Patients with hypothyroidism are routinely treated with thyroid hormone (l-thyroxine) for replacement therapy. Physicians monitor the thyroid hormone dose by measuring a thyroid stimulating hormone (TSH) level in the blood, with the goal of a normal level. However, recent data suggest that the "normal" TSH range is too broad, and that patients may still have symptoms if their TSH levels are at the top or bottom part of the normal range.

To study this issue, it is useful to address issues such as general health status, psychological symptoms, mood, memory, and metabolic status, since thyroid hormone has major effects on the brain adn metabolism, and since patients with treated hypothyroidism often have symptoms related to these areas.

In the present study, otherwise healthy subjects with treated hypothyroidism, ages 20-75 years, will be enrolled in a 7-11month study. At baseline, they will have tests of health status, psychological symptoms, mood, memory, body composition, and energy expenditure performed. Following these baseline measurements, subjects will receive either their usual doses of l-thyroxine, or a slightly higher or lower dose. The doses will be chosen to try to achieve either a low-normal TSH level, a high-normal TSH level, or a mildly elevated TSH level. Which target TSH the patient is assigned will be determined randomly, and neither the subject nor the study contacts will know which dose the patient is receiving. Subjects will be seen every 6 weeks during the study for brief visits to make sure they are not having any side effects, and to adjust the l-thyroxine doses if the TSH has not yet reached the target range. At the 24-week visit (end of study), the subjects will undergo the same tests that they had on the baseline visit.

Results from the study will be examined to see if minor changes in TSH or other thyroid hormone levels cause changes in any of the outcomes, and if the degree of TSH change correlates with the degree of outcome changes. These results may help physicians caring for patients with thyroid disease better determine the optimal dose of thyroid hormone for each patient.

• Experimental: Subjects with baseline TSH between 0.28 and 2.49. Treatment arm 1-A targets a THS of 0.28 -2.49 mU/L (the theoretical optimal range).
• Experimental: Subjects with baseline TSH levels between 0.28 and 2.49 mU/L, Treatment arm 1-B targeting a TSH of 2.5 - 5.0 mU/L
• Experimental: Subjects with baseline TSH levels between 0.28 and 2.49 mU/L. Treatment arm 1- C is targeting a TSH level o f 5.1-12.0 mU/L
• Experimental: Subjects with baseline TSH between 2.5 adn 5.0 mU/L. Treatment arm 2-A targets a THS of 0.28 -2.49 mU/L (the theoretical optimal range).
• Experimental: Subjects with baseline TSH between 2.5 adn 5.0 mU/L. Treatment arm 2-B targeting a TSH of 2.5 - 5.0 mU/L
• Experimental: Subjects with baseline TSH between 2.5 adn 5.0 mU/L. Treatment arm 1- C is targeting a TSH level o f 5.1-12.0 mU/L

Inclusion Criteria:

• Ages 20-75
• Primary hypothyroidism on stable dose of L-T4 for > 3 months
• Documented elevated TSH off L-T4
• Normal TSH level on usual dose of L-T4
• No acute or chronic medical or psychiatric illnesses that affect thyroid function, mood or cognition
• No medication use that affects thyroid function, mood or cognition (oral contraceptives or estrogen therapy allowed)
• Normal score on screening MMSE (to test for dementia)
• Normal vision by screening examination
• Normal hearing by screening examination
• Non smoker

Exclusion Criteria:

• Failure to meet any of the above inclusion criteria
• Inability to speak and comprehend English
• A history of coronary artery disease
• Screening hgb <10
• Screening wbc > 10,000
• Clinically significant abnormalities on screening metabolic set
• Screening LDL cholesterol > 160
• Screening triglyceride > 300
• Significant abnormalities on screening ECG
• Pregnancy or intent to become pregnant in next 6 months
• Present or recent use of medications that affect thyroid hormone levels or interfere with thyroid hormone effects, including beta-blockers, lithium, glucocorticoids, or iodine containing agents
• MMSE score < 26