfatoximelatonina (6-SM), dosado por radioinmunoensayo, en muestras nocturnas (6PM a 8AM). Los niveles de 6-SM nocturna expresados como μg/unidad de tiempo fueron (media SEM) para el grupo peditrico: Ga = 6.50 ( 5.10) y Gb = 8.21 ( 5.31) (Test de Mann-Whitney, p = 0.82). Para los adultos fueron: Gc = 2.99 ( 1.17) y Gd = 6.60 ( 2.00) (Test de Mann-Whitney, p = 0.35). En algunas alteraciones hipotlamo-hipofisarias han sido descriptas modificaciones del patrn secretorio de melatonina, pero no se han caracterizado en forma completa an, las posibles variaciones en pacientes con GHD. Si bien en las condiciones de este estudio, no hallamos diferencias en la excrecin nocturna de 6-SM entre los GHD no tratados y los tratados en ambos grupos, ello no invalida la existencia de posibles diferencias que podran detectarse estudiando la secrecin diurna de melatonina y su diferencia con la secrecin nocturna. Todo ello podr contribuir al conocimiento de los posibles desrdenes cronobiolgicos involucrados en la deficiencia de GH.

Translated abstract

Melatonin, a hormone secreted by the pineal gland, constitutes a landmark in neuroendocrine integration. The relationship between melatonin and different pituitary hormones and sex steroids has been studied; however, the relationship between growth hormone (GH) and melatonin remains unclear. Considering that melatonin is an essential component of the so-called "biological clock", related to circadian rhythm, day-night cycle, and sleep-dependent hormonal alterations, and knowing that physiological GH secretion occurs predominantly at night, we decided to evaluate nocturnal melatonin secretion in a group of GH-deficient children and adults on and off replacement therapy. Patients and Methods: We studied 44 patients with GH deficiency (GHD), duly confirmed by pharmacological tests, divided into 4 groups: Group a (Ga ): untreated GHD children; Group b (Gb): GHD children on GH replacement therapy (0.16 mg/Kg/week, stable dose for at least 6 months); Group c (Gc): untreated GHD adults and Group d (Gd): GHD adults on GH replacement therapy (0.1- 0.8 mg/day, to maintain IGF1 between 0 and +2 SDS, stable dose for at least 6 months). All associated hormonal deficits were adequately replaced. Melatonin production was evaluated by measuring the excretion of its major urinary metabolite: 6-Sulphatoxymelatonin (6-SM). Urinary 6-SM was measured (radioimmunoassay, Stockgrand Ltd, Guildford, UK) in nocturnal samples (6PM to 8AM) in all patients. Results: Nocturnal 6-SM levels expressed as μg/unit of time were (mean SEM) for the pediatric group: Ga = 6.50 ( 5.10) and Gb = 8.21 ( 5.31) (Mann Whitney test, p = 0.82). For adults: Gc = 2.99 ( 1.17) and Gd = 6.60 ( 2.00) (Mann Whitney test, p = 0.35). Discussion and Conclusions: It is difficult to characterize the relationship between melatonin and GH in healthy individuals; however, the administration of intravenous melatonin stimulates GH secretion in normal adults. In some hypothalamic-pituitary alterations, changes in the secretory pattern of melatonin have been reported, but possible variations in GHD patients have not been thoroughly characterized yet. This led us to evaluate 6-SM concentrations in GH deficient children and adults on and off adequate replacement therapy. One of the major aspects of this study has been the evaluation of baseline 6-SM concentrations, with no physiological or pharmacological stimulation. Even if under the conditions of this study we found no differences in nocturnal excretion of 6-SM between untreated and treated GHD individuals in both groups, this does not rule out the potential existence of differences that might be detected by studying diurnal melatonin secretion and its difference with nocturnal secretion. Such studies may contribute to an understanding of potential chronobiological disorders involved in GH deficiency.