Familial Longevity is Associated with an Attenuated Thyroidal Response to Recombinant Human Thyroid Stimulating Hormone

Abstract

Context Longevity is associated with higher circulating levels of TSH in the absence of differences in circulating thyroid hormones (TH), as previously observed in F2 members of long-lived families (F2-LLS) and their partners (F2-Con). The mechanism underlying this observed difference remains unknown. Objective We hypothesized that the thyroid gland of members from long-lived families are less responsive to TSH stimulation, thereby requiring higher circulating TSH levels to maintain adequate TH levels. Methods We performed a case-control intervention study with a single intramuscular (gluteal) injection with 0.1 mg recombinant human TSH in a subgroup of 14 F2-LLS and 15 similarly aged F2-Con. They were followed for 4 days. No serious adverse events were reported. For analyses, we compared time trajectories of TSH and TH, and the ratio of TH to TSH using area under the curve (AUC) calculations. Results The AUC free T4/AUC TSH ratio was significantly lower in F2-LLS than in F2-Con (estimated mean [95% confidence interval] 1.6 [1.2-1.9] and 2.2 [1.9-2.6], respectively, P = 0.01). The AUC thyroglobulin/AUC TSH ratio was also lower in F2-LLS than in F2-Con (median [interquartile range] 2.1 [1.4-3.6] and 3.2 [2.7-7.4], respectively, P = 0.04). We observed the same trend with the AUC free T3/AUC TSH ratio, although the difference was not statistically significant (estimated mean [95% confidence interval] 0.6 [0.4-0.7] and 0.7 [0.6-0.8], respectively, P = 0.07). Conclusions The present findings show that members of long-living families have a lower thyroid responsivity to TSH compared with their partners.

Changes in Serum Thyroid Function Predict Cognitive Decline in the Very Old: Longitudinal Findings from the Newcastle 85+ Study

“…However, aging is also associated with pathophysiological changes in the central hypothalamo-pituitary-thyroid axis (28,29). A blunted pituitary response to thyrotropin releasing hormone (TRH) and a lesser degree of TSH elevation in response to hypothyroidism have been observed in older individuals, with or without dementia (30)(31)(32). Older people with hypothyroidism also require less levothyroxine replacement to maintain the same TSH (33).…”

Circulating Thyroid Hormone Profile in Response to a Triiodothyronine Challenge in Familial Longevity

“…Altogether, several findings provide clues regarding the mechanisms that might underlie the differences in thyroid axis (higher TSH levels in the absence of differences in thyroid hormones) between members of long-lived families and controls. We recently performed a challenge study with recombinant human TSH in a subpopulation of the LLS, showing that members of long-lived families have a lower thyroidal responsivity to TSH stimulation than similarly aged controls [ 4 ]. In this study, the findings point to similar T3 turnover and similar negative T3 feedback control of TSH secretion in offspring and controls.…”

“…This study is 1 of 2 studies we performed in parallel to further understand the mechanisms behind higher TSH in offspring than controls in the presence of similar thyroid hormone levels. We have recently shown that offspring have lower thyroidal response to TSH by performing a challenge study with recombinant human TSH [ 4 ]. We hypothesized that offspring might also have higher turnover of thyroid hormones and/or less negative feedback on TSH.…”

Determining the frequency of thyroid parameter measurements following rhTSH administration in a healthy, older population

“…Study participants were recruited from LLS [12] , underwent a medical screening and were excluded based on criteria outlined in detail elsewhere [13] . All participants gave written informed consent and the study was performed in accordance with the declaration of Helsinki.…”

“…For each participant, samples from the different time points were measured in the same batch. Assays and assay performance are reported in detail elsewhere [13] . In short, all measurements were performed with fully automated, software monitored equipment and diagnostics from Roche Diagnostics (Almere, The Netherlands) at the Department of Clinical Chemistry and Laboratory Medicine at Leiden University Medical Centre, The Netherlands.…”