Consequences of lifetime isolated Growth Hormone deficiency

描述（由申请人提供）：成人生长激素缺乏症（GHD）与身体组成、心血管功能、与心血管风险相关的代谢参数、骨密度和代谢的变化有关。这些观察结果已被用于支持GHD成人的生长激素治疗。然而，迄今为止发表的研究大多是在经常患有慢性疾病的患者中进行的，缺乏其他垂体激素，其替代疗法可能不是最佳的，和/或接受过放射治疗（所有因素都可能影响发病率）。关于GHD后果的可靠数据只能通过研究其他方面健康的患者来获得。由于GHRH受体（GHRHR）基因纯合突变，在巴西（Itabaianinha县）有大量GHRH幼稚成人GHD患者。我们建议对该突变纯合的个体进行研究，并与来自同一群体的正常个体进行比较。我们的主要目标是确定终身生长激素对身体组成、心血管功能和危险因素、骨密度和代谢以及甲状腺状态的影响，并测试通过6个月的生长激素替代治疗，哪些参数得到逆转。第二个目标是检验突变的杂合性导致在纯合正常和GHD个体之间的中间表型的假设。

DESCRIPTION (provided by applicant): GH deficiency (GHD) in adults has been associated with changes in body composition, cardiovascular function, metabolic parameters associated with cardiovascular risk, and bone density and metabolism. These observations have been used to advocate GH therapy in GHD adults. However, the studies published to date were mostly done in patients who are often chronically sick, lack other pituitary hormones whose replacement therapies may not be optimal, and/or have had radiation therapy (all factors able to influence morbidity). Reliable data on the consequences of GHD can only be obtained by studying patients that are otherwise healthy. A large population of GH-naive adults with GHD due to a homozygous mutation of the GHRH receptor (GHRHR) gene resides in Brazil (Itabaianinha county). We propose to study the subjects homozygous for this mutation and compare them with normal subjects from the same community. Our primary goal is to determine the consequences of life-long GHD on body composition, cardiovascular function and risk factors, bone density and metabolism, and thyroid status, and to test which of these parameters are reversed by 6 months of hGH replacement therapy. The secondary goal is to test the hypothesis that heterozygosity for the mutation causes a phenotype that is intermediate between homozygous normal and GHD individuals. SPECIFIC AIM 1: to study body composition, cardiovascular status, cardiovascular risk profile, metabolic parameters, thyroid status, and bone mineral density in twenty GH-naive GHD subjects and compare them with twenty age- and sex-matched controls from the same community. SPECIFIC AIM 2: to examine the response of GHD individuals to 6 months therapy with GH. SPECIFIC AIM 3: to genotype a large number of apparently normal members of the ltabaianinha community to separate subjects homozygous for the wild-type allele from subjects heterozygous for the GHRHR mutation, and to compare the phenotype of one hundred heterozygotes with the one observed in one hundred homozygous normal individuals.