MENTORED PATIENT-ORIENTED RESEARCH CAREER DEVELOPMENT AWARD

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DESCRIPTION (provided by applicant): The objective of this project is to determine what combination of thyroid hormones provides optimum replacement therapy for hypothyroidism. There are two circulating thyroid hormones, thyroxine and triiodothyronine, and standard thyroid hormone replacement consists of synthetic thyroxine (levothyroxine) alone. Although levothyroxine is converted into triiodothyronine in the circulation, triiodothyronine levels achieved may not be equal to those seen with intact thyroid function. Therefore, the overall hypothesis of this project is that levothyroxine replacement results in a subtle deficiency of triiodothyronine and provides incomplete treatment for hypothyroidism. The initial hypothesis to be tested in this project is whether, within individual patients, standard replacement with levothyroxine results in lower serum levels of triiodothyronine than those seen while the thyroid gland is functioning. Participants will be euthyroid individuals scheduled for thyroidectomy for benign nodular disease or thyroid cancer. Serum triiodothyronine levels prior to thyroid surgery will be compared with those after thyroidectomy, to determine if levothyroxine replacement results in lower, sub-physiologic triiodothyronine levels. Another hypothesis of this project is that a panel of genes can be identified whose expression level is reflective of thyroid status. Complimentary (c) DNA array technology will be used to develop a gene panel whose expression is regulated by thyroid hormone. This gene panel will be included in the biochemical markers used to assess thyroid status. The third hypothesis is that levothyroxinetriiodothyronine 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. The regimens will be compared to determine if the one that most closely reproduces the triiodothyronine levels seen with intact thyroid function, also has the most favorable impact on thyroid status. The final hypothesis of this project is that sustained release triiodothyronine is superior to commercially available triiodothyronine. Because of its short half-life, replacement with triiodothyronine leads to fluctuating serum levels. 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.