COMPARISON OF THYROID HORMONE LEVELS FOUND WITH NORMAL THYROID FUNCTIONING, C

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。该项目的目标是确定何种甲状腺激素组合能为甲状腺功能减退症提供最佳的替代疗法。甲状腺功能正常的人体内有两种循环的甲状腺激素，即甲状腺激素和三碘甲腺原氨酸。虽然一些三碘甲腺原氨酸是在类甲状腺腺体本身产生的，但大部分是在甲状腺激素的外周产生的。三碘甲腺原氨酸的半衰期也比甲状腺激素短得多。目前，标准的甲状腺激素替代疗法包括单独使用合成甲状腺激素(左旋甲状腺素)。虽然左旋甲状腺素在循环中转化为三碘甲腺原氨酸，但目前尚不清楚替代治疗后的三碘甲腺原氨酸水平是否与甲状腺功能完整的患者相同。最近一项联合使用左旋甲状腺素和三碘甲腺原氨酸的研究表明，患者更倾向于联合治疗。因此，该项目的总体假设是，左旋甲状腺素替代会导致三碘甲腺原氨酸的轻微缺乏，因此左旋甲状腺素对甲状腺功能减退症提供了不完全的治疗。具体目的1：比较甲状腺功能正常的人在甲状腺切除前的循环甲状腺激素和三碘甲腺原氨酸的浓度，以及甲状腺切除后用左旋甲状腺素替代甲状腺激素所获得的浓度。该项目要检验的初始假设是，在个别患者中，单独使用左旋甲状腺素标准替代是否会导致血清三碘甲腺原氨酸水平低于甲状腺正常运行时的水平。参与者将是甲状腺功能正常的人，他们计划因良性结节疾病或甲状腺癌而接受甲状腺切除术。甲状腺手术前的血清三碘甲腺原氨酸水平将与患者接受左旋甲状腺素治疗后的血清三碘甲腺原氨酸水平进行比较，以确定左旋甲状腺素替代治疗是否导致较低的亚生理性三碘甲状腺原氨酸水平。具体目标2：确定一组其表达水平受甲状腺激素影响的基因。甲状腺功能减退症的适当治疗是由许多参数来判断的。这些指标包括甲状腺激素和促甲状腺激素水平：甲状腺状态的体征、症状和生化指标；以及患者的情绪、神经心理功能和满意度。该项目的另一个假设是，可以识别出一组基因，它们的表达水平反映了甲状腺状况。免费的DNA微阵列技术将被用来开发一种由甲状腺激素调节表达的基因小组。这种甲状腺状况指数对甲状腺激素水平的变化以及在治疗方案中添加三碘甲腺原氨酸尤其敏感。这个基因小组将被包括在用于评估特定目标三和四的甲状腺状况的生化标记中。具体目的3：比较不同比例的左旋甲状腺素和三碘甲腺原氨酸的几种替代方案，以确定哪种方案对甲状腺状况指标的影响最有利。此外，最佳逆转甲状腺功能减退指数的方案所达到的三碘甲状腺原氨酸水平将与甲状腺功能正常的三碘甲状腺原氨酸水平进行比较。第三种假设是左旋甲状腺素/三碘甲腺原氨酸联合治疗甲状腺功能减退症效果更好。甲状腺状态的生化、生理和心理指标将在联合治疗期间与左旋甲状腺素单独治疗期间的指标进行比较，其中左旋甲状腺素和三碘甲状腺原氨酸的几个比率。血清三碘甲状腺原氨酸水平也将与甲状腺状况相关，以确定最接近地再现甲状腺功能完整的三碘甲状腺原氨酸水平的方案是否对甲状腺状况的生理、生化和心理指标也有最有利的影响。具体目的4：比较左旋甲状腺素/三碘甲腺原氨酸缓释方案与左旋甲状腺素/三碘甲腺原氨酸最佳方案替代治疗期间甲状腺激素状况的指标。该项目的最后一个假设是，缓释三碘甲状腺原氨酸将优于商业上可获得的三碘甲状腺原氨酸。由于其半衰期短，用三碘甲腺原氨酸替代会导致其循环水平的相当大的波动。使用一种新的缓释产品，使三碘甲腺原氨酸水平稳定，将提供更多的生理替代。这将与左旋甲状腺素、左旋甲状腺素和三碘甲腺原氨酸的治疗进行对比试验。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The objective of this project is to determine what combination of thyroid hormones provides optimum replacement therapy for hypothyroidism. In an individual with a functioning thyroid gland there are two circulating thyroid hormones, thyroxine and triiodothyronine. Although some triiodothyronine is produced within the thytoid gland itself, the majority is produced in the periphery from thyroxine. Triiodothyronine also has a much shorter half-life than thyroxine. At the present time, standard thyroid hormone replacement consists of synthetic thyroxine (levothyroxine) alone. Although levothyroxine is converted into triiodothyronine in the circulation, it is not clear that the triiodothyronine levels with replacement therapy are equal to those seen with intact thyroid function. A recent study using a combination of levothyroxine and triiodothyronine indicated a patient preference for the combination therapy. Therefore, the overall hypothesis of this project is that levothyroxine replacement results in a subtle deficiency of triiodothyronine, and that levothyroxine thus provides incomplete treatment for hypothyroidism. Specific Aim 1: To compare circulating thyroxine and triiodothyronine concentrations in individuals with normal thyroid function, prior to thyroidectomy, with concentrations achieved form thyroid hormone replacement with levothyroxine, after thyroidectomy. The initial hypothesis to be tested in this project is whether, within individual patients, standard replacement with levothyroxine alone results in lower serum levels of triiodothyronine than those seen while the thyroid gland is functioning. Participants will be euthyroid individuals who are scheduled for thyroidectomy for benign nodular disease or thyroid cancer. Serum triiodothyronine levels prior to thyroid surgery will be compared with those after thyroidectomy when participants have been stabilized on levothyroxine therapy, in order to determine if levothyroxine replacement results in lower, sub-physiologic triiodothyronine levels. Specific Aim 2: To identify a panel of genes whose level of expression is altered by thyroid hormone. Adequate treatment of hypothyroidism is judged by many parameters. These include thyroid hormone and thyroid stimulating hormone levels: signs, symptoms, and biochemical indices of thyroid status; and patient mood, neuropsychologic functioning, and satisfaction. Another hypothesis of this project is that a panel of genes can be identified whose expression level is reflective of thyroid status. Complimentary DNA microarray technology will be used to develop a gene panel whose expression is regulated by thyroid hormone. Such an index of thyroid status should be particularly sensitive to changes in thyroid hormone levels, and to addition of triiodothyronine to a treatment regimen. This gene panel will be included in the biochemical markers used to assess thyroid status in specific aims three and four. Specific Aim 3: To compare several replacement regimens using different ratios of levothyroxine and triiodothyronine, to determine which has the most favorable impact on indices of thyroid status. In addition, the triiodothyronine level achieved by the regimen that best reverses the indices of hypothyroidism will be compared with the levels of triiodothyronine seen with intact thyroid function. The third hypothesis is that levothyroxine/triiodothyronine combination will provide superior treatment of hypothyroidism. Biochemical, physiologic and psychologic indices of thyroid status will be compared during combination therapy with several ratios of levothyroxine and triiodothyronine to indices during treatment with levothyroxine alone. Serum triiodothyronine levels will also be correlated with thyroid status to determine if the regimen that most closely reproduces the triiodothyronine levels seen with intact thyroid function also has the most favorable impact on the physiologic, biochemical, and psychologic indices of thyroid status. Specific Aim 4: To compare indices of thyroid hormone status during replacement with a levothyroxine/sustained release triiodothyronine combination to indices achieved with an optimal levothyroxine/triiodothyronine regimen. The final hypothesis of this project is that sustained release triiodothyronine will be superior to commercially available triiodothyronine. Because of its short half-life, replacement with triiodothyronine leads to considerable fluctuations in its circulating levels. Use of a new sustained release product, which results in steady triiodothyronine levels, will furnish more physiologic replacement. This will be tested against treatment with levothyroxine, and levothyroxine and triiodothyronine.