Consequences of lifetime isolated GH deficiency

描述(申请人提供)：成人生长激素缺乏(GHD)与身体成分、心血管功能、与心血管风险相关的代谢参数以及骨密度和新陈代谢的变化有关。这些观察结果已被用于倡导生长激素在成人中的治疗。然而，到目前为止发表的研究大多是在那些经常患有慢性病、缺乏其他替代疗法可能并不理想的垂体激素、和/或接受过放射治疗的患者身上进行的(所有因素都能影响发病率)。只有通过研究其他方面健康的患者，才能获得关于GHD后果的可靠数据。巴西(Itabaianinha县)有大量因GHRH受体(GHRHR)基因纯合突变而患上GHD的GH幼稚成人。我们建议研究这种突变的纯合子受试者，并将他们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对身体成分、心血管功能和危险因素、骨密度和代谢以及甲状腺状况的影响，并测试这些参数中的哪些参数在hGH替代治疗6个月后被逆转。第二个目标是验证这样的假设，即突变的杂合性导致了介于纯合正常个体和GHD个体之间的表型。 具体目的1：研究20名GH-naive GHD受试者的身体成分、心血管状况、心血管风险状况、代谢参数、甲状腺状况和骨密度，并与来自同一社区的20名年龄和性别匹配的对照组进行比较。 特定目的2：观察生长激素缺乏症患者对6个月生长激素治疗的反应。 特异性目的3：对大量看似正常的Ltabaianinha群体成员进行基因分型，以区分野生型等位基因纯合者和GHRHR突变杂合者，并比较100例杂合子和100例正常个体的表型。

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.