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108. Calculated parameters of thyroid homeostasis

Author

Dietrich, Johannes Wolfgang Christian (PD Dr. med.), Landgrafe-Mende, Gabi, Wiora, Evelin, Chatzitomaris, Apostolos, Klein, Horst Harald (Prof. Dr. med.), Midgley, John Edward M. (Dr. phil.), and Hoermann, Rudolf (Prof. Dr. med.)

Subjects
endocrine system, endocrine system diseases, ddc:610
Abstract

Although technical problems of thyroid testing have largely been resolved by modern assay technology, biological variation remains a challenge. This applies to subclinical thyroid disease, non-thyroidal illness syndrome, and those 10% of hypothyroid patients, who report impaired quality of life, despite normal thyrotropin (TSH) concentrations under levothyroxine (L-T4) replacement. Among multiple explanations for this condition, inadequate treatment dosage and monotherapy with L-T4 in subjects with impaired deiodination have received major attention. Translation to clinical practice is difficult, however, since univariate reference ranges for TSH and thyroid hormones fail to deliver robust decision algorithms for therapeutic interventions in patients with more subtle thy-roid dysfunctions. Advances in mathematical and simulative modeling of pituitary–thyroid feedback control have improved our understanding of physiological mechanisms govern-ing the homeostatic behavior. From multiple cybernetic models developed since 1956, four examples have also been translated to applications in medical decision-making and clinical trials. Structure parameters representing fundamental properties of the processing structure include the calculated secretory capacity of the thyroid gland (SPINA-GT), sum activity of peripheral deiodinases (SPINA-GD) and Jostel’s TSH index for assessment of thyrotropic pituitary function, supplemented by a recently published algorithm for reconstructing the personal set point of thyroid homeostasis. In addition, a family of integrated models (University of California-Los Angeles platform) provides advanced methods for bioequivalence studies. This perspective article delivers an overview of current clinical research on the basis of mathematical thyroid models. In addition to a summary of large clinical trials, it provides previously unpublished results of validation studies based on simulation and clinical samples.

Published
2016

109. Calculated Parameters of Thyroid Homeostasis: Emerging Tools for Differential Diagnosis and Clinical Research

Author

Dietrich, Johannes W., Landgrafe-Mende, Gabi, Wiora, Evelin, Chatzitomaris, Apostolos, Klein, Harald H., Midgley, John E. M., and Hoermann, Rudolf

Subjects
thyroid hormones, feedback control, endocrine system, Endocrinology, endocrine system diseases, SPINA-GT, SPINA-GD, sum activity of peripheral deiodinases, thyroid’s secretory capacity, homeostasis, set point
Abstract

Although technical problems of thyroid testing have largely been resolved by modern assay technology, biological variation remains a challenge. This applies to subclinical thyroid disease, non-thyroidal illness syndrome, and those 10% of hypothyroid patients, who report impaired quality of life, despite normal thyrotropin (TSH) concentrations under levothyroxine (L-T4) replacement. Among multiple explanations for this condition, inadequate treatment dosage and monotherapy with L-T4 in subjects with impaired deiodination have received major attention. Translation to clinical practice is difficult, however, since univariate reference ranges for TSH and thyroid hormones fail to deliver robust decision algorithms for therapeutic interventions in patients with more subtle thyroid dysfunctions. Advances in mathematical and simulative modeling of pituitary–thyroid feedback control have improved our understanding of physiological mechanisms governing the homeostatic behavior. From multiple cybernetic models developed since 1956, four examples have also been translated to applications in medical decision-making and clinical trials. Structure parameters representing fundamental properties of the processing structure include the calculated secretory capacity of the thyroid gland (SPINA-GT), sum activity of peripheral deiodinases (SPINA-GD) and Jostel’s TSH index for assessment of thyrotropic pituitary function, supplemented by a recently published algorithm for reconstructing the personal set point of thyroid homeostasis. In addition, a family of integrated models (University of California-Los Angeles platform) provides advanced methods for bioequivalence studies. This perspective article delivers an overview of current clinical research on the basis of mathematical thyroid models. In addition to a summary of large clinical trials, it provides previously unpublished results of validation studies based on simulation and clinical samples.

Published
2016
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110. Homeostatic Control of the Thyroid–Pituitary Axis: Perspectives for Diagnosis and Treatment

Author

Hoermann, Rudolf, Midgley, John E. M., Larisch, Rolf, and Dietrich, Johannes W.

Subjects
thyroid hormones, deiodinase, endocrine system, Endocrinology, endocrine system diseases, TSH, feedback regulation, homeostasis, Review, set point
Abstract

The long-held concept of a proportional negative feedback control between the thyroid and pituitary glands requires reconsideration in the light of more recent studies. Homeostatic equilibria depend on dynamic inter-relationships between thyroid hormones and pituitary thyrotropin (TSH). They display a high degree of individuality, thyroid-state-related hierarchy, and adaptive conditionality. Molecular mechanisms involve multiple feedback loops on several levels of organization, different time scales, and varying conditions of their optimum operation, including a proposed feedforward motif. This supports the concept of a dampened response and multistep regulation, making the interactions between TSH, FT4, and FT3 situational and mathematically more complex. As a homeostatically integrated parameter, TSH becomes neither normatively fixed nor a precise marker of euthyroidism. This is exemplified by the therapeutic situation with l-thyroxine (l-T4) where TSH levels defined for optimum health may not apply equivalently during treatment. In particular, an FT3–FT4 dissociation, discernible FT3–TSH disjoint, and conversion inefficiency have been recognized in l-T4-treated athyreotic patients. In addition to regulating T4 production, TSH appears to play an essential role in maintaining T3 homeostasis by directly controlling deiodinase activity. While still allowing for tissue-specific variation, this questions the currently assumed independence of the local T3 supply. Rather it integrates peripheral and central elements into an overarching control system. On l-T4 treatment, altered equilibria have been shown to give rise to lower circulating FT3 concentrations in the presence of normal serum TSH. While data on T3 in tissues are largely lacking in humans, rodent models suggest that the disequilibria may reflect widespread T3 deficiencies at the tissue level in various organs. As a consequence, the use of TSH, valuable though it is in many situations, should be scaled back to a supporting role that is more representative of its conditional interplay with peripheral thyroid hormones. This reopens the debate on the measurement of free thyroid hormones and encourages the identification of suitable biomarkers. Homeostatic principles conjoin all thyroid parameters into an adaptive context, demanding a more flexible interpretation in the accurate diagnosis and treatment of thyroid dysfunction.

Published
2015

131. Mathematical Modeling of the Pituitary--Thyroid Feedback Loop: Role of a TSH-T3-Shunt and Sensitivity Analysis.

Author

Berberich, Julian, Dietrich, Johannes W., Hoermann, Rudolf, and Müller, Matthias A.

Subjects
THYROTROPIN, THYROID hormones, SENSITIVITY analysis
Abstract

Despite significant progress in assay technology, diagnosis of functional thyroid disorders may still be a challenge, as illustrated by the vague upper limit of the reference range for serum thyrotropin (TSH). Diagnostical problems also apply to subjects affected by syndrome T, i.e., those 10% of hypothyroid patients who continue to suffer from poor quality of life despite normal TSH concentrations under substitution therapy with levothyroxine (L-T4). In this paper, we extend a mathematical model of the pituitary--thyroid feedback loop in order to improve the understanding of thyroid hormone homeostasis. In particular, we incorporate a TSH-T3-shunt inside the thyroid, whose existence has recently been demonstrated in several clinical studies. The resulting extended model shows good accordance with various clinical observations, such as a circadian rhythm in free peripheral triiodothyronine (FT3). Furthermore, we perform a sensitivity analysis of the derived model, revealing the dependence of TSH and hormone concentrations on different system parameters. The results have implications for clinical interpretation of thyroid tests, e.g., in the differential diagnosis of subclinical hypothyroidism. [ABSTRACT FROM AUTHOR]

Published
2018
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132. Selective Loss of Levator Ani and Leg Muscle Volumes in Men Undergoing Androgen Deprivation Therapy.

Author

Cheung, Ada S, Cunningham, Christopher, Ko, Dong-Kyoon Daniel, Ly, Vivian, Gray, Hans, Hoermann, Rudolf, Strauss, Boyd J G, Bani Hassan, Ebrahim, Duque, Gustavo, Ebeling, Peter, Pandy, Marcus G, Zajac, Jeffrey D, and Grossmann, Mathis

Abstract

Androgen deprivation therapy (ADT) for prostate cancer (PCa) leads to a selective loss of leg muscle function during walking. Rodent models of ADT have demonstrated that the levator ani is exquisitely androgen sensitive.

Published
2019
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139. Measuring thyroid peroxidase antibodies on the day nulliparous women present for management of miscarriage: a descriptive cohort study

Author

Grossmann, Mathis, primary, Hoermann, Rudolf, additional, Francis, Claire, additional, Hamilton, Emma J, additional, Tint, Aye, additional, Kaitu’u-Lino, Tu’uhevaha, additional, Kuswanto, Kent, additional, Lappas, Martha, additional, Sikaris, Ken, additional, Zajac, Jeffery D, additional, Permezel, Michael, additional, and Tong, Stephen, additional

Published
2013
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143. The role of supporting and disruptive mechanisms of FT3 homeostasis in regulating the hypothalamic–pituitary–thyroid axis

Author

Hoermann, Rudolf, Pekker, Mark J., Midgley, John E. M., and Dietrich, Johannes W.

Abstract

Background: Thyroid hormones are controlled by the hypothalamic–pituitary–thyroid (HPT) axis through a complex network of regulatory loops, involving the hormones TRH, TSH, FT4, and FT3. The relationship between TSH and FT4 is widely used for diagnosing thyroid diseases. However, mechanisms of FT3 homeostasis are not well understood.Objective: We used mathematical modelling to further examine mechanisms that exist in the HPT axis regulation for protecting circulating FT3 levels.Methods: A mathematical model consisting of a system of four coupled first-order parameterized non-linear ordinary differential equations (ODEs) was developed, accounting for the interdependencies between the hormones in the HPT axis regulation. While TRH and TSH feed forward to the pituitary and thyroid, respectively, FT4 and FT3 feed backward to both the pituitary and hypothalamus. Stable equilibrium solutions of the ODE system express homeostasis for a particular variable, such as FT3, if this variable stays in a narrow range while certain other parameter(s) and system variable(s) may vary substantially.Results: The model predicts that (1) TSH-feedforward protects FT3 levels if the FT4 production rate declines and (2) combined negative feedback by FT4 and FT3 on both TSH and TRH production rates keeps FT3 levels insensitive to moderate changes in FT4 production rates and FT4 levels. The optimum FT4 and FT3 feedback and TRH and TSH-feedforward ranges that preserve FT3 homeostasis were found by numerical continuation analysis. Model predictions were in close agreement with clinical studies and individual patient examples of hypothyroidism and hyperthyroidism.Conclusions: These findings further extend the concept of HPT axis regulation beyond TSH and FT4 to integrate the more active sister hormone FT3 and mechanisms of FT3 homeostasis. Disruption of homeostatic mechanisms leads to disease. This provides a perspective for novel testable concepts in clinical studies to therapeutically target the disruptive mechanisms.

Published
2023
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146. Relapse of Graves' Disease After Successful Outcome of Antithyroid Drug Therapy: Results of a Prospective Randomized Study on the Use of Levothyroxine

Author

Hoermann, Rudolf, primary, Quadbeck, Beate, additional, Roggenbuck, Ulla, additional, Szabolcs, István, additional, Pfeilschifter, Johannes, additional, Meng, Wieland, additional, Reschke, Kirsten, additional, Hackenberg, Klaus, additional, Dettmann, Juergen, additional, Prehn, Brigitte, additional, Hirche, Herbert, additional, and Mann, Klaus, additional

Published
2002
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149. Letter to the Editor: Hoermann Response to Fitzgerald et al. (DOI: 10.1089/thy.2019.0535).

Author

Hoermann, Rudolf, Midgley, John E.M., Larisch, Rolf, and Dietrich, Johannes W.

Subjects
*THYROID hormone regulation, *THYROID gland, *THYROID hormones, *MEDICAL sciences
Abstract

B Dear Editor: b A recent debate has evaluated the primary test schema for assessing thyroid function, direct measurement of thyroid hormones, or the pituitary hormone thyrotropin (TSH). In normal physiology, TSH expression is interlocked with thyroid hormones, acting as a driver for attaining euthyroid circulating fT4 concentration. This was shown in experimental animals treated with various thyroid hormone combinations wherein tissue hypothyroidism persisted on levothyroxine monotherapy despite TSH normalization. [Extracted from the article]

Published
2020
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