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NOMOTHETICOS: Nonlinear Modelling of Thyroid Hormones' Effect on Thyrotropin Incretion in Confirmed Open-loop Situation

Information source: Ruhr University of Bochum
ClinicalTrials.gov processed this data on August 23, 2015
Link to the current ClinicalTrials.gov record.

Condition(s) targeted: Hypothyroidism; Hyperthyroidism

Phase: N/A

Status: Enrolling by invitation

Sponsored by: Ruhr University of Bochum

Official(s) and/or principal investigator(s):
Johannes W Dietrich, M.D., Principal Investigator, Affiliation: Medical Hospital I, Bergmannsheil University Hospitals, Ruhr University of Bochum
Harald H Klein, M.D., Study Chair, Affiliation: Medical Hospital I, Bergmannsheil University Hospitals, Ruhr University of Bochum
Johannes W Dietrich, M.D., Study Director, Affiliation: Medical Hospital I, Bergmannsheil University Hospitals, Ruhr University of Bochum

Summary

The NOMOTHETICOS study is a unicentric cross-sectional study for a quantitative analysis of feedback-inhibition in the thyrotropic homeostatic control. Structural parameters are obtained in vivo from open-loop analysis in patients with disconnected feedback, i. e. with overt thyroid dysfunction or full dose substitution therapy with levothyroxine.

Clinical Details

Official title: NOMOTHETICOS: Nonlinear Modelling of Thyroid Hormones' Effect on Thyrotropin Incretion in Confirmed Open-loop Situation. A Correlation Study

Study design: Observational Model: Cohort, Time Perspective: Cross-Sectional

Primary outcome: Nonlinear correlation of thyrotropin levels with peripheral levothyroxine levels.

Secondary outcome: Parameters of feedback inhibition.

Detailed description: Control of thyroid hormone homeostasis is essential for function and development of the organism and hence for individual health. It is therefore not surprising that the thyroid's function is controlled by a complex, multi-loop feedback control system. Today, the central component of the thyrotropic feedback control system is still poorly understood on a physiological level. Therefore, in mathematical models different functional relations describing the feedback-inhibition of thyrotropin incretion by thyroid hormones have been suggested [Danziger and Elmergreen 1956, Roston 1959, Norwich and Reiter 1965, DiStefano and Stear 1968, DiStefano 1969, Saratchandran et al. 1973, Li et al. 1995, Dietrich et al. 2004, Degon et al. 2008, Jonklaas and Soldin 2008, Hörmann et al. 2010]. Most of these models fail in delivering biochemical explanations for the functional interrelations they postulate. Nevertheless, some clinical applications of these models have been developed, although their diagnostical potential is usually rather limited [Yagi et al. 1997, Pohlenz et al. 1999, Jostel et al. 2009]. Assuming that the pituitary's response to peripheral thyroid hormones is determined by active transmembrane thyroxine transport mechanisms [Dietrich et al. 2008], intracellular deiodination of thyroxine (T4), binding of resulting triiodothyronine (T3) to iodothyronine receptors and, finally, their inhibiting effect on mRNA expression, translation and release of TRH, a novel, physiologically motivated model has been developed that is based on compartment-analytical approaches, Michaelis-Menten kinetics and non competitive divisive inhibition [Dietrich et al 2004]. However, this model has not been sufficiently evaluated in a clinical context. It is the aim of the NOMOTHETICOS study to deliver new systems-level insights into the pituitary's thyrotropic function. This unicentric cross-sectional study compares different models of feedback-inhibition by means of modern statistical methods like nonlinear regression and Akaike information criterion. Structural parameters are obtained in vivo from open-loop analysis in patients with disconnected feedback in equilibrium. These parameters can serve as theoretical basis for possible future trials developing advanced diagnostical evaluation methods of thyrotropic pituitary function.

Eligibility

Minimum age: 14 Years. Maximum age: N/A. Gender(s): Both.

Criteria:

Inclusion Criteria:

- Outpatients with disconnected feedback control due to the following conditions:

- Overt primary hypothyroidism with TSH level over 10 mU/l and FT4 level below 0. 5

ng/l (Partition 1)

- Overt primary hyperthyroidism with TSH level below 0. 1 mU/l and FT4 level over

25 ng/l (Partition 3)

- All other constellations, if the patient receives substitution therapy with more

1. 75 µg Levothyroxin per kg of body mass (Partition 2).

- System in equilibrium (e. g. unchanged substitution dose over the past six weeks)

Exclusion Criteria:

- Pituitary or hypothalamic dysfunction

- Severe illness that may be associated with euthyroid sick syndrome (non-thyroidal

illness syndrome)

- Medication influencing pituitary function

- Pregnancy

- Missing consent for participation in the study

Locations and Contacts

Klinikum Ludwigsburg-Bietigheim, Bietigheim, BW D-74321, Germany

Department for visceral surgery, Bergmannsheil University Hospitals, Ruhr University of Bochum, Bochum, NRW D-44789, Germany

Institute for diagnostical radiology, interventional radiology and nuclear medicine, Bergmannsheil University Hospitals, Ruhr University of Bochum, Bochum, NRW D-44789, Germany

Medical Hospital I, Bergmannsheil University Hospitals, Ruhr University of Bochum, Bochum, NRW D-44789, Germany

Additional Information

Related publications:

Norwich KH, Reiter R. Homeostatic control of thyroxin concentration expressed by a set of linear differential equations. Bull Math Biophys. 1965 Jun;27(2):133-44.

DiStefano JJ 3rd, Stear EB. Neuroendocrine control of thyroid secretion in living systems: a feedback control system model. Bull Math Biophys. 1968 Mar;30(1):3-26.

DiStefano JJ 3rd. A model of the normal thyroid hormone glandular secretion mechanism. J Theor Biol. 1969 Mar;22(3):412-7.

Saratchandran P, Carson ER, Reeve J. An improved mathematical model of human thyroid hormone regulation. Clin Endocrinol (Oxf). 1976 Sep;5(5):473-83.

Li G, Liu B, Liu Y. A dynamical model of the pulsatile secretion of the hypothalamo-pituitary-thyroid axis. Biosystems. 1995;35(1):83-92.

Degon M, Chipkin SR, Hollot CV, Zoeller RT, Chait Y. A computational model of the human thyroid. Math Biosci. 2008 Mar;212(1):22-53. doi: 10.1016/j.mbs.2007.10.009. Epub 2007 Nov 6.

Dietrich JW, Brisseau K, Boehm BO. [Absorption, transport and bio-availability of iodothyronines]. Dtsch Med Wochenschr. 2008 Aug;133(31-32):1644-8. doi: 10.1055/s-0028-1082780. Review. German.

Yagi H, Pohlenz J, Hayashi Y, Sakurai A, Refetoff S. Resistance to thyroid hormone caused by two mutant thyroid hormone receptors beta, R243Q and R243W, with marked impairment of function that cannot be explained by altered in vitro 3,5,3'-triiodothyroinine binding affinity. J Clin Endocrinol Metab. 1997 May;82(5):1608-14.

Pohlenz J, Weiss RE, Macchia PE, Pannain S, Lau IT, Ho H, Refetoff S. Five new families with resistance to thyroid hormone not caused by mutations in the thyroid hormone receptor beta gene. J Clin Endocrinol Metab. 1999 Nov;84(11):3919-28.

Jostel A, Ryder WD, Shalet SM. The use of thyroid function tests in the diagnosis of hypopituitarism: definition and evaluation of the TSH Index. Clin Endocrinol (Oxf). 2009 Oct;71(4):529-34. doi: 10.1111/j.1365-2265.2009.03534.x. Epub 2009 Feb 18.

Jonklaas J, Soldin SJ. Tandem mass spectrometry as a novel tool for elucidating pituitary-thyroid relationships. Thyroid. 2008 Dec;18(12):1303-11. doi: 10.1089/thy.2008.0155.

Danziger L, Elmergreen GL. The Thyroid-Pituitary Homeostatic Mechanism. Bulletin of Mathematical Biophysics 18 : 1-13, 1956.

Roston S: Mathematical Represention of Some Endocrinological Systems. Bulletin of Mathematical Biophysics, 21:271-282, 1959.

Dietrich JW,Tesche A, Pickardt, CR, Mitzdorf U. Thyrotropic Feedback Control: Evidence for an Additional Ultrashort Feedback Loop from Fractal Analysis. Cybernetics and Systems 35 (4): 315-31, 2004.

Hoermann R, Eckl W, Hoermann C, Larisch R. Complex relationship between free thyroxine and TSH in the regulation of thyroid function. Eur J Endocrinol. 2010 Jun;162(6):1123-9. doi: 10.1530/EJE-10-0106. Epub 2010 Mar 18.

Dietrich JW, Landgrafe G, Fotiadou EH. TSH and Thyrotropic Agonists: Key Actors in Thyroid Homeostasis. J Thyroid Res. 2012;2012:351864. doi: 10.1155/2012/351864. Epub 2012 Dec 30.

Starting date: June 2010
Last updated: February 12, 2015

Page last updated: August 23, 2015

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