Hypothyroidism is common, affecting 3% of the U.S. population, and up to 20% of older women. Therapy is straightforward, with optimization of target organ function expected when thyroid stimulating hormone (TSH) levels are normalized using L-thyroxine (L-T4). Despite this, millions of patients have mildly elevated TSH levels, and recent data also imply that patients may be undertreated if their TSH levels are high- normal. Decrements in quality of life, mood, cognitive function, and fuel metabolism are seen in hypothyroidism, but much less is known regarding these outcomes in mild hypothyroidism, or in L-T4 treated subjects with high-normal TSH levels. Preliminary data: The investigator's work utilizes a unique experimental model of experimentally-induced mild thyroid disease in hypothyroid subjects on chronic L-T4 therapy. This NIDDK R21-funded work has resulted in intriguing preliminary data that form the basis for the current R01 application. Experimental design: The current proposal is to extend this model to the mildest forms of hypothyroidism, associated with high-normal or mildly elevated TSH levels. L-T4 treated hypothyroid subjects will be randomized to doses of L-T4 that target three TSH ranges: 0.28 2.49 mU/L (the lower normal range, the theoretical optimal range), 2.5 5.0 mU/L (the upper normal range), or 5.1 12 mU/L (the mild hypothyroid range). Precisely titrated L-T4 doses will be given in a double-blinded, parallel study lasting 6 months, in order to achieve these TSH levels. Outcomes focus on the most clinically relevant and least studied systems: the brain (mood and cognition) and intermediary metabolism (energy expenditure and body composition), for which the investigator has already found effects in previous work. These outcome variables will be measured using validated techniques at baseline and at 6 months, with interim visits to allow precise titration of L-T4 doses. Relevance: This is the first investigation that focuses on neurocognitive and metabolic effects of mild hypothyroidism utilizing a rigorous study design and validated, relevant outcome measures. There is no consensus over whether to treat patients with TSH levels in the ranges proposed in this study, and these TSH ranges are the subject of intense debate within the thyroid field. Therefore, this study has major public health implications for the millions of Americans who receive thyroid hormone replacement therapy, as well as for the additional millions with high-normal serum TSH levels.

Public Health Relevance

Millions of people in the U.S. have mild hypothyroidism or thyroid function in the low-normal range. Recent preliminary studies, including those from the investigator's laboratory, suggest that there are clinically relevant end-organ effects of thyroid function in this range, but there is a dearth of conclusive data, especially in the critical areas of brain function and fuel metabolism. This study will utilize a rigorous interventional design and validated outcome measures to study this for the first time, with results that have the potential to inform treatment decisions for millions of people.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Integrative and Clinical Endocrinology and Reproduction Study Section (ICER)
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Malozowski, Saul N
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Oregon Health and Science University
Internal Medicine/Medicine
Schools of Medicine
United States
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Samuels, Mary H; Kolobova, Irina; Niederhausen, Meike et al. (2018) Effects of Altering Levothyroxine Dose on Energy Expenditure and Body Composition in Subjects Treated With LT4. J Clin Endocrinol Metab 103:4163-4175
Samuels, Mary H; Kolobova, Irina; Niederhausen, Meike et al. (2018) Effects of Altering Levothyroxine (L-T4) Doses on Quality of Life, Mood, and Cognition in L-T4 Treated Subjects. J Clin Endocrinol Metab 103:1997-2008
Samuels, Mary H; Kolobova, Irina; Antosik, Megan et al. (2017) Thyroid Function Variation in the Normal Range, Energy Expenditure, and Body Composition in L-T4-Treated Subjects. J Clin Endocrinol Metab 102:2533-2542
Samuels, Mary H; Kolobova, Irina; Smeraglio, Anne et al. (2016) Effect of Thyroid Function Variations Within the Laboratory Reference Range on Health Status, Mood, and Cognition in Levothyroxine-Treated Subjects. Thyroid 26:1173-84
Samuels, Mary H; Kolobova, Irina; Smeraglio, Anne et al. (2016) Effects of Levothyroxine Replacement or Suppressive Therapy on Energy Expenditure and Body Composition. Thyroid 26:347-55
Samuels, Mary H (2014) Psychiatric and cognitive manifestations of hypothyroidism. Curr Opin Endocrinol Diabetes Obes 21:377-83
Samuels, Mary H; Kolobova, Irina; Smeraglio, Anne et al. (2014) The effects of levothyroxine replacement or suppressive therapy on health status, mood, and cognition. J Clin Endocrinol Metab 99:843-51