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

NCT01145040 | Unknown DMC

• 4 other identifiers: TFC-UK103718-10U1111-1122-3273DRKS00003153
• Study Type: observational
• Target: 138
• Locations: 1 country
• Sites: 3

Brief 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.

Conditions

Hypothyroidism; Hyperthyroidism

Keywords

Overt primary hypothyroidism; Overt primary hyperthyroidism; Thyrotropic feedback control; Mathematical modelling; Nonlinear modelling; Thyroid; Pituitary; Physiological cybernetics; Full-dose levothyroxine substitution therapy; Syndrome T

Outcome Measures

Primary Outcomes (1)

• Nonlinear correlation of thyrotropin levels with peripheral levothyroxine levels.

  Nonlinear modeling of the pituitary response with different models (logarithmic, polynomial, non-competitive divisive inhibition). Selection of one out of different possible mathematical models that suffices an optimal combination of * best nonlinear fit (minimal p-value), * minimal entropy (as expressed by minimal values for Akaike information criterion, Bayesian information criterion and Hannan-Quinn information criterion) and * best compatibility with biochemical mechanisms.

  Data of individual patients are obtained one work day after consultation (to allow for laboratory investigations). Model comparison will take place immediately after the inclusion of the 100th patient.

Secondary Outcomes (1)

• Parameters of feedback inhibition.

  Data of individual patients are obtained one work day after consultation (to allow for laboratory investigations). Parameter estimation will take place immediately after the inclusion of the 100th patient.

Study Arms (3)

Partition 1

Overt primary hypothyroidism

Partition 2

Hypothyroidism with "full dose" levothyroxine substitution therapy (more than 1.75 µg per kg of body mass)

Partition 3

Overt primary hyperthyroidism

Eligibility Criteria

• Age: 14 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)
• Sampling Method: Probability Sample

Study Population

Outpatients with "open-loop" thyrotropic feedback control (disconnection at the site of the thyroid)

You may qualify if:

• Outpatients with disconnected feedback control due to the following conditions:
• Overt primary hypothyroidism with TSH level higher than 10 mU/l and FT4 concentration below 7 pmol/L (5.4 ng/L) (Partition 1)
• Overt primary hyperthyroidism with TSH level below 0.1 mU/l and FT4 concentration higher than 18 pmol/L (14 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)

You may not qualify if:

• 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

Sponsors & Collaborators

• Ruhr University of Bochum: lead

Study Sites (3)

Klinikum Ludwigsburg-Bietigheim

Bietigheim, Baden-Wurttemberg, D-74321, Germany

Location

Institute for diagnostical radiology, interventional radiology and nuclear medicine, Bergmannsheil University Hospitals, Ruhr University of Bochum

Bochum, North Rhine-Westphalia, D-44789, Germany

Location

Medical Hospital I, Bergmannsheil University Hospitals, Ruhr University of Bochum

Bochum, North Rhine-Westphalia, D-44789, Germany

Location

Related Publications (20)

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  PMID: 5832691 BACKGROUND

• 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. doi: 10.1007/BF02476936. No abstract available.

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• DiStefano JJ 3rd. A model of the normal thyroid hormone glandular secretion mechanism. J Theor Biol. 1969 Mar;22(3):412-7. doi: 10.1016/0022-5193(69)90013-7. No abstract available.

  PMID: 5803330 BACKGROUND

• Saratchandran P, Carson ER, Reeve J. An improved mathematical model of human thyroid hormone regulation. Clin Endocrinol (Oxf). 1976 Sep;5(5):473-83. doi: 10.1111/j.1365-2265.1976.tb01976.x.

  PMID: 825330 BACKGROUND

• 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. doi: 10.1016/0303-2647(94)01484-o.

  PMID: 7772725 BACKGROUND

• 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.

  PMID: 18291425 BACKGROUND

• 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. German.

  PMID: 18651367 BACKGROUND

• 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. doi: 10.1210/jcem.82.5.3945.

  PMID: 9141558 BACKGROUND

• 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. doi: 10.1210/jcem.84.11.6080.

  PMID: 10566629 BACKGROUND

• 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.

  PMID: 19226261 BACKGROUND

• 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.

  PMID: 19067639 BACKGROUND

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

  BACKGROUND

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

  BACKGROUND

• 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.

  BACKGROUND

• 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.

  PMID: 20299491 BACKGROUND

• 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.

  PMID: 23365787 BACKGROUND

• Dietrich JW, Leow MK, Goede SL, Midgley JE, Landgrafe G, Hoermann R. Do thyroid-stimulating hormone, body weight, or body mass index serve as adequate markers to guide levothyroxine dose titration? J Am Coll Surg. 2013 Oct;217(4):752-3. doi: 10.1016/j.jamcollsurg.2013.06.008. No abstract available.

  PMID: 24054412 BACKGROUND

• Dietrich JW, Landgrafe-Mende G, Wiora E, Chatzitomaris A, Klein HH, Midgley JE, Hoermann R. Calculated Parameters of Thyroid Homeostasis: Emerging Tools for Differential Diagnosis and Clinical Research. Front Endocrinol (Lausanne). 2016 Jun 9;7:57. doi: 10.3389/fendo.2016.00057. eCollection 2016.

  PMID: 27375554 BACKGROUND

• Dietrich JW, Midgley JEM, Hoermann R. Editorial: "Homeostasis and Allostasis of Thyroid Function". Front Endocrinol (Lausanne). 2018 Jun 5;9:287. doi: 10.3389/fendo.2018.00287. eCollection 2018. No abstract available.

  PMID: 29922229 BACKGROUND

• Berberich J, Dietrich JW, Hoermann R, Muller MA. Mathematical Modeling of the Pituitary-Thyroid Feedback Loop: Role of a TSH-T3-Shunt and Sensitivity Analysis. Front Endocrinol (Lausanne). 2018 Mar 21;9:91. doi: 10.3389/fendo.2018.00091. eCollection 2018.

  PMID: 29619006 BACKGROUND

MeSH Terms

Conditions

Hypothyroidism; Hyperthyroidism; Thyroid Diseases; Pituitary Diseases

Condition Hierarchy (Ancestors)

Endocrine System Diseases; Hypothalamic Diseases; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases

Study Officials

• Johannes W Dietrich, M.D.

  Medical Hospital I, Bergmannsheil University Hospitals, Ruhr University of Bochum

  PRINCIPAL INVESTIGATOR

• Harald H Klein, M.D.

  Medical Hospital I, Bergmannsheil University Hospitals, Ruhr University of Bochum

  STUDY CHAIR

• Johannes W Dietrich, M.D.

  Medical Hospital I, Bergmannsheil University Hospitals, Ruhr University of Bochum

  STUDY DIRECTOR

• Bojana Bazika-Gerasch, M.D.

  Medical Hospital I, Bergmannsheil University Hospitals, Ruhr University of Bochum

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: CROSS SECTIONAL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Senior consultant endocrinologist

Study Record Dates

• First Submitted: June 14, 2010
• First Posted: June 16, 2010
• Study Start: June 1, 2010
• Primary Completion: July 31, 2018
• Study Completion: January 31, 2021
• Last Updated: October 8, 2020

Record last verified: 2020-10

Data Sharing

• IPD Sharing: Will share
• Shared Documents: ANALYTIC CODE

Locations

DE (3)