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

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。该项目的目的是确定甲状腺激素的哪种组合为甲状腺功能减退提供最佳的替代疗法。在一个甲状腺功能正常的个体中，有两种循环的甲状腺激素，甲状腺素和三碘甲状腺原氨酸。虽然一些三碘甲状腺原氨酸是由甲状腺本身产生的，但大多数是由甲状腺素在周围产生的。三碘甲状腺原氨酸的半衰期也比甲状腺素短得多。目前，标准的甲状腺激素替代仅由合成甲状腺素（左甲状腺素）组成。虽然左旋甲状腺素在循环中转化为三碘甲状腺原氨酸，但尚不清楚替代治疗后的三碘甲状腺原氨酸水平是否与甲状腺功能完好的患者水平相同。最近一项联合使用左甲状腺素和三碘甲状腺原氨酸的研究表明，患者倾向于联合治疗。因此，本项目的总体假设是，左旋甲状腺素替代导致三碘甲状腺原氨酸的轻微缺乏，因此左旋甲状腺素不能完全治疗甲状腺功能减退症。特异性目的1：比较甲状腺功能正常个体在甲状腺切除术前与甲状腺切除术后用左旋甲状腺素替代甲状腺激素后的循环甲状腺素和三碘甲状腺原氨酸浓度。在这个项目中要测试的最初假设是，在个别患者中，单独使用左旋甲状腺素的标准替代是否会导致血清中三碘甲状腺原氨酸的水平低于甲状腺功能正常时的水平。参与者将是甲状腺功能正常的个体，他们计划因良性结节疾病或甲状腺癌进行甲状腺切除术。将甲状腺手术前的血清三碘甲状腺原氨酸水平与甲状腺切除术后稳定左旋甲状腺素治疗的血清三碘甲状腺原氨酸水平进行比较，以确定左旋甲状腺素替代是否会导致较低的亚生理性三碘甲状腺原氨酸水平。特异性目的2：鉴定一组表达水平被甲状腺激素改变的基因。甲状腺功能减退症的适当治疗是由许多参数来判断的。其中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；病人的情绪，神经心理功能和满意度。该项目的另一个假设是，可以确定一组基因，其表达水平反映甲状腺状态。互补DNA微阵列技术将用于开发一种表达受甲状腺激素调节的基因面板。这种甲状腺状态指标应该对甲状腺激素水平的变化以及在治疗方案中添加三碘甲状腺原氨酸特别敏感。该基因面板将包括在生化标记中，用于评估特定目标3和4的甲状腺状态。具体目的3：比较几种使用不同比例左甲状腺素和三碘甲状腺原氨酸的替代方案，以确定哪种方案对甲状腺状态指标的影响最有利。此外，最好逆转甲状腺功能减退指标的方案所达到的三碘甲状腺原氨酸水平将与甲状腺功能完好的三碘甲状腺原氨酸水平进行比较。第三种假设是左甲状腺素/三碘甲状腺原氨酸联合治疗甲状腺功能减退症效果更好。将左旋甲状腺素和三碘甲状腺原氨酸的不同比例与单用左旋甲状腺素治疗时的生化、生理和心理指标进行比较。血清三碘甲状腺原氨酸水平也将与甲状腺状态相关，以确定与甲状腺功能完好时三碘甲状腺原氨酸水平最接近的方案是否对甲状腺状态的生理、生化和心理指标也有最有利的影响。具体目标4：比较左甲状腺素/三碘甲状腺原氨酸缓释组合替代期间的甲状腺激素状态指标与最佳左甲状腺素/三碘甲状腺原氨酸方案获得的指标。本项目的最终假设是缓释三碘甲状腺原氨酸将优于市售三碘甲状腺原氨酸。由于其半衰期短，用三碘甲状腺原氨酸替代会导致其循环水平出现相当大的波动。使用一种新的缓释产品，其结果是稳定的三碘甲状腺原氨酸水平，将提供更多的生理替代。这将与左甲状腺素，左甲状腺素和三碘甲状腺原氨酸治疗进行对比。

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.