Unstable Thyroid Function in Older Adults Is Caused by Alterations in Both Thyroid and Pituitary Physiology and Is Associated with Increased Mortality
Open accessAbstract
Background: Average thyrotropin (TSH) levels are known to be higher in older adults when measured in cross-sectional populations. Possible etiologies include differential survival, neutral aging changes, or increased disease prevalence at older ages. This study aimed to elucidate the mechanisms underlying changing thyroid function during aging, and to determine the association of changes with survival, by analyzing the individual thyroid axis over time. Methods: Individual patterns of changing TSH and free thyroxine (fT4) were determined in 640 participants in the Baltimore Longitudinal Study of Aging who had at least three measures of serum TSH and fT4, not on medications, over an average of seven years of follow-up. Participants with changing phenotypes were identified based on quintiles for both slopes. Those with alterations in primary thyroid gland function demonstrated intact negative feedback (rising TSH with declining fT4 or declining TSH with rising fT4). Other participants had a parallel rise or fall of TSH and fT4 levels, consistent with pituitary dysfunction. Predictors of phenotype were analyzed by logistic regression. Differential survival between thyroid aging phenotypes was analyzed using multivariate Cox regression. Results: While the majority of participants at all ages had stable thyroid function, changes were more common among older adults, with 32.3% of those aged >80 years but only 9.5% of those aged <60 years demonstrating thyroid function changes in the highest and lowest quintiles. Regression to the mean accounts for some of the changes, for example increased baseline TSH was associated with a falling TSH pattern (odds ratio = 1.4 [confidence interval 1.1–1.7] per 1 mIU/L). Importantly, changing thyroid function in either the upper or lower quintiles of slope for TSH and fT4 was associated with increased risk of death compared to stable thyroid status (hazard ratio = 5.4 [confidence interval 3.1–9.5]). Conclusions: Changing thyroid hormone function is increasingly common at older ages and is associated with decreased survival. Nonetheless, the tendency for abnormal thyroid function tests to resolve, along with altered pituitary responsiveness underlying some TSH elevations, suggests that an elevated TSH level should be not assumed to represent subclinical hypothyroidism in older adults. Thus, caution is appropriate when determining the need for thyroid hormone supplements in older adults.
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Three other longitudinal studies did not confirm age-related TSH increases.
“Three other longitudinal studies in contrast did not confirm age-related TSH increases [99–101].”
From Age-related variation in thyroid function – a narrative review highlighting important implications for research and clinical practice (2023) · cites this paper as [100]
In the Baltimore Longitudinal Study of Aging, mean TSH was higher in older individuals at baseline, but TSH remained stable in the majority of participants.
“Although mean TSH was higher in older individuals at baseline, the TSH remained stable in the majority of participants.”
From Age-related variation in thyroid function – a narrative review highlighting important implications for research and clinical practice (2023) · cites this paper as [100]
Time-related changes in TSH were more common in older individuals, associated with decreased survival, and showed a heterogeneous pattern including progression to primary thyroid disease as well as non-pathological TSH elevations.
“Time-related changes were more common in older individuals, associated with decreased survival and showed a heterogeneous pattern of change that included progression to primary thyroid disease as well as non-pathological TSH elevations [100].”
From Age-related variation in thyroid function – a narrative review highlighting important implications for research and clinical practice (2023) · cites this paper as [100]
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Self-citationBiological variation in thyroid function tests in older adults and clinical implications
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- Authors
- Mammen, J. S., McGready, J., Ladenson, P. W., & Simonsick, E. M.
- Affiliations
- Johns Hopkins University (US)
- National Institutes of Health (US)
- Corresponding author
- Mammen, Jennifer S.
- Venue
- Thyroid®
- Publisher
- SAGE Publications
- Published
- 2017-11
- Volume
- 27
- Issue
- 11
- Pages
- 1370-1377
- ISSN
- 1050-7256 (ISSN-L)
- 1557-9077
- PMC
- PMC5672620
- OpenAlex
- W2751216069
- Cited by
- 34
- References
- 32
- Citations by year
- 2026: 5 · 2025: 1 · 2024: 4 · 2023: 7 · 2022: 4 · 2021: 4 · 2020: 1 · 2019: 5 · 2018: 2 · 2017: 1
- FWCI
- 1.95
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Thyroid (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of Diabetes and Digestive and Kidney Diseases (K23DK095954)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Thyroid Disorders and Treatments
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Hormonal and reproductive studies
- Health Sciences › Medicine › Surgery › Thyroid and Parathyroid Surgery
- Keywords
- thyroid function, aging, thyroid-stimulating hormone, free thyroxine, pituitary dysfunction, hypothalamic-pituitary-thyroid axis, mortality, subclinical hypothyroidism, regression to the mean, thyroid hormone replacement, older adults, Baltimore Longitudinal Study of Aging
- MeSH terms
- Aged, Aged, 80 and over, Cause of Death, Female, Humans, Longitudinal Studies, Male, Middle Aged, Pituitary Gland, Predictive Value of Tests, Prognosis, Risk Factors, Thyroid Diseases, Thyroid Function Tests, Thyroid Gland, Thyrotropin, Thyroxine, Time Factors, Baltimore, Biomarkers, Multivariate Analysis, Logistic Models, Proportional Hazards Models
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