Thyroid disease represents a significant medical and public health challenge in the United States affecting over 19 million Americans. Hypothyroidism (HT) found in 4.6% of the US population, is increasingly common in the elderly affecting more than 20% of women and 11% of men. Hypothyroidism is defined by an elevated serum thyroid stimulating hormone (TSH) concentration with low serum thyroxine (T4) and tri- iodothyronine (T3) concentrations. Population studies demonstrate an age-related elevation in TSH concentrations, but at present, there is no consensus regarding the TSH concentration at which replacement therapy should be initiated. Another significant gap in knowledge is a lack of pharmacokinetic data of levothyroxine specifically in aging. The presence of endogenous thyroxine makes it impossible to differentiate between internally and externally-derived thyroxine using conventional laboratory tests.
In Aims 1 we will conduct pharmacokinetic studies of 13C-LT4 in the elderly. We have designed and validated this method, using state-of- the-art technology, which permit the measurement of exogenous LT4 and conduct pharmacokinetic studies of single dose oral LT4 replacement. A secondary aim (Aim 2) will examine the bioactivity of TSH, assuming the age-related elevation in TSH concentrations consists of relatively more inactive TSH.
Aim 3 will examine age-related thyroid hormone activity in peripheral tissues reflecting drug effectiveness. Our experience in patient recruitment and conducting PK studies using state-of-the- art liquid chromatography tandem mass spectrometry (LC/MS/MS) at Georgetown University Medical Center (GUMC), as well as our preliminary data, assure the success of this proposal. If the goals of this research are achieved it will advance the knowledge in the field and have a major impact on the aging population;with the aging of America's baby boomers the need to fully understand the progression thyroid disease, to improve diagnosis and treatment is vitally important to our nation and to our healthcare systems. We believe that these unique and innovative studies will provide a wealth of information that will translate to improved diagnosis, evaluation and management of therapeutic interventions.

Public Health Relevance

Thyroid disease represents a significant medical and public health challenge in the United States affecting over 19 million Americans. In order to diagnose, treat and manage hypothyroid disease appropriately we need elucidate and characterize the age- associated differences in thyroid hormone metabolism, especially in women. This will help in setting therapeutic goals and help millions in diagnosis, treatment and management of thyroid disease in aging.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG033867-04
Application #
8527654
Study Section
Integrative and Clinical Endocrinology and Reproduction Study Section (ICER)
Program Officer
Zieman, Susan
Project Start
2010-09-01
Project End
2015-05-31
Budget Start
2013-09-01
Budget End
2014-05-31
Support Year
4
Fiscal Year
2013
Total Cost
$348,574
Indirect Cost
$121,490
Name
Georgetown University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
049515844
City
Washington
State
DC
Country
United States
Zip Code
20057
Estrada, Joshua M; Soldin, Danielle; Buckey, Timothy M et al. (2014) Thyrotropin isoforms: implications for thyrotropin analysis and clinical practice. Thyroid 24:411-23
Jonklaas, Jacqueline; Sathasivam, Anpalakan; Wang, Hong et al. (2014) 3,3'-diiodothyronine concentrations in hospitalized or thyroidectomized patients: results from a pilot study. Endocr Pract 20:797-807
Jonklaas, Jacqueline; Sathasivam, Anpalakan; Wang, Hong et al. (2014) Total and free thyroxine and triiodothyronine: measurement discrepancies, particularly in inpatients. Clin Biochem 47:1272-8
Mehran, L; Tohidi, M; Sarvghadi, F et al. (2013) Management of thyroid peroxidase antibody euthyroid women in pregnancy: comparison of the american thyroid association and the endocrine society guidelines. J Thyroid Res 2013:542692
Soldin, Offie P; Chung, Sarah H; Colie, Christine (2013) The Use of TSH in Determining Thyroid Disease: How Does It Impact the Practice of Medicine in Pregnancy? J Thyroid Res 2013:148157
Soldin, Offie P (2011) Innovative studies in women by use of stabilized isotopes in pregnancy. J Popul Ther Clin Pharmacol 18:e528-32