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

 -  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)

 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