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      The Relationship between Population T4/TSH Set Point Data and T4/TSH Physiology

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          Abstract

          Context. Population studies of the distribution of T4/TSH set points suggest a more complex inverse relationship between T4 and TSH than that suggested by physiological studies. The reasons for the similarities and differences between the curves describing these relationships are unresolved. Methods. We subjected the curve, derived from empiric data, describing the TSH suppression response to T4, and the more mathematically derived curve describing the T4 response to TSH, to the different possible models of population variation. The implied consequences of these in terms of generating a population distribution of T4/TSH equilibrium points (a “population curve”) were generated and compared to the empiric population curve. The physiological responses to primary hypothyroidism and hyperthyroidism were incorporated into the analysis. Conclusions. Though the population curve shows a similarly inverse relationship, it is describing a different relationship than the curve describing the suppression of TSH by T4. The population curve is consistent with the physiological studies of the TSH response to T4 and implies a greater interindividual variation in the positive thyroid T4 response to TSH than in the central inhibitory TSH response to T4. The population curve in the dysthyroid states is consistent with known physiological responses to these states.

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          Most cited references34

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          The relationship between TSH and free T₄ in a large population is complex and nonlinear and differs by age and sex.

          The relationship between TSH and T₄ is thought to be inverse log-linear, but recent studies have challenged this. There are limited data regarding age and sex differences in the TSH-T₄ relationship. The purpose of this study was to evaluate the TSH-free T₄ relationship in a large sample. In a cross-sectional, retrospective study, we analyzed TSH and free T₄ results from 152 261 subjects collected over 12 years by a single laboratory. For each free T₄ value (in picomoles per liter), the median TSH was calculated and analyzed by sex and age (in 20-year bands). The relationship between log TSH and free T₄ was nonlinear. Mathematical modeling confirmed that it was described by 2 sigmoid curves with inflexion points at free T₄ concentrations of 7 and 21 pmol/L. For free T₄ within the reference range (10-20 pmol/L), median TSH was higher in men than in women (P < .001) and increased across age bands with the highest values in those 80 years and older (P < .001). In contrast, in overt hypothyroidism (n = 4403), TSH was lower in older age groups than in those aged 20-39 years (P < .001). The TSH-free T₄ relationship is not inverse log-linear but can be described by 2 overlapping negative sigmoid curves. At physiological free T₄ concentrations, TSH is higher in men and in older people, whereas the TSH response to hypothyroidism is more robust in younger people. These results advance understanding of the TSH-free T₄ relationship, which is central to thyroid pathophysiology and laboratory diagnosis of thyroid disease.
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            Replacement dose, metabolism, and bioavailability of levothyroxine in the treatment of hypothyroidism. Role of triiodothyronine in pituitary feedback in humans.

            A change in the formulation of the levothyroxine preparation Synthroid (Flint) in 1982 prompted us to reevaluate the replacement dose of this drug in 19 patients with hypothyroidism. The dose was titrated monthly until thyrotropin levels became normal. The mean replacement dose (+/- SD) was 112 +/- 19 micrograms per day, significantly less (P less than 0.001) than the dose of an earlier formulation--169 +/- 66 micrograms per day--used in a similar study (Stock JM, et al. N Engl J Med 1974; 290:529-33). The fractional gastrointestinal absorption of a tablet of the current formulation is 81 percent, considerably higher than the earlier estimate of 48 percent. Using high-performance liquid chromatographic analysis, we found that the current tablet contains the amount of thyroxine stated by the manufacturer. By measuring the bioavailability of the earlier type of tablet in five patients, we inferred that the strength of the previous tablet had been overestimated. In the present study, the thyrotropin levels of patients on replacement therapy returned to normal when serum triiodothyronine concentrations were not significantly different from those of controls (122 vs. 115 ng per deciliter [1.87 vs. 1.77 nmol per liter]), but when serum thyroxine levels were significantly above those of controls (11.3 vs. 8.7 micrograms per deciliter [145 vs. 112 nmol per liter], P less than 0.001). These findings suggest the possibility that in humans, serum triiodothyronine may play a more important part than serum thyroxine in regulating the serum thyrotropin concentration.
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              Circadian and Circannual Rhythms in Thyroid Hormones: Determining the TSH and Free T4 Reference Intervals Based Upon Time of Day, Age, and Sex.

              Establishing the reference interval for thyrotropin (TSH) and free thyroxine (T4) is clinically important because a number of disease states have been linked to alterations in TSH and free T4 concentrations that are within the 95% confidence interval for normal thyroid hormone values. Age, sex, time of day, and ethnicity are known to affect circulating levels of TSH and free T4 but have not been used to establish reference intervals. The purpose of this study was to define the reference interval for TSH and free T4 taking into account age, sex, ethnicity, and circadian and circannual variability.
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                Author and article information

                Journal
                J Thyroid Res
                J Thyroid Res
                JTR
                Journal of Thyroid Research
                Hindawi Publishing Corporation
                2090-8067
                2042-0072
                2016
                31 March 2016
                : 2016
                : 6351473
                Affiliations
                1Department of Internal Medicine and Department of Endocrinology, The Royal Adelaide Hospital, Adelaide, SA 5000, Australia
                2School of Medicine, The University of Adelaide, Adelaide, SA 5005, Australia
                3School of Mathematical Sciences, The University of Adelaide, Adelaide, SA 5005, Australia
                4ARC Centre of Excellence for Mathematical and Statistical Frontiers, The University of Adelaide, Adelaide, SA 5005, Australia
                Author notes
                *Stephen Paul Fitzgerald: stephen.fitzgerald2@ 123456sa.gov.au

                Academic Editor: Massimo Tonacchera

                Article
                10.1155/2016/6351473
                4830732
                27123359
                58df202a-b67b-4d03-af02-07b5f764be7b
                Copyright © 2016 S. P. Fitzgerald and N. G. Bean.

                This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 29 December 2015
                : 29 February 2016
                Categories
                Research Article

                Endocrinology & Diabetes
                Endocrinology & Diabetes

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