STEROID HORMONE REGULATION OF TSH SUBUNIT BIOSYNTHESIS

在美国，数百万患者服用左旋甲状腺素， 治疗甲状腺功能减退或抑制甲状腺肿或甲状腺 结节 我们最近的临床研究表明，l-甲状腺素在 足以抑制TSH的剂量可能导致骨质过多 再吸收 在大鼠体内，有两种酶将T4转化为 T3 脑垂体2型酶在转化 T4比T3的1型酶存在于肝脏和肾脏。 以来 组织T3受体占有率与甲状腺激素相关 效应可能是给定剂量的l-甲状腺素将导致 垂体T3受体占有率较高， 当外周组织T3受体被抑制时， 不饱和的 关于这方面的资料很少。 两种甲状腺激素T4和T3对骨骼的相对影响。 在一项研究中，T4和T3在引起骨吸收方面是等效的 器官培养。 T_4和T_3对骨的相对作用可能 对优化甲状腺类型有重要意义， 给予患者激素制剂以替代，或 抑制疗法 本项目的目的是利用甲状腺功能减退的大鼠和小鼠 同时描述不同的 T4和T3的组合对骨吸收和垂体TSH的影响 抑制，并表征T4至T3转化的性质 在骨头里。 将使用这些不同的模型。 用于体内 研究，年轻大鼠，广泛预标记45 Ca或3H- 四环素在子宫内和新生儿期间，将接受 不同浓度的甲状腺激素;骨吸收和 垂体TSH亚单位mRNA浓度将在 同样的动物。 这将决定血清TSH浓度是否 是监测甲状腺激素对 以及一些甲状腺激素制剂是否具有较少的 对骨吸收的影响优于其他制剂。 用于体外 骨吸收研究，钙预标记的新生小鼠颅骨将 用于器官培养，以确定甲状腺的直接影响 以及甲状腺激素的相互作用 与其他已知的骨吸收介质。 T4的动力学 将在颅骨器官培养中研究骨中T3的转化， 以及在利用几种人和大鼠的细胞培养物中 骨肉瘤细胞系。 这些信息将有助于 不同甲状腺激素制剂的疗效比较 TSH抑制及其对骨的潜在不良影响 矿物质浓度

Millions of patients in the United States take l-thyroxine for treatment of hypothyroidism or suppression of goiters or thyroid nodules. Our recent clinical studies suggest that l-thyroxine in doses sufficient to suppress TSH may result in excessive bone resorption. In the rat there are two enzymes that convert T4 to T3. The pituitary type 2 enzyme is more effective at converting T4 to T3 than the type 1 enzyme present in liver and kidney. Since tissue T3 receptor occupancy is correlated with thyroid hormone effect it is possible that a given dose of l-thyroxine would result in higher pituitary T3 receptor occupancy and suppression of serum TSH at a time when peripheral tissues T3 receptors were unsaturated. Little information is available regarding the relative effects of the two thyroid hormones, T4 and T3, on bone. In one study, T4 and T3 were equipotent in causing bone resorption in organ culture. The relative effects or T4 and T3 on bone may have important implications for optimizing the type of thyroid hormone preparation administered to patients for replacement or suppressive therapy. The goals of this project are to use the hypothyroid rat and mouse to simultaneously characterize the effects of different combinations of T4 and T3 on bone resorption and pituitary TSH suppression, and to characterize the nature of T4 to T3 conversion in bone. These different models will be used. For in vivo studies, young rats, extensively prelabeled with 45Ca or 3H- tetracycline in utero and during the neonatal period, will receive different concentrations of thyroid hormones; bone resorption and pituitary TSH subunit mRNA concentrations will be determined in the same animals. This will determine whether serum TSH concentration is a useful index to monitor the effects of thyroid hormone on bone, and whether some thyroid hormone preparations have less effect on bone resorption than other preparations. For in vitro bone resorption studies, Ca prelabeled neonatal mouse calvaria will be used in organ culture to determine the direct effects of thyroid hormone on bone, as well as the interaction of thyroid hormones with other known mediators of bone resorption. The kinetics of T4 to T3 conversion in bone will be studied in calvaria organ culture, as well as in cell culture utilizing several human and rat osteosarcoma cell lines. This information will be useful in comparing the efficacy of different thyroid hormone preparations for TSH suppression with their potential adverse effects upon bone mineral concentration.