John Edward M Midgley

Independent Researcher · Research & Development

Background Thyroid hormones are controlled by the hypothalamic–pituitary–thyroid (HPT) axis through a complex network of regulatory loops, involving the hormones TRH, TSH, FT4, and FT3. The relationship between TSH and FT4 is widely used for diagnosing thyroid diseases. However, mechanisms of FT3 homeostasis are not well understood. Objective We u...

Endocrine regulation in the hypothalamic-pituitary-thyroid (HPT) axis is orchestrated by physiological circuits which integrate multiple internal and external influences. Essentially, it provides either of the two responses to overt biological challenges: to defend the homeostatic range of a target hormone or adapt it to changing environmental cond...

We read with great interest the current debate on the controversial issues that have long surrounded the treatment of subclinical hypothyroidism (1). The fact that the two discussants disagreed so strongly in their approach to a prevalent problem, routinely faced by clinicians around the globe, may indicate severe shortcomings in the current approa...

Elevated concentrations of free thyroid hormones are established cardiovascular risk factors, but the association of thyrotropin (TSH) levels to hard endpoints is less clear. This may, at least in part, ensue from the fact that TSH secretion depends not only on the supply with thyroid hormones but on multiple confounders including genetic traits, m...

A recent debate has evaluated the primary test schema for assessing thyroid function, direct measurement of thyroid hormones or the pituitary hormone TSH.

We read with great interest the Methodology Editorial on ‘Choosing between parametric and non-parametric tests’ by le Cessie et al. in the Journal (1). The topic is of wide interest to readers given that this is a frequent issue clinical researchers face in their daily work. The authors argue that the use of a t-test is preferable over non-parametr...

Background: Subclinical hyperthyroidism/thyrotoxicosis originates from different causes and clinical conditions, sharing the laboratory constellation of a suppressed TSH in the presence of thyroid hormone concentrations within the reference range. Aim: Presentation of hyperthyroidism can manifest itself in several ways. We questioned whether there...

Background: Defined by thyroid-pituitary feedback control, clinical diagnosis of hypothyroidism and hyperthyroidism has become synonymous with TSH measurement. Study aim: We combined in silico analysis and in vivo data to explore the central influences on thyroidal T3 production. Materials & methods: A system of five coupled first order nonlin...

Background: For significant numbers of patients dissatisfied on standard levothyroxine (LT4) treatment for hypothyroidism, patient-specific responses to T4 could play a significant role. Aim: To assess response heterogeneity to LT4 treatment, identifying confounders and hidden clusters within a patient panel, we performed a secondary analysis using...

Levothyroxine (LT4) therapy has a long history, a well-defined pharmacological profile and a favourable safety record in the alleviation of hypothyroidism. However, questions remain in defining the threshold for the requirement of treatment in patients with subclinical hypothyroidism, assessing the dose adequacy of the drug, and selecting the best...

Background In the treatment for hypothyroidism, a historically symptom-orientated approach has given way to reliance on a single biochemical parameter, thyroid stimulating hormone (TSH). Main body The historical developments and motivation leading to that decision and its potential implications are explored from pathophysiological, clinical and st...

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 de...

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...

Aim The present study examines the relationship between the sensitivity of TSH feedback and thyroid capacity in untreated patients with thyroid autoimmune disease (n= 86) and healthy controls (n= 271). Functional capacity was estimated at maximum TSH stimulation, and pituitary TSH response was FT4‐standardised with two established indices, the TSH...

Aim Patients on levothyroxine-treatment frequently have complaints although TSH is within the reference range. Moreover, FT3 is often low in these patients. The clinical significance of this disequilibrium is studied here. Patients, methods We conducted a retrospective longitudinal study including 319 patients with differentiated thyroid carcinoma...

In thyroid health, the pituitary hormone thyroid-stimulating 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. In equilibrium defining the euthyroid state, the relationship between...

Introduction The relationship between pituitary TSH and thyroid hormones is central to our understanding of thyroid physiology and thyroid function testing. Here, we generated distribution patterns by using validated tools of thyroid modelling. Methods We simulated patterns of individual set points under various conditions, based on a homeostatic...

S2 Table. De-identified patient data in data interchange format.

S1 File. Supplementary code for the statistical platform R.

S1 Table. De-identified patient data in Office Open XML format.

Supplementary code for the statistical platform R. (DOC)

De-identified patient data in Office Open XML format. (XLSX)

De-identified patient data in data interchange format. (DIF)

The hypothalamus–pituitary–thyroid feedback control is a dynamic, adaptive system. In situations of illness and deprivation of energy representing type 1 allostasis, the stress response operates to alter both its set point and peripheral transfer parameters. In contrast, type 2 allostatic load, typically effective in psychosocial stress, pregnancy,...

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...

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,...

Background/aim: Operating far from its equilibrium resting point, the thyroid gland requires stimulation via feedback-controlled pituitary thyrotropin (TSH) secretion to maintain adequate hormone supply. We explored and defined variations in the expression of control mechanisms and physiological responses across the euthyroid reference range. Met...

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...

Although pituitary thyrotropin (TSH) and thyroid hormones are physiologically interrelated, interpretation of measurements is conventionally done separately. Classification of subclinical thyroid dysfunction depends by definition solely on an abnormal TSH. This study examines a composite multivariate approach to disease classification. Methods: Bi...

In their Comment in The Lancet Diabetes & Endocrinology,1 Elizabeth McAninch and Antonio Bianco1 raise the important issue of the variable effectiveness of levothyroxine (LT4) monotherapy for hypothyroidism. Residual hypothyroid symptoms in 12% of patients on LT4 treatment in the USA, the European Union, and China translates to more than 13 million...

The long-held concept of a proportional negative feedback control between the thyroid and pituitary glands requires reconsideration in the light of more recent studies. Homeostatic equilibria depend on dynamic inter-relationships between thyroid hormones and pituitary thyrotropin (TSH). They display a high degree of individuality, thyroid-state-rel...

Objective: Several influences modulate biochemical responses to weight-adjusted levothyroxine (L-T4) replacement dose. We conducted a secondary analysis of the relationship of L-T4 dose to TSH and FT3, using a prospective observational study examining the interacting equilibria between thyroid parameters. Methods: We studied 353 patients on steady-...

Several influences modulate biochemical responses to a weight-adjusted levothyroxine (L-T4) replacement dose. We conducted a secondary analysis of the relationship of L-T4 dose to TSH and free T3 (FT3), using a prospective observational study examining the interacting equilibria between thyroid parameters. We studied 353 patients on steady-state L-...

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. T3 concentrati...

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 acc...

This is an online supplement to the research paper titled "Homeostatic Equilibria Between Free Thyroid Hormones and Pituitary Thyrotropin Are Modulated By Various Influences Including Age, Body Mass Index and Treatment" (doi 10.1111/cen.12527). It shows correlation between ln TSH and FT3, FT4 and total deiodinase activity (SPINA-GD). Additionally,...

Objective: We examined the interrelationships of pituitary thyrotropin (TSH) with circulating thyroid hormones to determine whether they were expressed either invariably or conditionally and distinctively related to influences such as levothyroxin e (L-T4) treatment. Design and Methods: This prospective study employing 1912 consecutive patients an...

Recently in JACS, Ojomo and coauthors published a retrospective evaluation of patients post-thyroidectomy, concluding that maintenance levothyroxine (L-T4) doses are best predicted by body mass index (BMI) rather than by the traditional practice of measuring body weight. Others concomitantly used an even larger cohort, showing instead that L-T4 dos...

Aims: Understanding the exact relationship between serum thyrotropin/thyroid stimulating hormone (TSH) and free thyroxine (FT(4)) is a prerequisite for improving diagnostic reliability and clinical decision making. Methods: We (1) retrospectively studied the relationship between TSH and FT(4) in a large unselected clinical sample (n=6641) of pri...

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 triiodot...

Background: In light of several recent recommendations to use total thyroxine (T4) measurements in the diagnosis of thyroid function in pregnancy (in particular, "Clinical Practice Guidelines for Hypothyroidism in Adults," cosponsored by the American Thyroid Association and the American Association of Clinical Endocrinologists, which promote the u...

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 a...

To examine the merits of measuring free analytes by ultrafiltration using either diluted or undiluted serum. Confidence in the accuracy of measurements is affected both by problems identified in current systems using semipermeable membranes, the sensitivity of the system to artefacts and comparisons with other imperfect assays. All "gold standard"...

We have read with interest recent reports of the measurement of free thyroxine and free triiodothyronine by ultrafiltration and tandem mass spectrometry (1)(2)(3)(4). There is, however, a fundamental flaw in these studies that we wish to bring to general attention. Ultrafiltration of serum was routinely carried out close to room temperature (25 °C)...

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. An analysis of the important series...

I read with misgivings the recent communication by Fritz et al. (1) alleging that because under some circumstances an analog free thyroxine (FT4) immunoassay correlates total T4 and FT4 values, it does not measure FT4 but something akin to T4. I have shown repeatedly through mass action analyses (2)(3)(4) that many experiments, including the one re...

Thyroid hormone uptake tests perform inadequately in several areas of thyroid function diagnosis. The theory underpinning this class of tests, typified by T3 (triiodo-thyronine)-uptake, has been reexamined using equilibrium Mass Action principles. Regardless of whether labeled T3, or any equivalent substitute, either does or does not saturate the u...

The rules governing one-step analog immunoassays for free thyroid hormones remain controversial. By the use of mass action theory, this commentary seeks to resolve the disagreements by reemphasizing the criteria underpinning valid free thyroxine assays. The legitimacy of one-step immunoassays for free thyroxine has also been questioned from experim...

For the diagnosis of thyroid disease, measurement of "free hormone" is generally accepted as an appropriate measure. However, valid assays measuring the free fraction of thyroxine (FT4) ideally must perform without bias, despite large variations in the concentrations and affinities of serum T4-binding proteins in the population. Several approaches...

We describe a one-step, labeled-antibody radioassay for measuring free thyroxin (FT4) in serum or plasma, based on a novel principle. FT4 in the sample competes with a gross molar excess (over antibody) of a cross-reactant (L-triiodothyronine, T3), chemically coupled to magnetizable polymer particles, for binding to avid 125l-labeled monoclonal ant...

Free thyroxin (FT4) estimates by two immunoassays were compared with the concentrations of albumin in serum of apparently euthyroid subjects who either were (n = 99) or were not (n = 327) suffering from severe nonthyroidal illness (sNTI). In neither group was FT4 significantly correlated with albumin (P greater than 0.05), according to a "labeled a...

Free thyroxin (FT4) concentrations, total thyroxin/thyroxin-binding globulin (T4/TBG) ratios, and thyrotropin (TSH) and albumin concentrations were measured in serum in a longitudinal study in each of the three trimesters of 25 normal pregnancies. In late pregnancy, FT4 estimates by assays reputedly either affected or unaffected by albumin were in...

We studied the effect of adding purified human albumin to sera on free thyroxine (FT4) values obtained with Amerlex radioimmunoassays. Apparent FT4 values increased with progressive addition of albumin in vitro. The effect was smallest with low and greatest with high initial FT4 concentrations, which were also linearly correlated with the increment...

We determined binding characteristics of the triiodothyronine (T3) analog tracer used in the Amerlex and Amerlex-M FT3 radioimmunoassay for the three endogenous binding proteins in serum: thyroxin-binding globulin (TBG), thyroxin binding prealbumin (PA), and albumin. Both T3 and its analog bind to the same sites on TBG and PA. However, the analog h...

The basic theory of thyroxin-analog-based radioimmunoassays for free thyroxin has been extended to evaluate definitively the effects arising from residual binding of the tracer analog to serum proteins. Using experimentally determined binding constants and computer simulation techniques, we studied the effects of thyroxin-analog binding to serum pr...

Age-related trends in serum free thyroxine (FT4) and free triiodothyronine (FT3) concentrations were measured in 7248 euthyroid subjects (age-range 3 months to 106 years). 5700 were patients referred to hospitals for investigation of suspected thyroid dysfunction, but who were diagnosed euthyroid. 1548 were healthy blood donors (age-range 18-63 yea...

Thyroid function in long term aspirin therapy.pdf

The interferences in FT4 assays reported by Boss et al. and Lundberg et al. are largely the result of uncontrolled conversion of plasma triglycerides in vitro by lipolytic activity stimulated in vivo by heparin. The question posed by Boss et al. as to which FT4 method gives the 'true' result invites the reply that no assay can give accurate FT4 est...

A new method is reported for the determination of the binding constants of homologous ligands relative to that of the parent ligand. The technique minimizes the effects of random and bias errors inherent in absolute methods and obviates the need to quantitate the radiolabelled tracer concentration. In addition, it is likely to be of general applica...