Mechanistic Study of Subclinical Hypothyroidism In the Elderly

Study Overview
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Brief Summary
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Subclinical hypothyroidism, defined as an elevated TSH in the setting of normal thyroid hormone levels, is a common diagnosis in the elderly. The purpose of this study is to examine the hypothalamic-pituitary-thyroid axis in men and women aged 70 years and older with persistent subclinical hypothyroidism. To evaluate the mechanism behind this condition, participants will undergo thyrotropin releasing hormone stimulation testing at 3 visits: baseline and while taking two different thyroid hormone preparations, levothyroxine and liothyronine. The investigators will also assess physiologic responses to these two different thyroid hormone medications to help us understand how the thyroid works in advanced age.

Official Title
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The Thyroid Axis in Older Individuals With Persistent Subclinical Hypothyroidism: a Mechanistic, Randomized, Double-Blind, Cross-Over Study of Levothyroxine and Liothyronine Administration

Conditions
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Subclinical Hypothyroidism

Intervention / Treatment
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* Drug: Levothyroxine
* Drug: Liothyronine
* Drug: Thyrotropin-Releasing Hormone


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: men and women aged 70 and older TSH between 4.5 and 19.9 mU/L as an outpatient ability to provide informed consent Exclusion Criteria: Laboratory Tests: TSH <4.5 mU/L or >20 mU/L on repeat testing at least four weeks later or free T4 level outside the reference range thyroid peroxidase (TPO) antibody positive abnormal liver function tests (LFTs >3 x upper limit of normal) hemoglobin <11 g/dL Surgeries or Procedures: thyroid surgery pituitary surgery bariatric surgery bowel resection involving the jejunum and upper ileum radioactive iodine therapy radiation treatments to head or neck Medical Conditions: diagnosis of pituitary disease diagnosis of amyloidosis, sarcoidosis, hemochromatosis diagnosis of adrenal insufficiency obesity with BMI > 35 mg/kg2 history of stroke chronic or ongoing angina, Class II or higher congestive heart failure, or uncontrolled hypertension with current blood pressure greater than 160/100 diabetes mellitus with hemoglobin A1C level greater than 8.0% in the past six months celiac sprue, Crohn's disease, ulcerative colitis, Zollinger-Ellison syndrome renal insufficiency with calculated glomerular filtration rate <45 cc/min cognitive impairment with Mini Mental State Exam[30] <24/30 history of any seizures unstable medical or psychological condition in the judgment of the principal investigator Medications: thyroid hormone preparations antithyroid drugs medications that interfere with the absorption or metabolism of thyroid hormone medications that interfere with the TRH stimulation test proton pump inhibitors

Ages Eligible for Study
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Minimum Age: 70 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: Other
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Levothyroxine First<br>Participants will start on the thyroid hormone Levothyroxine prior to crossing over to Liothyronine | Drug: Levothyroxine<br>* Oral levothyroxine with a total starting dose of 0.7mcg/kg/day split into three daily doses will be titrated to a target TSH level of 0.5 -1.5mU/L<br>* Other names: Synthroid;Drug: Liothyronine<br>* Oral liothyronine with a starting dose of 1/3 of the weight-based LT4 dose divided into three daily doses titrated to a target TSH level of 0.5 -1.5mU/L<br>* Other names: Cytomel;Drug: Thyrotropin-Releasing Hormone<br>* 200 µg intravenous TRH will be given at study visit 1 (baseline), study visit 2 (on first thyroid treatment), and study visit 3 (on second thyroid treatment).<br>|
| Experimental: Liothyronine First<br>Participants will start on the thyroid hormone Liothyronine prior to crossing over to Levothyroxine | Drug: Levothyroxine<br>* Oral levothyroxine with a total starting dose of 0.7mcg/kg/day split into three daily doses will be titrated to a target TSH level of 0.5 -1.5mU/L<br>* Other names: Synthroid;Drug: Liothyronine<br>* Oral liothyronine with a starting dose of 1/3 of the weight-based LT4 dose divided into three daily doses titrated to a target TSH level of 0.5 -1.5mU/L<br>* Other names: Cytomel;Drug: Thyrotropin-Releasing Hormone<br>* 200 µg intravenous TRH will be given at study visit 1 (baseline), study visit 2 (on first thyroid treatment), and study visit 3 (on second thyroid treatment).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| TSH Area Under the Curve | TSH area under the curve within 60 minutes of TRH stimulation when TSH is at goal | 0, 5, 10, 15, 20, 30, and 60 min post TRH | 
| TSH Max | The maximum concentration of TSH after TRH stimulation when TSH is at goal | Between 0 and 180 min after TRH stimulation | 
| Free T4 Level | Free thyroxine level when TSH level is at goal on therapy. | An average of 7 months after initiating therapy | 
| Total T3 Level | Total triiodothyronine level when TSH is at goal on therapy | An average of 7 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Levothyroxine, Liothyronine, Thyrotropin Releasing Hormone, Aging, Hypothyroidism, Thyroid diseases