STEROID HORMONE REGULATION OF TSH SUBUNIT BIOSYNTHESIS

美国数以百万计的患者服用L-甲状腺素治疗 治疗甲状腺功能减退症或抑制甲状腺肿大或甲状腺 结节。我们最近的临床研究表明，L-甲状腺素在 足以抑制TSH的剂量可能会导致骨骼过多 再吸收。在大鼠体内，有两种酶将T4转化为 T3。脑垂体2型酶在转化过程中更有效 T4~T3高于肝脏和肾脏中存在的1型酶。自.以来 组织T3受体占有率与甲状腺激素相关 作用：一定剂量的L-甲状腺素有可能导致 在高位垂体中T3受体的占据和血清的抑制 TSH在外周组织中的T3受体 不饱和的。目前关于这一事件的信息很少 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相同的 在器官培养方面。T4和T3对骨骼的相对影响可能 对优化甲状腺类型有重要意义 为患者提供激素制剂以进行替代或 抑制性治疗。 这个项目的目标是用甲状腺功能低下的大鼠和小鼠 同时描述不同因素的影响 T4和T3联合应用对骨吸收和垂体促甲状腺激素的影响 抑制，并表征T4到T3转换的性质 骨瘦如柴。这些不同的模型将被使用。用于活体内 研究，幼鼠，广泛预先标记45Ca或~3H- 四环素在宫内和新生儿期内，将收到 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 是监测甲状腺激素对健康的影响的有用指标 骨骼，以及某些甲状腺激素制剂是否含有较少的 对骨吸收的作用优于其他制剂。用于体外实验 骨吸收研究，钙预先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 骨骼上的激素，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 将在头盖骨器官培养中研究骨骼向T3的转化， 以及在细胞培养中利用几个人和大鼠 骨肉瘤细胞系。这些信息将在 不同甲状腺激素制剂的疗效比较 抑制促甲状腺激素及其对骨骼的潜在不良影响 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.