The proposed study design is a prospective, randomized, double-blind, crossover study. After informed consent is obtained, patients will be randomized to receive either desiccated thyroid in capsules, or L-T4/L-T3 (ThyrolarTM) in capsules, or L-T4 alone capsules. All study participants, physician investigators, those administering the neurocognitive tests and those analyzing test results will be blinded throughout the study.

Subjects will undergo memory testing, a disease specific symptom questionnaire, a general mental health assessment, a complete physical examination, baseline EKG, and biochemical testing consisting of serum TSH, free T4, total T4, total T3, free T3, T3 resin uptake, reverse T3, sex hormone binding globulin (SHBG), serum iodine, a lipid panel, insulin, glucose and leptin. This testing and DXA scan of body composition will be performed at baseline and after each 3 month treatment period. Deiodinase type 2 (DIO2) polymorphisms analyses - will also be performed at the beginning of the study and the results will be blinded to the investigators performing the memory testing.

After 5-6 weeks on the study medication, TSH levels will be checked and the medication adjusted to maintain TSH level between 0.46-4.68 mIU/L. Once the TSH level is in the desired range, subjects will continue the medication for an additional 6 weeks. Subjects will then be crossed-over to the other treatment arm for 3 months. Again, testing will be performed after each treatment period. Finally the subjects will again switched over to the 3rd arm and testing will be performed after treatment period.

A cross-over design is preferred because we are assessing subjective symptoms such as clinical well-being and other parameters. Therefore, we will be able to evaluate the effectiveness of L-T4/T3 (ThyrolarTM) vs DTE vs T4 alone in the same patientssubjects. This is also supported by the previous study by Escobar-Morreale et al.

Additionally, the Wechsler memory scale, DEXA for body composition, measurment of reverse T3, insulin, leptin, and DIO2 polymorphisms analysis will be included for the research portion of this study. Further, the frequency of serum blood draws, for research purposes, will be at intervals of 0, 6, 12, 18, 24, 30 and 36 weeks.

Inclusion Criteria:

• Subjects will be between the ages of 18 to 65 and will have been on levothyroxine for primary hypothyroidism for at least 6 months
• Department of Defense beneficiaries living within 60 miles of Besthesda, MD

Exclusion Criteria:

• Subjects will be excluded if they have the following problems: pregnancy, plan for pregnancy in the next 12 months, cardiac disease, especially coronary artery disease, chronic obstructive lung disease, malabsorption disorder, gastrointestinal surgeries, significant renal or liver dysfunction, seizure disorders, thyroid and non-thyroid active cancers, uncontrolled psychosis, psychotropic medication use, steroid use, amiodarone, chemotherapy for cancer, iron supplement more than 325mg per day, carafate/ proton pump inhibitor use, cholestyramine use, and those with recent orders who are expected to move out of the geographic area, age less than 18 years old or older than 65 years old. Patients scheduled for deployment will be excluded.
• Subjects with subclinical hypothyroidism will be excluded. If we include patients with subclinical hypothyroidism, it will be difficult to assess the outcomes. This is because only a very small percentage of patients with subclinical hypothyroidism benefit from thyroid hormone therapy and therefore, a cross-over study as done in this project will not show a difference between the therapies.
• Females of child-bearing age will be screened with initial assessment for pregnancy as part of standard of care (eg history of amnenorrhea and/or positive pregnancy testing via hCG). There is no experience in using desiccated thyroid extract in pregnant women and there is no published paper in this area. Desiccated thyroid extract is rated Category-A drug in pregnancy which means there are no known risks to the fetus.