Consequences of lifetime isolated GH deficiency

描述（由申请方提供）：成人GH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以及骨密度和代谢的变化相关。这些观察结果已被用于倡导GH治疗GHD成人。然而，迄今为止发表的研究大多是在经常患有慢性病、缺乏其他垂体激素的患者中进行的，这些患者的替代疗法可能不是最佳的，和/或接受过放射治疗（所有因素都能影响发病率）。关于GHD后果的可靠数据只能通过研究其他健康的患者来获得。巴西（Itabaianinha县）有大量GHRH受体（GHRHR）基因纯合突变导致的GHD成人GH初治人群。我们建议研究该突变的纯合子受试者，并将其与来自同一社区的正常受试者进行比较。我们的主要目标是确定终身GHD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，并测试这些参数中哪些可以通过6个月的hGH替代治疗逆转。第二个目标是检验突变的杂合性导致介于纯合正常和GHD个体之间的表型的假设。 具体目标1：研究20名GH初治GHD受试者的身体组成、心血管状况、心血管风险状况、代谢参数、甲状腺状况和骨矿物质密度，并将其与来自同一社区的20名年龄和性别匹配的对照组进行比较。 具体目的2：检查GHD个体对6个月GH治疗的反应。 具体目标3：对Itabaianinha群体的大量明显正常的成员进行基因分型，以将野生型等位基因纯合的受试者与GHRHR突变杂合的受试者分开，并将100个杂合子的表型与在100个纯合正常个体中观察到的表型进行比较。

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.