Unstable Thyroid Function in Older Adults Is Caused by Alterations in Both Thyroid and Pituitary Physiology and Is Associated with Increased Mortality

Abstract

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.

Keywords: aging; longitudinal study; thyroid function.

FIG. 1.

Change in thyroid function over time for healthy aging individuals. Slopes representing the change in TSH (A) free T4 (B) and free T3 (C) are derived by linear regression for each individual in the phenotyping cohort. All values were normalized to the current assay (see methods). The distribution of these slopes is graphed according to initial age category. Boxes represent median and 25th and 75th percentiles; whiskers represent the 5th and 95th percentiles; dots are individual outliers. TSH, thyrotropin.

FIG. 2.

Individual examples of thyroid aging phenotypes. The patterns of change in thyroid function over time at various ages can be classified into groups, depending on the movement of TSH and the correlating movement of fT4. In (A) and (B), the change in TSH is opposite to that in fT4, consistent with changes in primary thyroid gland function, while in (C) and (D), the changes occur in parallel, suggesting a central origin from pituitary changes.

FIG. 3.

Relationship between changing thyroid axis hormones. The change in TSH versus the change in fT4 is graphed for all participants in the phenotyping cohort (n = 640). The change phenotypes were defined based on top and bottom quintiles for both slopes, in four combinations, and are denoted by gray circles.