Response To Hennessey Re: "Clinical Parameters Are More Likely To Be Associated With Thyroid Hormone Levels Than With Thyrotropin Levels: A Systematic Review And Meta-Analysis"

Background: Though the functional states of other endocrine systems are not defined on the basis of levels of controlling hormones, the assessment of thyroid function is based on levels of the controlling hormone thyrotropin (TSH). We, therefore, addressed the question as to whether levels of thyroid hormones [free thyroxine (fT4), total triiodothyronine (TT3)/free triiodothyronine (fT3)], or TSH levels, within and beyond the reference ranges, provide the better guide to the range of clinical parameters associated with thyroid status. Methods: A PubMed/MEDLINE search of studies up to October 2019, examining associations of levels of thyroid hormones and TSH, taken simultaneously in the same individuals, with clinical parameters was performed. We analyzed atrial fibrillation, other cardiac parameters, osteoporosis and fracture, cancer, dementia, frailty, mortality, features of the metabolic syndrome, and pregnancy outcomes. Studies were assessed for quality by using a modified Newcastle-Ottawa score. Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines were followed. A meta-analysis of the associations was performed to determine the relative likelihood of fT4, TT3/fT3, and TSH levels that are associated with the clinical parameters. Results: We identified 58 suitable articles and a total of 1880 associations. In general, clinical parameters were associated with thyroid hormone levels significantly more often than with TSH levels-the converse was not true for any of the clinical parameters. In the 1880 considered associations, fT4 levels were significantly associated with clinical parameters in 50% of analyses. The respective frequencies for TT3/fT3 and TSH levels were 53% and 23% (p < 0.0001 for both fT4 and TT3/fT3 vs. TSH). The fT4 and TT3/fT3 levels were comparably associated with clinical parameters (p = 0.71). More sophisticated statistical analyses, however, indicated that the associations with TT3/fT3 were not as robust as the associations with fT4. Conclusions: Thyroid hormones levels, and in particular fT4 levels, seem to have stronger associations with clinical parameters than do TSH levels. Associations of clinical parameters with TSH levels can be explained by the strong negative population correlation between thyroid hormones and TSH. Clinical and research components of thyroidology currently based on the measurement of the thyroid state by reference to TSH levels warrant reconsideration.