Publications: John E. Midgley, thyroid scientist

Selected publications

PARLIAMENTARY TESTIMONY (VIDEO)

• The Scottish Parliament. (2017). Public Petitions Committee – Scottish Parliament: 15 June 2017. Retrieved from https://www.youtube.com/watch?v=Tcx640AJuF8

AS SINGLE-AUTHOR AND LEAD AUTHOR

Midgley, John E. M., Larisch, R., Dietrich, J. W., & Hoermann, R. (2015). Variation in the biochemical response to l-thyroxine therapy and relationship with peripheral thyroid hormone conversion efficiency. Endocrine Connections, 4(4), 196–205. https://doi.org/10.1530/EC-15-0056

Stratifying patients by deiodinase activity categories of <23, 23-29 and >29 nmol/s revealed an increasing FT3-FT4 dissociation; the poorest converters showed the lowest FT3 levels in spite of the highest dose and circulating FT4 (P<0.001).

An l-T4-related FT3-TSH disjoint was also apparent; some patients with fully suppressed TSH failed to raise FT3 above the median level.

These findings imply that thyroid hormone conversion efficiency is an important modulator of the biochemical response to l-T4; FT3 measurement may be an additional treatment target; and l-T4 dose escalation may have limited success to raise FT3 appropriately in some cases.

Midgley, J. E. (2014, October 18). History of Thyroid Testing: Transcript of the talk by Dr John Midgley at the Thyroid UK 2014 Conference. Thyroid UK. Retrieved from https://thyroiduk.org/getting-a-diagnosis/thyroid-testing-info/history-of-thyroid-function-tests/

Now we come to the present day. We have simultaneously in existence licensed, manufactured and used in diagnosis, tests based on the discredited thyroid hormone uptake test, tests based on sound methodology but including the earlier imperfect tests up to the modern improved ones, and tests offered that are to be run invalidly at room temperature.

This implies a complete failure to regulate by the international regulators whose job it is to ensure equivalence of results. The composite failure of the manufacturers to produce consistent FT4 and FT3 tests has already been mentioned. The failure of the medical thyroidology fraternity to ensure consistency of the tests they use is an additional factor in the diagnostic chaos that is now present.

No wonder TSH only screening has gained credence in such an atmosphere.

There is a triple failure that has led to a diagnostic hiatus that urgently needs correcting.

The paradigm of the TSH-FT4 relationship is wrong, especially in treatment.

The whole conceptual thinking behind diagnosis thyroidology and the importance of personal diagnosis based on the patient rather than whether the numbers fall in or out of the normal range is fatally flawed. For the moment mechanical thinking has traduced medical diagnosis.

Midgley, John E. M., Hoermann, R., Larisch, R., & Dietrich, J. W. (2013). Physiological states and functional relation between thyrotropin and free thyroxine in thyroid health and disease: in vivo and in silico data suggest a hierarchical model. Journal of Clinical Pathology, 66(4), 335–342. https://doi.org/10.1136/jclinpath-2012-201213

Understanding the exact relationship between serum thyrotropin/thyroid stimulating hormone (TSH) and free thyroxine (FT4) is a prerequisite for improving diagnostic reliability and clinical decision making.

Conclusions: Our data suggest that the states of hypothyroidism, euthyroidism and hyperthyroidism can be regarded as differently regulated entities. The apparent complexity could be replicated by mathematical modelling suggesting a hierarchical type of feedback regulation involving patterns of operative mechanisms unique to each condition.

For clinical purposes and assay evaluation, neither the standard model relating logTSH with FT4, nor an alternative model based on non-competitive inhibition can be reliably represented by a single correlation comparing all samples for both hormones in one all-inclusive group.

Midgley, John E. M., & Christofides, N. D. (2009). Point: legitimate and illegitimate tests of free-analyte assay function. Clinical Chemistry, 55(3), 439–441. https://doi.org/10.1373/clinchem.2008.116525

In the history of clinical immunoassay, even up to the present day, no group of tests has been subjected to more scrutiny and controversy than analog-type free-analyte assays (1)(2)(3)(4).

Unfortunately, inappropriate design of many experiments has led users to an incorrect perspective of how analog assays work. …

The calibration of analog-type assays is analogous to water pressure measurement in a pipe from a reservoir, as illustrated in Fig. 1 …

Finally, well-designed analog-type free-analyte immunoassays no longer suffer the protein effects that affected initial designs (14)(15). Attempts to show otherwise (5)(6)(7)(8)(9)(10) are essentially illegitimate unless the fundamental criterion of validity described above is obeyed. Such experiments are meaningless and have nothing useful to say about analog assay performance.

Assays work legitimately only over a limited range of permitted concentrations and properties of ingredients, and analytic experiments must be conducted with respect to this fact.

Midgley, John E. M. (2001). Direct and Indirect Free Thyroxine Assay Methods: Theory and Practice. Clinical Chemistry, 47(8), 1353–1363. Retrieved from http://clinchem.aaccjnls.org/content/47/8/1353

SUMMARY:  The performance of convenient assays for FT4 has improved greatly since the first attempts (FTI) in 1965. Index methods were accepted until it became clear that they were still strongly influenced by TBG.

In the meantime, certain “truths” had come to be accepted by many workers, not the least that in late pregnancy, FT4 results should lie in the middle of or in the upper regions of the euthyroid reference intervals.

Better assays, correcting more completely for TBG concentrations, forced a sometimes painful period of readjustment in this and other areas, which has taken 20 years or more to reconcile in some regions of the world.

By now, the better assays for FT4 have eliminated the biasing effects that arose in the early assays from residual binding of labels to serum albumin. The most recent improvements have also largely addressed the remaining problem of T4 autoantibodies in serum.

The main problem outstanding in using FT4 assays is that of diagnosis in NTI. This is a problem that lies more in the vagaries of patient physiology than in any hope of a final, simple, and definitive answer in an ideal assay.

The scope for further improvement in FT4 assay methodology is very limited. Most of the residual problems (albumin dependency, dilution performance) have been addressed, and a final decision can be taken by diagnosticians, not merely whether to terminate their use of FTI, with all its shortcomings, but which direct FT4 assay to use, based on simple comparisons of each assay’s diagnostic properties with those of other assays.

Midgley, J. E. (1993). The free thyroid hormone hypothesis and measurement of free hormones. Clinical Chemistry, 39(6), 1342–1344. Retrieved from http://clinchem.aaccjnls.org/content/39/6/1342

Letter about methods of measuring in laboratories

Midgley, John Edward M. (2006). Thyroid hormone-uptake test: A concept based on false premises. Journal of Clinical Ligand Assay, 29(3), 146–151.

COAUTHORED WITH OTHERS

Larisch, R., Midgley, J. E. M., Dietrich, J. W., & Hoermann, R. (2018a). Symptomatic Relief is Related to Serum Free Triiodothyronine Concentrations during Follow-up in Levothyroxine-Treated Patients with Differentiated Thyroid Cancer. Experimental and Clinical Endocrinology & Diabetes: Official Journal, German Society of Endocrinology [and] German Diabetes Association, 126(9), 546–552. https://doi.org/10.1055/s-0043-125064

RESULTS: 26% of patients expressed hypothyroid and 9.7% hyperthyroid complaints at any one visit, rates per visit being 6.5% and 2%, respectively. During follow-up, median changes in spans were as follows, LT4-dose 0.49 [IQR 0.29,0.72] µg/kg, FT3 1.77 [1.25,2.32] pmol/l, FT4 9.80 [6.70,12.8] pmol/l and TSH 1.25 [0.42,2.36] mIU/l.

While rates of both hypothyroid or hyperthyroid symptoms were significantly related to all three thyroid parameters, the relationship of hypothyroid symptoms with FT3 extended to a below reference TSH range.

Hypothyroid symptom relief was associated with both a T4 dose giving TSH-suppression below the lower reference limit and FT3 elevated further into the upper half of its reference range.

In multivariable analysis, relationships between complaints and FT3 concentrations remained significant after adjusting for gender, age and BMI.

CONCLUSION: Residual hypothyroid complaints in LT4-treated patients are specifically related to low FT3 concentrations. This supports an important role of FT3 for clinical decision making on dose adequacy, particularly in symptomatic athyreotic patients.

Hoermann, Rudolf, Midgley, J. E. M., Dietrich, J. W., & Larisch, R. (2017). Dual control of pituitary thyroid stimulating hormone secretion by thyroxine and triiodothyronine in athyreotic patients. Therapeutic Advances in Endocrinology and Metabolism, 8(6), 83–95. https://doi.org/10.1177/2042018817716401

Background: Patient responses to levothyroxine (LT4) monotherapy vary considerably. We sought to differentiate contributions of FT4 and FT3 in controlling pituitary thyroid stimulating hormone (TSH) secretion.

Methods: We retrospectively assessed the relationships between TSH and thyroid hormones in 319 patients with thyroid carcinoma through 2914 visits on various LT4 doses during follow-up for 5.5 years (median, IQR 4.2, 6.9). We also associated patient complaints with the relationships.

Results: Under varying dose requirements (median 1.84 µg/kg, IQR 1.62, 2.11), patients reached TSH targets below 0.4, 0.1 or 0.01 mIU/l at 73%, 54% and 27% of visits. While intercept, slope and fit of linearity of the relationships between lnTSH and FT4/FT3 varied between individuals, gender, age, LT4 dose and deiodinase activity influenced the relationships in the cohort (all p < 0.001). Deiodinase activity impaired by LT4 dose significantly affected the lnTSH–FT4 relationship. Dose increase and reduced conversion efficiency displaced FT3–TSH equilibria. In LT4-treated patients, FT4 and FT3 contributed on average 52% versus 38%, and by interaction 10% towards TSH suppression. Symptomatic presentations (11%) accompanied reduced FT3 concentrations (–0.23 pmol/l, p = 0.001) adjusted for gender, age and BMI, their relationships being shifted towards higher TSH values at comparable FT3/FT4 levels.

Conclusions: Variation in deiodinase activity and resulting FT3 levels shape the TSH–FT4 relationship in LT4-treated athyreotic patients, suggesting cascade control of pituitary TSH production by the two hormones. Consequently, measurement of FT3 and calculation of conversion efficiency may identify patients with impaired biochemistry and a resulting lack of symptomatic control.

Hoermann, Rudolf, & Midgley, J. E. M. (2012). TSH Measurement and Its Implications for Personalised Clinical Decision-Making. Journal of Thyroid Research, 2012, 438037. https://doi.org/10.1155/2012/438037

Advances in assay technology have promoted thyrotropin (TSH) measurements from participation in a multi-analyte assessment of thyroid function to a statistically defined screening parameter in its own right.

While this approach has been successful in many ways, it has some grave limitations.

This includes the basic question of what constitutes an agreed reference range and the fact that the population-based reference range by far exceeds the variation of the intraindividual set point. Both problems result in a potential misdiagnosis of normal and pathological thyroid function in a substantial proportion of patients.

From a physiological perspective, TSH plays an integrated role in thyroid homeostasis. Few attempts have been made to adopt physiological insights into thyroid homeostasis for medical decision-making. Some emerging novel findings question the widely assumed log-linear TSH-FT(4) relationship over the entire thyroid function spectrum. This data favours more complex hierarchically structured models.

With a better understanding of its role in thyroid homeostasis in thyroid health and disease, TSH can be revisited in the context of thyroid regulation. This, in turn, could help overcome some of the limitations arising from its isolated statistical use and offer new prospects towards a more personalised interpretation of thyroid test results.

Hoermann, R., Midgley, J. E. M., Larisch, R., & Dietrich, J. W. (2015b). Integration of Peripheral and Glandular Regulation of Triiodothyronine Production by Thyrotropin in Untreated and Thyroxine-Treated Subjects. Hormone and Metabolic Research = Hormon- Und Stoffwechselforschung = Hormones Et Metabolisme, 47(9), 674–680. https://doi.org/10.1055/s-0034-1398616

The objective of the study was to evaluate the roles of central and peripheral T3 regulation.

In a prospective study involving 1,796 patients, the equilibria between FT3 and TSH were compared in untreated and L-T4-treated patients with varying functional states, residual thyroid secretory capacities and magnitudes of TSH stimulation.

[…]

These findings suggest that the thyroid gland and peripheral tissues are integrated in the physiological process of T3 homeostasis in humans via a feed-forward TSH motif, which coordinates peripheral and central regulatory mechanisms.

Regulatory and capacity deficiencies collectively impair T3 homeostasis in L-T4-treated patients.

Larisch, R., Giacobino, A., Eckl, W., Wahl, H.-G., Midgley, J. E. M., & Hoermann, R. (2015b). Reference range for thyrotropin. Post hoc assessment. Nuklearmedizin. Nuclear Medicine, 54(3), 112–117. https://doi.org/10.3413/Nukmed-0671-14-06

Setting the reference range for thyrotropin (TSH) remains a matter of ongoing controversy.

PATIENTS, METHODS: We used an indirect method to determine the TSH reference range post hoc in a large sample. A total of 399 well characterised subjects showing no evidence of thyroid dysfunction were selected for definition of the TSH reference limits according to the method of Katayev et al.. To this end, the cumulative frequency was plotted against the individual logarithmic TSH values. Reference limits were calculated by extrapolating the middle linear part of the regression line to obtain the cut-offs for the 95% confidence interval. We also examined biological variation in a sample of 65 subjects with repeat measurements to establish reference change values (RCVs).

RESULTS: Based on these, the reference interval obtained by the novel technique was in close agreement with the conventionally established limits, but differed significantly from earlier recommendations.

DISCUSSION: Following unverified recommendations could result in a portion of patients with subclinical thyroid dysfunctions being missed, an important consideration in a setting with a high prevalence of thyroid autonomy.

CONCLUSION: Indirect post hoc verification of reference intervals from a large retrospective sample is a modern approach that gives plausible results. The method seems particularly useful to assess the adequacy and performance of reference limits reported or established by others in a particular setting. The present data should encourage re-evaluation of reference systems on a broader scale.

Hoermann, Rudolf, Midgley, J. E. M., Larisch, R., & Dietrich, J. W. (2013). Is pituitary TSH an adequate measure of thyroid hormone-controlled homoeostasis during thyroxine treatment? European Journal of Endocrinology, 168(2), 271–280. https://doi.org/10.1530/EJE-12-0819

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.

Hoermann, Rudolf, Midgley, J. E. M., Larisch, R., & Dietrich, J. W. (2016). Relational Stability in the Expression of Normality, Variation, and Control of Thyroid Function. Frontiers in Endocrinology, 7. https://doi.org/10.3389/fendo.2016.00142

OVERVIEW: Thyroid hormone concentrations only become sufficient to maintain a euthyroid state through appropriate stimulation by pituitary thyroid-stimulating hormone (TSH). In such a dynamic system under constant high pressure, guarding against overstimulation becomes vital. Therefore, several defensive mechanisms protect against accidental overstimulation, such as plasma protein binding, conversion of T4 into the more active T3, active transmembrane transport, counter-regulatory activities of reverse T3 and thyronamines, and negative hypothalamic–pituitary–thyroid feedback control of TSH.

FINDINGS: TSH has gained a dominant but misguided role in interpreting thyroid function testing in assuming that its exceptional sensitivity thereby translates into superior diagnostic performance. However, TSH-dependent thyroid disease classification is heavily influenced by statistical analytic techniques such as uni- or multivariate-defined normality. This demands a separation of its conjoint roles as a sensitive screening test and accurate diagnostic tool. Homeostatic equilibria (set points) in healthy subjects are less variable and do not follow a pattern of random variation, rather indicating signs of early and progressive homeostatic control across the euthyroid range. In the event of imminent thyroid failure with a reduced FT4 output per unit TSH, conversion efficiency increases in order to maintain FT3 stability. In such situations, T3 stability takes priority over set point maintenance.

CONCLUSIONS: This suggests a concept of relational stability. These findings have important implications for both TSH reference limits and treatment targets for patients on levothyroxine. The use of archival markers is proposed to facilitate the homeostatic interpretation of all parameters.

Hoermann, Rudolf, Midgley, J. E. M., Larisch, R., & Dietrich, J. W. (2017a). Recent advances in thyroid hormone regulation: Toward a new paradigm for optimal diagnosis and treatment. Frontiers in Endocrinology, 8. https://doi.org/10.3389/fendo.2017.00364

BACKGROUND: In thyroid health, the pituitary hormone TSH raises glandular thyroid hormone production to a physiological level and enhances formation and conversion of T4 to the biologically more active T3. Overstimulation is limited by negative feedback control.

FINDINGS: In equilibrium defining the euthyroid state, the relationship between TSH and FT4 expresses clusters of genetically determined, interlocked TSH-FT4 pairs, which invalidates their statistical correlation within the euthyroid range. Appropriate reactions to internal or external challenges are defined by unique solutions and homeostatic equilibria. Permissible variations in an individual are much more closely constrained than over a population. Current diagnostic definitions of subclinical thyroid dysfunction are laboratory-based, and do not concur with treatment recommendations.

An appropriate TSH level is a homeostatic concept that cannot be reduced to a fixed range consideration. The control mode may shift from feedback to tracking where TSH becomes positively, rather than inversely related with FT4. This is obvious in pituitary disease and severe non-thyroid illness, but extends to other prevalent conditions including aging, obesity and levothyroxine treatment.

CONCLUSIONS: Treatment targets must both be individualised and respect altered equilibria on levothyroxine. To avoid amalgamation bias clinically meaningful stratification is required in epidemiological studies.

In conclusion, pituitary TSH cannot be readily interpreted as a sensitive mirror image of thyroid function because the negative TSH-FT4 correlation is frequently broken, even inverted, by common conditions.

The interrelationships between TSH and thyroid hormones and the interlocking elements of the control system are individual, dynamic and adaptive. This demands a paradigm shift of its diagnostic use.

Hoermann, Rudolf, Midgley, J. E. M., Larisch, R., & Dietrich, J. W. (2018a). Lessons from Randomised Clinical Trials for Triiodothyronine Treatment of Hypothyroidism: Have They Achieved Their Objectives? Journal of Thyroid Research, Article ID 3239197. https://doi.org/10.1155/2018/3239197

Randomised controlled trials are deemed to be the strongest class of evidence in evidence-based medicine. Failure of trials to prove superiority of T3/T4 combination therapy over standard LT4 monotherapy has greatly influenced guidelines, while not resolving the ongoing debate. Novel studies have recently produced more evidence from the examination of homeostatic equilibria in humans and experimental treatment protocols in animals. This has exacerbated a serious disagreement with evidence from the clinical trials.

We contrasted the weight of statistical evidence against strong physiological counterarguments. Revisiting this controversy, we identify areas of improvement for trial design related to validation and sensitivity of QoL instruments, patient selection, statistical power, collider stratification bias, and response heterogeneity to treatment. Given the high individuality expressed by thyroid hormones, their interrelationships, and shifted comfort zones, the response to LT4 treatment produces a statistical amalgamation bias (Simpson’s paradox), which has a key influence on interpretation. In addition to drug efficacy, as tested by RCTs, efficiency in clinical practice and safety profiles requires reevaluation.

Accordingly, results from RCTs remain ambiguous and should therefore not prevail over physiologically based counterarguments.

In giving more weight to other forms of valid evidence which contradict key assumptions of historic trials, current treatment options should remain open and rely on personalised biochemical treatment targets.

Optimal treatment choices should be guided by strict requirements of organizations such as the FDA, demanding treatment effects to be estimated under actual conditions of use.

Various improvements in design and analysis are recommended for future randomised controlled T3/T4 combination trials.

Dietrich, J. W., Midgley, J. E. M., & Hoermann, R. (Eds.). (2018b). Homeostasis and Allostasis of Thyroid Function. Lausanne: Frontiers Media. Retrieved from https://www.frontiersin.org/articles/10.3389/fendo.2018.00287/full

The discovery of the negative feedback of thyroid hormones on pituitary thyroid-stimulating hormone (TSH) secretion, a classical endocrine feedback control system, has shaped diagnosis and treatment of thyroid disease for the last decades. Based on this concept, a unique diagnostic category of subclinical thyroid disorders was introduced, being defined exclusively by an abnormal TSH response in the presence of thyroid hormone concentrations within the reference range. Although this approach was able to deliver a conceptually straightforward disease definition problems surfaced in clinical practice as neither the diagnostic reference range nor the appropriate threshold for initiating substitution treatment are universally agreed upon for subclinical thyroid disorders.

The situation is further aggravated by the so-called syndrome T, which comprises a substantial but heterogeneous group of L-T4 treated patients with hypothyroidism with reduced quality of life despite “normal” TSH values.

A limited understanding of the physiological relationships between TSH and thyroid hormones may be a main reason for clinical difficulties in dealing with the causes of syndrome T and tailoring substitution therapy for hypothyroid patients with subclinical thyroid disorders.

Feedback regulation has recently been shown to be much more complex than previously assumed. The concept of homeostatic control has also been extended to include the lesser known but equally important allostatic thyroid regulation. The latter aims at adaptive homeostasis or stability through changing setpoints and modulating structural parameters of feedback control, as may be appropriate to adapt to a vast array of conditions spanning from fetal life, aging, pregnancy, exercise, starvation, obesity, psychiatric disorders to the severe non-thyroidal illness syndrome.

A better understanding of homeostatic and allostatic mechanisms, which govern the behaviour of pituitary-thyroid feedback control, is on the horizon. This promises to improve the diagnostic utility of laboratory methods, laying the foundation for personalised methods to optimise dosage and modality of substitution therapy.

The emerging new world of thyroid physiology is reflected on the side of clinical medicine in a new, relational paradigm for diagnosis and treatment.

Considerable progress has been made in this respect in the following key areas:

• the significance of complementary information processing structures within the feedback loop, in particular ultrashort feedback of TSH on its own secretion and the action of a TSH-T3 shunt unburdening the thyroid from T4 synthesis in imminent thyroid failure,
• the unravelling of spatio-temporal dynamics of hormone concentrations ranging from ultradian to circannual rhythms and including hysteresis effects,
• the emergence of “non-canonical” mechanisms of thyroid hormone signalling beyond transcriptional control of gene expression,
• the physiological actions of thyronine metabolites, which have been previously regarded as biologically inactive, such as thyronamines and iodothyroacetates,
• the characterisation of distinct patterns in the adaptive processes to stress and strain and their conclusive explanation through reactions to type 1 and type 2 allostatic load.

Dietrich, J. W., Landgrafe-Mende, G., Wiora, E., Chatzitomaris, A., Klein, H. H., Midgley, J. E. M., & Hoermann, R. (2016). Calculated Parameters of Thyroid Homeostasis: Emerging Tools for Differential Diagnosis and Clinical Research. Frontiers in Endocrinology, 7. https://doi.org/10.3389/fendo.2016.00057

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.

Hoermann, Rudolf, Midgley, J. E. M., Larisch, R., & Dietrich, J. W. (2018b). The role of functional thyroid capacity in pituitary thyroid feedback regulation. European Journal of Clinical Investigation, 48(10), e13003. https://doi.org/10.1111/eci.13003

Hoermann, Rudolf, Midgley, J. E. M., Larisch, R., & Dietrich, J. W. C. (2017b). Advances in applied homeostatic modelling of the relationship between thyrotropin and free thyroxine. PLoS ONE, 12(11), e0187232. https://doi.org/10.1371/journal.pone.0187232

Hoermann, Rudolf, Midgley, J. E. M., Giacobino, A., Eckl, W. A., Wahl, H. G., Dietrich, J. W., & Larisch, R. (2014). Homeostatic equilibria between free thyroid hormones and pituitary thyrotropin are modulated by various influences including age, body mass index and treatment. Clinical Endocrinology, 81(6), 907–915. https://doi.org/10.1111/cen.12527

Dietrich, J. W., Midgley, J. E. M., Larisch, R., & Hoermann, R. (2015). Of rats and men: thyroid homeostasis in rodents and human beings. The Lancet Diabetes & Endocrinology, 3(12), 932–933. https://doi.org/10.1016/S2213-8587(15)00421-0

Chatzitomaris, A., Hoermann, R., Midgley, J. E., Hering, S., Urban, A., Dietrich, B., … Dietrich, J. W. (2017). Thyroid Allostasis–Adaptive Responses of Thyrotropic Feedback Control to Conditions of Strain, Stress, and Developmental Programming. Frontiers in Endocrinology, 8. https://doi.org/10.3389/fendo.2017.00163