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.