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Research Papers on TSH


Homeostatic Control of the Thyroid–Pituitary Axis:
Perspectives for Diagnosis and Treatment

Front. Endocrinol., 20 November 2015

Rudolf Hoermann1, John E. M. Midgle2y, Rolf Larisch1 and Johannes W. Dietrich3,4

1Department of Nuclear Medicine, Klinikum Luedenscheid, Luedenscheid, Germany
2North Lakes Clinical, Ilkley, UK
3Medical Department I, Endocrinology and Diabetology, Bergmannsheil University Hospitals, Ruhr University of Bochum, Bochum, Germany
4Ruhr Center for Rare Diseases (CeSER), Ruhr University of Bochum and Witten/Herdecke University, Bochum, Germany

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-related hierarchy, and adaptive conditionality.

Molecular mechanisms involve multiple feedback loops on several levels of organization, different time scales, and varying conditions of their optimum operation, including a proposed feedforward motif. This supports the concept of a dampened response and multistep regulation, making the interactions between TSH, FT4, and FT3 situational and mathematically more complex.

As a homeostatically integrated parameter, TSH becomes neither normatively fixed nor a precise marker of euthyroidism. This is exemplified by the therapeutic situation with l-thyroxine (l-T4) where TSH levels defined for optimum health may not apply equivalently during treatment.

In particular, an FT3–FT4 dissociation, discernible FT3–TSH disjoint, and conversion inefficiency have been recognized in l-T4-treated athyreotic patients. In addition to regulating T4 production, TSH appears to play an essential role in maintaining T3 homeostasis by directly controlling deiodinase activity.

While still allowing for tissue-specific variation, this questions the currently assumed independence of the local T3 supply. Rather it integrates peripheral and central elements into an overarching control system. On l-T4 treatment, altered equilibria have been shown to give rise to lower circulating FT3 concentrations in the presence of normal serum TSH. While data on T3 in tissues are largely lacking in humans, rodent models suggest that the disequilibria may reflect widespread T3 deficiencies at the tissue level in various organs.

As a consequence, the use of TSH, valuable though it is in many situations, should be scaled back to a supporting role that is more representative of its conditional interplay with peripheral thyroid hormones.

This reopens the debate on the measurement of free thyroid hormones and encourages the identification of suitable biomarkers. Homeostatic principles conjoin all thyroid parameters into an adaptive context, demanding a more flexible interpretation in the accurate diagnosis and treatment of thyroid dysfunction.

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To read the article online, go here http://journal.frontiersin.org/article/10.3389/fendo.2015.00177/full#h1



Reference range for thyrotropin. Post hoc assessment.

R. Larisch1; A. Giacobino1; W. Eckl1; H.-G. Wahl2; J. E. M. Midgley3; R. Hoermann1
1Klinik für Nuklearmedizin, Klinikum Lüdenscheid, Germany; 2Institut für Laboratoriumsmedizin, Klinikum
Lüdenscheid, Germany; 3North Lakes Clinical, Ilkley, UK

epub ahead of print: January 8, 2015

Summary 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.

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.

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.

The above abstract can be viewed here http://www.ncbi.nlm.nih.gov/pubmed/25567792

To download a PDF of the full article for personal or educational use only, click here

Does fasting or postprandial state affect thyroid function testing?

Rakesh Nair, Shriraam Mahadevan,1 R. S. Muralidharan, and S. Madhavan

Indian J Endocrinol Metab. 2014 Sep-Oct; 18(5): 705–707.


Thyroid stimulating hormone (TSH) levels vary with the time of the day and probably in relation to food. In this study, we addressed the question of whether a fasting or non-fasting sample would make a clinically significant difference in the interpretation of thyroid function tests.
Fifty seven adult ambulatory patients were selected from our laboratory database and were divided into Group A [Normal free thyroxine (T4) and TSH], Group B (subclinical hypothyroid with increased TSH and normal free T4) and Group C (overt hypothyroid with low free T4 and high TSH). Thyroid functions (free T4 and TSH) were done in fasting state and 2 hours postprandially.
TSH was suppressed in all subjects after food irrespective of the fasting levels. Free T4 values did not change significantly. This resulted in reclassification of 15 out of 20 (75%) subjects as subclinical hypothyroidism (SCH) based on fasting values whose TSH values were otherwise within range in the postprandial sample. This may have an impact on the diagnosis and management of hypothyroidism especially where even marginal changes in TSH may be clinically relevant as in SCH and in pregnancy.
TSH levels showed a statistically significant decline postprandially in comparison to fasting values. This may have clinical implications in the diagnosis and management of hypothyroidism, especially SCH.


Link to above abstract in PubMed http://www.ncbi.nlm.nih.gov/pubmed/25285290

The full paper is available here http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4171896



July 2014

Clinical Endocrinology Journal coverThyroid UK advisors Rudolf Hoermann, John E.M. Midgley and Johannes W. Dietrich have just had a new research paper published in the Clinical Endocrinology Journal.

Dr John Midgley tells us:

"What it proves is that there is no such thing as a TSH range that is suitable for everyone, and that the range is different according to the effect of independent influences such as age, body mass, size of working thyroid volume and whether someone is on T4 or not.

The T4 therapy range is very much lower than the "normal" untreated and sits around the 1 or lower mark. The 3-4 upper level that works for the normal person is not satisfactory and can indicate undertreatment.

Also we're finding that people with no thyroid working at all cannot easily regain normal FT3 with T4 alone and that TSH suppression often has to happen, and in some people no amount of T4 will regain normal FT3 levels. Recent reviews by the gurus now admit that some people cannot handle T4 only and regain health. Just thought you'd like to know that the avalanche is beginning."

Homeostatic equilibria between free thyroid hormones and pituitary thyrotropin are modulated by various influences including age, body mass index and treatment

Rudolf Hoermann*, John E.M. Midgley†, Adrienne Giacobino*, Walter A. Eckl*, Hans G€unther Wahl‡, Johannes W. Dietrich§ and Rolf Larisch*

*Department of Nuclear Medicine, Klinikum Luedenscheid, Luedenscheid, Germany, †North Lakes Clinical, Ilkley, UK, ‡Institute for Laboratory Medicine, Klinikum Luedenscheid, Luedenscheid, and §Medical Department I, Endocrinology and Diabetology, Ruhr University of Bochum, Bochum, Germany

Clinical Endocrinology (2014)


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 levothyroxine (L-T4) treatment.

This prospective study employing 1912 consecutive patients analyses the interacting equilibria of TSH and free triiodothyronine (FT3), free thyroxine (FT4) in the circulation.

The complex interrelations between FT3, FT4 and TSH were modulated by age, body mass, thyroid volume, antibody status and L-T4 treatment. By group comparison and confirmation by more individual TSH-related regression, FT3 levels were significantly lower in L-T4 treated versus untreated non-hypothyroid autoimmune thyroiditis (median 4.6 vs 4.9 pmol/l, p<0.001), despite lower TSH (1.49 vs 2.93 mU/l, p< 0.001) and higher FT4 levels (16.8 vs 13.8 pmol/l, p< 0.001) in the treated group. Compared with disease-free controls, the FT3-TSH relationship was significantly displaced in treated carcinoma patients, with median TSH of 0.21 vs 1.63 (p< 0.001) at a comparable FT3 of 5.0 pmol/l in the groups. Disparities were reflected by calculated deiodinase activity and remained significant even after accounting for confounding influences in a multivariable model.

TSH, FT4 and FT3 each have their individual, but also interlocking roles to play in defining the overall patterns of thyroidal expression, regulation and metabolic activity. Equilibria typical of the healthy state are not invariant, but profoundly altered for example by L-T4 treatment. Consequently, this suggests the revisitation of strategies for treatment optimisation. This article is protected by copyright. All rights reserved.

The above abstract can be viewed here:

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Patients and/or caregivers may access this content for use in relation to their own personal healthcare or that of a family member only.
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Is it safe for patients taking thyroxine to have a low but not suppressed serum TSH concentration?

Endocrine Abstracts (2010) 21 OC5.6

Graham Leese & Robert Flynn
University of Dundee, Tayside, UK

For patients taking thyroxine replacement guidelines generally recommend aiming for a target TSH within the laboratory reference range. The evidence for this guidance is generally based on an extrapolation of data from patients with endogenous subclinical thyroid disease. We aimed to examine the safety of having a TSH which was either suppressed (≤0.03 mU/l), low (0.04–0.4 mU/l), 'normal' (0.4–4.0 mU/l) or raised (>4.0 mU/l) in a population-based cohort of patients all of whom were treated with thyroxine.

We used a population-based thyroid register (TEARS) linked to outcomes data from hospitalisation records, death certification data and other datasets between 1993 and 2001. The endpoints of cardiovascular disease, dysrhythmias and fractures were assessed. Patients were categorised, using a time weighted mean of all TSH recordings.

There were a total of 16 426 patients on thyroxine replacement (86% female, mean age 60 years) with a total follow-up of 74 586 years. Cardiovascular disease, dysrhythmias and fractures were increased in patients with a high TSH (adjusted hazards ratio 1.95 (1.73–2.21), 1.80 (1.33–2.44) and 1.83 (1.41–2.37) respectively), and patients with a suppressed TSH (1.37 (1.17–1.6), 1.6 (1.1–2.33) and 2.02 (1.55–2.62) respectively), when compared to patients with a TSH in the laboratory reference range. Patients with a low TSH did not have an increased risk of any of these outcomes (HR: 1.1 (0.99–1.123), 1.13 (0.88–1.47) and 1.13 (0.92–1.39) respectively.

People on long-term thyroxine with a high or suppressed TSH are at increased risk of cardiovascular disease, dysrhythmias and fractures. People with a low but not suppressed TSH did not have an increased risk of these outcomes in this study. It may be safe for patients treated with thyroxine to have a low but not suppressed serum TSH concentration.



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

Eur J Endocrinol. 2013 Jan 17;168(2):271-80. doi: 10.1530/EJE-12-0819. Print 2013 Feb.

Hoermann R, Midgley JE, Larisch R, Dietrich JW.

Department of Nuclear Medicine, Klinikum Luedenscheid, Paulmannshoeher Street 14, D-58515 Luedenscheid, Germany. rudolf.hoermann@gmail.com

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.
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.
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.
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.



TSH may not be a good marker for adequate thyroid hormone replacement therapy.

Wien Klin Wochenschr. 2005 Sep;117(18):636-40.

Alevizaki M, Mantzou E, Cimponeriu AT, Alevizaki CC, Koutras DA.
Endocrine Unit, Dept Medical Therapeutics, Alexandra Hospital, Athens University School of Medicine, Athens, Greece. mani@OTENET.gr

The objective of this study was to evaluate parameters of thyroid function and indices of peripheral thyroid hormone action (such as SHBG) in patients whose hypothyroidism was considered well controlled under current criteria. Eighty-five patients with T4-treated hypothyroidism, 28 of whom had athyria, were compared with 114 normal individuals with the same TSH levels. T3 levels were significantly lower in hypothyroidism although mean T4 and fT4 levels were significantly higher. Furthermore, mean SHBG levels were significantly lower in hypothyroidism independently of age. The difference remained when stricter criteria for adequate treatment were applied (TSH < 2.5 microgU/ml). Significant negative correlations were found between logTSH and T3. The slopes of the regression lines of T3 to TSH were significantly different in the control group and the hypothyroid group: thus, for the same TSH levels, T3 levels were lower in the hypothyroid group. We conclude that patients with T4-treated hypothyroidism have lower T3 levels, lower T3/T4 ratio and lower SHBG than normal individuals with the same TSH, perhaps indicating relative tissue hypothyroidism in the liver. TSH levels used to monitor substitution, mostly regulated by intracellular T3 in the pituitary, may not be such a good indicator of adequate thyroid hormone action in all tissues. The co-administration of T3 may prove more effective in this respect, provided novel suitable preparations are developed. Until this is accomplished, substitution in hypothyroidism should aim at low normal TSH, to ensure normal T3 levels.