Thyroid stimulating hormone (TSH) autoregulation reduces variation in the TSH response to thyroid hormones

Fitzgerald, Stephen P.; Bean, Nigel

doi:10.1080/23328940.2018.1513110

Cited by 12 publications

(8 citation statements)

References 29 publications

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“…Some individual pathologies, for example, frailty, mortality, and dementia may increase with deviations either side of the middle of the range. It seems likely that evolutionary mechanisms have arisen to minimize variation from the middle of the reference range of thyroid hormones ( 127 ).…”

Section: Discussionmentioning

confidence: 99%

Clinical Parameters Are More Likely to Be Associated with Thyroid Hormone Levels than with Thyrotropin Levels: A Systematic Review and Meta-Analysis

Fitzgerald

Bean

Falhammar

et al. 2020

Thyroid

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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.

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Section: Discussionmentioning

confidence: 99%

Clinical Parameters Are More Likely to Be Associated with Thyroid Hormone Levels than with Thyrotropin Levels: A Systematic Review and Meta-Analysis

Fitzgerald

Bean

Falhammar

et al. 2020

Thyroid

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“…The pattern of population correlations suggests in fact that there is a general pattern in physiological regulation, by which the population variation in the controlling hormone physiology (e.g., erythropoietin response to hemoglobin), is less than the population variation in the parameter physiology (e.g., hemoglobin response to erythropoietin) (Fitzgerald and Bean ). In the circumstance of a given variation in parameter physiology, such an arrangement leads to a minimisation in intra‐, and inter‐individual variation in parameter levels (Fitzgerald and Bean 2018b). Such an outcome is particularly advantageous with the parameter, hemoglobin.…”

Section: Discussionmentioning

confidence: 99%

Population data provide evidence against the presence of a set point for hemoglobin levels or tissue oxygen delivery

et al. 2019

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Hemoglobin levels are believed to be regulated as per a set point model of regulation. This model of regulation, by which specific levels of a parameter are targeted and defended by physiological systems, implies a particular population correlation between the parameter and its controlling hormone. Empirical population correlations of other parameters and their controlling hormones, have denied the presence of such set point‐based regulation. To assess if hemoglobin is regulated according to a set point model we performed a systematic search of PubMed/ MEDLINE and Web of Science identifying relevant reports published up to November 2018. Population hemoglobin/erythropoietin level correlations were retrieved, and these empirically derived correlations were compared with the positive correlation implied by a set point model of regulation. Authors of papers containing potentially suitable data were contacted with requests for further analyses, and a meta‐analysis was performed. Twelve correlations between hemoglobin and erythropoietin levels from eleven papers were analyzed. None of these correlations were significantly positive, three, restricted to the normal range of hemoglobin, were significantly negative. All but one of the other correlations showed a negative trend. New analyses of previously published data sets resulted in similar findings. In particular a new analysis of large data sets of males ( n = 2417) and females ( n = 2592) with normal range hemoglobin levels, revealed significantly negative correlations. A meta‐analysis of our results indicated that the data overall are not consistent with a positive relationship between hemoglobin and erythropoietin ( P < 0.0001). Population data indicate that individuals do not have set point levels of hemoglobin.

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“…On the other hand, physiological processes such as TSH autoregulation ( 47 ), and FT4/TSH feedback regulation ( 48 ) act to minimise inter-individual and intra-individual variation in TFTs, such that these levels cluster around the middle of the population range ( 49 ). This would suggest that there are evolutionary advantages to such levels.…”

Section: Euthyroidismmentioning

confidence: 99%

Redefinition of Successful Treatment of Patients With Hypothyroidism. Is TSH the Best Biomarker of Euthyroidism?

Fitzgerald

Falhammar

2022

Front. Endocrinol.

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In recent years evidence has accumulated supporting a revised view of the nature of euthyroidism and the biomarkers of thyroid function. Within the normal range, variations in thyroid hormone levels are associated with variations in clinical parameters and outcomes. There are therefore no readily identified individually specific optimum levels of thyroid hormones for any individual. Levels around the middle of the normal population range may best reflect euthyroidism. These levels may have evolutionary advantages on the basis that adverse outcomes often increase with divergence from such levels, and physiological processes tend to minimise such inter-individual and intra-individual divergence. In populations of predominantly untreated individuals, levels of thyroid hormones and in particular levels of free thyroxine (FT4) correlate more often with clinical parameters than do levels of thyrotropin (TSH). Levels of thyroid hormones may therefore be regarded as the best available biomarkers of euthyroidism and dysthyroidism. It follows that ‘subclinical hypothyroidism’ (normal FT4/raised TSH levels), rather than being an accurate marker of peripheral tissue hypothyroidism is more a marker of decreased thyroid reserve and prognosis. The recent evidence suggests that treatment of hypothyroxinemia, regardless of the TSH level, and monitoring therapy using FT4 and/or triiodothyronine levels, depending on the replacement regime, may result in more successful treatment of hypothyroidism than relying on thyrotropin levels for patient selection and subsequent treatment monitoring. The equivalents of mid-range levels of thyroid hormones (especially FT4), adjusted by individual comorbidity concerns, may be rational general replacement targets. These implications of the new evidence may create opportunities for novel trials of thyroid replacement therapy.

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Thyroid stimulating hormone (TSH) autoregulation reduces variation in the TSH response to thyroid hormones

Cited by 12 publications

References 29 publications

Clinical Parameters Are More Likely to Be Associated with Thyroid Hormone Levels than with Thyrotropin Levels: A Systematic Review and Meta-Analysis

Clinical Parameters Are More Likely to Be Associated with Thyroid Hormone Levels than with Thyrotropin Levels: A Systematic Review and Meta-Analysis

Population data provide evidence against the presence of a set point for hemoglobin levels or tissue oxygen delivery

Redefinition of Successful Treatment of Patients With Hypothyroidism. Is TSH the Best Biomarker of Euthyroidism?

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