Neurocognitive and Metabolic Effects of Mild Hypothyroidism

Study Overview
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Brief Summary
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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 and 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.

Detailed Description
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Thyroid hormone is essential for neurocognitive and metabolic function, and patients with overt thyroid dysfunction have well-described alterations in mood, cognition, energy expenditure, and body composition. However, it is not clear that patients with more mild degrees of thyroid dysfunction have clinically significant alterations in these parameters. In addition, recent data suggest that variations in thyroid function within the laboratory reference range may also affect these parameters. Patients with hypothyroidism are routinely treated with levothyroxine (L-T4) as replacement therapy. Physicians monitor the L-T4 dose by measuring serum thyroid stimulating hormone (TSH) levels, with the goal of a normal level. However, many patients with normal TSH levels continue to report symptoms, primarily in neurocognitive and metabolic areas. For this reason, patients with hypothyroidism often request higher L-T4 doses, but the clinical consequences of this are unknown. In the present study, otherwise healthy subjects with treated hypothyroidism and normal TSH levels, ages 20-75 years, will be enrolled in a 7-11 month study. At baseline, the following tests will be performed to measure health status, psychological symptoms, mood, memory, body composition, and energy expenditure: the Short Form Health Survey-36 (SF-36), Profile of Mood States (POMS), Affective Lability Scale (ALS), Letter Cancellation Test (LCT), Trail Making Test, Iowa Gambling Task (IGT), N-Back Test, Subject-Ordered Pointing, Paragraph Recall, Pursuit Rotor, Motor Sequence Learning Test, resting energy expenditure (REE) and thermic effect of food (TEF) by indirect calorimetry, total energy expenditure (TEE) by doubly labelled water, physical activity energy expenditure (PAEE) by accelerometry, diet intake by 24-hour diet recalls, and body composition by dual energy x-ray absorptiometry (DEXA). Following these baseline measurements, subjects will receive either their usual doses of L-T4, 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 L-T4 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.

Official Title
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Neurocognitive and Metabolic Effects of Mild Hypothyroidism

Conditions
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Hypothyroidism

Intervention / Treatment
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* Drug: L-thyroxine (L-T4)


Participation Criteria
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Eligibility Criteria
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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 Mini-Mental State Exam (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

Ages Eligible for Study
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Minimum Age: 20 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1 (Low-normal TSH target)<br>Treatment arm 1 targets a thyroid stimulating hormone (TSH) of 0.28 -2.49 milliunits/liter (mU/L) (the theoretical optimal range). The intervention is as follows: Levothyroxine (L-T4) doses will be adjusted in this arm to achieve this target TSH range. L-T4 is the intervention. L-T4 is given once per day, in the morning, while fasted. Dose ranges for the study are calculated based on each subject's TSH levels monitored during the study. Duration of the intervention is the duration of the study, after which subjects return to taking their usual L-T4 doses. | Drug: L-thyroxine (L-T4)<br>* L-thyroxine (L-T4) is the intervention for each arm/group. In each arm/group, the dose of L-T4 is adjusted to achieve TSH levels in the randomly assigned arm. L-thyroxine at doses appropriate to attain target TSH levels for the different arms for 24 weeks<br>* Other names: Subjects on generic L-T4 will be switched to Levoxyl.;|
| Experimental: 2 (High-normal TSH target)<br>Treatment arm 2 targeting a TSH of 2.5 - 5.0 mU/L. The intervention is as follows: Levothyroxine (L-T4) doses will be adjusted in this arm to achieve this target TSH range. L-T4 is the intervention. L-T4 is given once per day, in the morning, while fasted. Dose ranges for the study are calculated based on each subject's TSH levels monitored during the study. Duration of the intervention is the duration of the study, after which subjects return to taking their usual L-T4 doses. | Drug: L-thyroxine (L-T4)<br>* L-thyroxine (L-T4) is the intervention for each arm/group. In each arm/group, the dose of L-T4 is adjusted to achieve TSH levels in the randomly assigned arm. L-thyroxine at doses appropriate to attain target TSH levels for the different arms for 24 weeks<br>* Other names: Subjects on generic L-T4 will be switched to Levoxyl.;|
| Experimental: 3 (Mildly elevated TSH target)<br>Treatment arm 3 is targeting a TSH level o f 5.1-12.0 mU/L. The intervention is as follows: Levothyroxine (L-T4) doses will be adjusted in this arm to achieve this target TSH range. L-T4 is the intervention. L-T4 is given once per day, in the morning, while fasted. Dose ranges for the study are calculated based on each subject's TSH levels monitored during the study. Duration of the intervention is the duration of the study, after which subjects return to taking their usual L-T4 doses. | Drug: L-thyroxine (L-T4)<br>* L-thyroxine (L-T4) is the intervention for each arm/group. In each arm/group, the dose of L-T4 is adjusted to achieve TSH levels in the randomly assigned arm. L-thyroxine at doses appropriate to attain target TSH levels for the different arms for 24 weeks<br>* Other names: Subjects on generic L-T4 will be switched to Levoxyl.;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Executive Function | Iowa Gambling Task Net-5. Four decks of cards are shown face down on a computer screen. The subject chooses cards from any deck, resulting in the gain or loss of money. The subject is unaware that 2 decks are advantageous (small gains, smaller losses), while 2 are disadvantageous (large gains, larger losses). The subject's choices are classified as advantageous (X) or disadvantageous (Y), with a net score of X-Y, over 5 trials of 100 cards each. The outcome reported here is the score on the fifth trial, which is generally the best trial due to practice effects. The minimum score is -20 and the maximum score is +20. Higher scores indicate a better outcome. | 24 weeks | 
| Resting Energy Expenditure | Measurement of resting energy expenditure (REE) by indirect calorimetry, corrected for lean body mass. Indirect calorimetry is performed at 21.1° C after the participant has fasted for 12h and abstains from significant physical activity for 24h. The indirect calorimeter (VMax Encore 29N Indirect Calorimeter, SensorMedics Viasys Healthcare, Yorba Linda, CA) samples expired air and analyzes it for the volume of oxygen consumed (VO2) and the volume of carbon dioxide produced (VCO2) each minute for 30mins. REE is then calculated using the modified Weir equation. Minimum REE is 23 kcal/kg LBM/day and maximum REE is 39 kcal/kg LBM/day. Within that range, higher levels are considered better for the purposes of this study. | 24 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Cognition, Metabolism, Hypothyroidism