Thyrotropic Feedback Control: Evidence for an Additional Ultrashort Feedback Loop From Fractal Analysis

Objective: In recognition of its primary role in pituitary-thyroid feedback, TSH determination has become a key parameter for clinical decision-making. This study examines the value of TSH as a measure of thyroid hormone homoeostasis under thyroxine (T 4 ) therapy. Design and methods: We have examined the interrelationships between free triiodothyronine (FT 3 ), free T 4 (FT 4 ) and pituitary TSH by means of i) a retrospective analysis of a large clinical sample comprising 1994 patients either untreated or on varying doses of L-T 4 and ii) independent mathematical simulation applying a model of thyroid homoeostasis, together with a sensitivity analysis. Results: Over a euthyroid to mildly hyperthyroid functional range, we found markedly different correlation slopes of log TSH vs FT 3 and FT 4 between untreated patients and L-T 4 groups. Total deiodinase activity (G D ) was positively correlated with TSH in untreated subjects. However, G D was significantly altered and the correlation was lost under increasing L-T 4 doses. Ninety-five per cent confidence intervals for FT 3 and FT 4 , when assessed in defined TSH concentration bands, differed significantly for L-T 4 -treated compared with untreated patients. Higher doses were often needed to restore FT 3 levels within its reference range. Sensitivity analysis revealed the influence of various structural parameters on pituitary TSH secretion including an important role of pituitary deiodinase type 2. Conclusion: The data reveal disjoints between FT 4 -TSH feedback and T 3 production that persist even when sufficient T 4 apparently restores euthyroidism. T 4 treatment displays a compensatory adaptation but does not completely re-enact normal euthyroid physiology. This invites a study of the clinical consequences of this disparity.

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Calculations Models and Statistical Methodsmentioning

confidence: 99%

See 1 more Smart Citation

Is pituitary TSH an adequate measure of thyroid hormone-controlled homoeostasis during thyroxine treatment?

Hoermann

Midgley²,

Larisch

et al. 2013

“…It does not investigate the diversity of mechanisms and multitude of parameters involved in pituitary thyroid regulation, such as short loop feedback, pulsatility of TSH secretion, stimulation of TSH by TRH and others that could be modelled from a cybernetic perspective (24,25).…”

Section: Value ((Xka)mentioning

confidence: 99%

Complex relationship between free thyroxine and TSH in the regulation of thyroid function

Hoermann

Eckl²,

Hoermann³

et al. 2010

100

Objective: The present study re-evaluates the inverse log TSH-free thyroxine (fT 4 ) relationship, which has generally been assumed to characterize the thyroid pituitary hypothalamic feedback regulation in thyroid function. Design and Methods: The correlation between fT 4 and TSH was analyzed in two data sets from differing time periods involving 3223 and 6605 patients referred for thyroid testing, representing the whole range of thyroid functions from hypothyroidism to hyperthyroidism. Results: We found that the data do not support a linear log TSH-fT 4 relationship; instead, the correlation's gradient varies with thyroid function. As a consequence, an alternate model, based on the error function, was introduced. When directly comparing the models by means of curve fitting, using F-test and Akaike criteria, the alternate model results in a significantly better fit. The model was verified in the independent second set of data. Subgroup analysis of untreated patients added further proof to the non-linear model. Conclusions: We propose a refined non-linear model to describe the relationship between TSH and fT 4 . It implies that TSH response to a deviating fT 4 value may not be log-linear, but may be disproportionally related to the extent of the deviation from an optimum set point. A better understanding of the complex nature of the TSH-fT 4 relationship may further the development of more precise clinical models and aid in better defining subclinical states of thyroid dysfunction. Also, it may encourage other biological interrelations to be reconsidered in the wake of advanced measurement techniques and more powerful computerized statistical procedures.

“…Maximum TSH levels, circadian rhythm, and pulses of TSH secretion are influenced by sleep, age, season, and fasting (32,33,34) but are not strongly dependent on age, sex, and body weight (35). TSH values measured in 324 750 healthy individuals at different times of the day confirmed the dependence on sex, age, and time of blood collection (36).…”

Section: Regulation Of Tsh Secretionmentioning

confidence: 72%

MECHANISMS IN ENDOCRINOLOGY: Impact of isolated TSH levels in and out of normal range on different tissues

Frőhlich

Wahl

2016

Routine treatment of thyroid cancer (TC) includes long-term suppression of TSH. The necessity of this treatment in low-and intermediate-risk patients as well as the extent of TSH suppression is currently under discussion. A literature search was performed to illustrate the role of TSH in extrathyroidal cells and to identify potential reasons for different effects of exogenously suppressed and endogenously low TSH levels. Although adverse effects of subnormal and supranormal TSH blood levels on heart and brain have not been consistently found, studies show a clear negative effect of suppressed TSH levels on bone mineral density. Experimental data also support an important role of TSH in the immune system. The ability of levothyroxine (L-T 4 ) to regulate TSH levels and triiodothyronine levels in a physiological manner is limited. Reduction of circadian changes in TSH levels, decrease of thyroid hormone-binding proteins, prevention of potential compensatory increases of TSH levels (e.g., in old age), and unresponsiveness of TSH-producing cells to TRH on L-T 4 treatment might cause adverse effects of suppressed TSH levels. In view of the adverse effects of aggressive TSH suppression, achieving the suggested levels of TSH between 0.9 and 1 mU/l in the treatment of low-to-intermediate risk TC patients appears justified.