Enteroendocrine Connections in Congenital Isolated GH Deficiency Due to a GHRH Receptor Gene Mutation.

CONTEXT: GH and IGF-1 are crucial for attainment of normal body size and regulation of food intake, nutrient storage, and insulin sensitivity. Enteroendocrine connections exist between the GH-IGF-1 axis and insulin, ghrelin, and glucagon-like peptide 1 (GLP-1). The status of these connections in GH deficiency (GHD) is unknown. OBJECTIVE: To study the enteroendocrine connections before and after a standard meal test in a homogeneous population of adults with congenital untreated isolated GHD (IGHD) due to a mutation in the GHRH receptor gene. DESIGN: In a cross-sectional study of 20 individuals with IGHD and 20 control subjects, we measured glucose, insulin, ghrelin, and GLP-1 before and 30, 60, 120, and 180 minutes after a standardized test meal. Homeostasis model assessment index of insulin resistance (HOMA-IR) and homeostasis model assessment (HOMA)-ß were calculated. Participants scored feelings of hunger, fullness, and prospective food consumption on a visual analog scale. MAIN OUTCOME MEASURES: Area under the curve (AUC) values of glucose, insulin, ghrelin, GLP-1, hunger, fullness, and prospective food consumption. RESULTS: Fasting HOMA-IR and HOMA-ß were lower in individuals with IGHD than in control subjects (P = 0.002 and P = 0.023, respectively). AUC was higher for hunger (P < 0.0001), glucose (P = 0.0157), ghrelin (P < 0.0001), and GLP-1 (P < 0.0001) and smaller for fullness (P < 0.0001) in individuals with IGHD compared with control subjects. There was no difference in AUC for prospective food consumption or insulin. CONCLUSIONS: Untreated IGHD is associated with increased GLP-1 secretion and reduced postprandial ghrelin and hunger attenuation in response to a mixed meal. These enteroendocrine connections can result in a favorable outcome in terms of environmental adaptation and guaranteeing appropriate food intake and can confer metabolic benefits.

Prolactin and sex steroids levels in congenital lifetime isolated GH deficiency.

Growth hormone (GH) and prolactin share similarities in structure and function. We have previously shown that women with congenital isolated GH deficiency (IGHD) caused by a homozygous mutation in the GHRH receptor gene (GHRHR) (MUT/MUT) have a short reproductive life, with anticipated climacteric. At climacteric, they have lower prolactin levels than normal controls (N/N). Because they are able to breast feed, we hypothesized that this prolactin reduction is limited to climacteric, as result of lower estradiol exposure of the lactotrophs. The purposes of this work were to assess prolactin levels in broader age adults homozygous and heterozygous (MUT/N) for the mutation and in normal controls (N/N), and to correlate them to sex steroids levels. We enrolled 24 GH-naïve MUT/MUT (12 female), 25 MUT/N (14 female), and 25 N/N (11 female) subjects, aged 25-65 years. Anthropometric data and serum prolactin, estradiol, total testosterone, and sex hormone binding globulin (SHBG) were measured. Free testosterone was calculated. Prolactin levels were similar in the three groups. In males, testosterone and SHBG levels were higher in MUT/MUT in comparison to N/N. There was no difference in free testosterone among groups. In all 74 individuals, prolactin correlated inversely with age (p < 0.0001) and directly with serum estradiol (p = 0.018). Prolactin levels in subjects with IGHD due to a homozygous GHRHR mutation are similar to heterozygous and normal homozygous, but total testosterone and SHBG are higher in male MUT/MUT, with no difference in free testosterone. The reduced prolactin level is limited to climacteric period, possibly due to reduced estrogen exposure.

Diagnóstico da deficiência de hormônio de crescimento, a rigor de IGF-1 / Diagnosis of growth hormone deficiency, in severity of IGF-1

O diagnóstico da deficiência de IGF-1 por anormalidade do eixo GH-IGF deve utilizar os parâmetros diagnósticos mais adequados para cada faixa etária e estágio puberal. Propomos o diagnóstico da deficiência de GH (DGH) baseado em uma hierarquia de dados clínicos e laboratoriais. A avaliaçäo clínica e os exames laboratoriais gerais, incluindo funçäo tireoideana, permitem excluir etiologias de deficiência de IGF que näo as intrínsecas ao eixo GH-IGF. Nestas, a dosagem do IGF-1 sérico deve ser o primeiro hormônio a ser dosado nos grupos pré-púberes, púberes e idosos. No grupo de adultos jovens, a dosagem do ALS livre é a mais adequada. As concentraçöes de IGF-1 podem caracterizar 4 situaçöes: muito reduzido, reduzido, normal e elevado. IGF-1 menor que 35pg/L ou -2 DP da média para a idade cronológica (EDP-IC) permite o diagnóstico de deficiência de IGF-1. Nesta situaçäo, a realizaçäo de apenas um teste de secreçäo de GH é necessária para diferenciar deficiência e resistência ao GH. O teste de geraçäo de IGF-1 ajuda a confirmar o diagnóstico de resistência ao GH. IGF-1 menor que 70Ng/L em pré-púberes ou adultos e menor que 170pg/L em indivíduos púberes, ou entre -2 e -1 EDP-IC indicam provável deficiência de IGF-1. A realizaçäo de 2 testes de secreçäo de GH é recomendada; resposta sub-normal em ambos indica DGH. Exame de imagem da regiäo hipotáiamo-hipofisária deve ser realizado nos casos de DGH. Resposta normal ao teste de secreçäo do GH frente à forte suspeita clínica e laboratorial de deficiência de IGF-1 indica a realizaçäo de perfil noturno de GH para afastar o diagnóstico de disfunçäo neurossecretora de GH. IGF-1 maior que -1 DP, mas menor que a média para idade cronológica sugere ausência de deficiência de IGF-1. Concentraçöes altas de IGF-1 impöem a dosagem das IGFBPs e consideraçäo da resistência ao IGF-1. Apesar das dificuldades, todo o esforço deve ser feito no sentido de diagnosticar adequadamente as alteraçöes do eixo GH-IGF para instituir a terapia apropriada.