Relational stability among thyroid hormones and TSH, part 1

In a series of posts, I’m sharing my plainer-English paraphrase of a very important article in thyroid science.

My hope is that the public, doctors, and educated thyroid patients can better understand and appreciate its insights.

This article by Dr. Rudolf Hoermann and colleagues Midgley, Larisch, and Dietrich explains the complex interrelationships between TSH, T4 and T3 hormones.

  • Hoermann, R., 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.

I often cite and comment on articles by Hoermann and colleagues on our blog, and I plan to comment soon on some of their more recent work. This article’s concepts provide a good foundation for understanding what they’ve been publishing in 2019 and will publish in 2020.

Why is this article by Hoermann and team so important?

Most models of the Hypothalamus – Pituitary – Thyroid axis (HPT axis) omit or deemphasize the most powerful and essential thyroid hormone, T3.

Many scientists and medical textbooks are still citing oversimplified models of the HPT axis developed in the early 2000s and earlier. The scientific understanding is evolving and shifting among the experts who focus on this area.

It is part of human psychology and the process of scientific change to resist a paradigm shift as long as possible. Many have a strong reluctance to integrate the power of T3 hormone into an updated understanding of the system, preferring to see thyroid health and disease through the lenses of an older, simpler, TSH-T4 dominant paradigm.

Seeing the HPT axis through Dr. Hoermann and team’s scientific eyes can be very helpful when interpreting laboratory results as they shift from three situations — from 1) thyroid health, to 2) thyroid disease, to 3) thyroid disease + thyroid hormone therapy.

If a doctor or patient misunderstands how TSH, FT3 and FT4 hormones shift and distort as a “trio” or as a triangle with different shapes, they can be mistaken in assessing whether the person’s thyroid gland is permanently damaged or not (before therapy), and whether the person with a thyroid disability is euthyroid, or not, on a dose of thyroid hormones.

Who is Dr. Hoermann’s research team?

Dr. Rudolf Hoermann and his coauthors are some of the world’s leading research scientists who have examined the HPT axis from various clinical and theoretical angles.

Many of their articles present original clinical research findings. All of their articles engage in extensive review and citation of prior thyroid science, not only to reiterate their principles but to build on or critique them.

Collectively, they carry knowledge of the technical aspects of FT4 and FT3 as laboratory tests (Midgley), the HPT axis alterations in illness (Dietrich), the operation of TSH-receptor antibodies on TSH and thyroid health (Dietrich & Hoermann), and the treatment of patients on LT4 monotherapy (Hoermann & Larisch).

In collaboration with other scientists, Hoermann’s research team has created an updated mathematical model of the pituitary – thyroid feedforward and feedback loop (Berberich et al, 2018). They have examined the shifts in the axis during illness and common health conditions (Chatzitomaris et al, 2017). One of their core team members. Johannes Dietrich, has developed a very practical tool — a free downloadable app, SPINA-Thyr, which enables clinicians and researchers to enter TSH, FT4 and FT3 results to analyze gland production ability, even mild degrees of TSH under- or oversecretion, and T4-T3 hormone conversion capacity (Dietrich et al, 2016).

They are one of the few research teams in endocrinology that are moving thyroid therapy forward by helping us see the vulnerability of TSH and the challenges of maintaining euthyroid levels of T3.

Their articles have strongly and openly advocated for Free T3 testing in thyroid therapy. In patients whose metabolism cannot adapt well to LT4 monotherapy, they suggest that T3-hormone-based therapies offer a logical solution. In recent years, they have occasionally provided incisive critiques of the tradition of clinical research on T3-T4 combination therapy.

This team has not yet engaged in their own clinical studies of T3-based hormone therapies. Their studies of LT4 monotherapy, however, provide many insights into treatment that can be translated, with adjustment, to T3-based therapy contexts.

Overall, they have integrated the T3 hormone into the model and have enabled us all to see the flexibility, limitations, and high degree of individuality of the HPT axis.

About my paraphrase

I initially made the paraphrase for my personal use to aid my own understanding of its profound concepts. I see now that it is a service to thyroid patients and doctors to share my paraphrase with the public.

The article deserves a paraphrase because Dr. Hoermann and team tend to write in high English style, using complex grammar and erudite vocabulary. Since they also use a lot of technical language at the same time, it can make for quite dense reading and re-reading of sentences.

I have aimed to communicate as accurately as possible the concepts and word choice of the article through a mixture of direct quotation, paraphrase, summary, and elaboration.

Plainer English style was was achieved by strategies such as simplifying grammar and syntax, reorganizing the order of phrases and words within sentences without changing their meaning, and clarifying pronoun reference and comparisons where they were indirect or implied.

I have occasionally omitted highly technical passages and examples or digressions that I believe are of secondary importance — you can find them in the original.

I have occasionally inserted some definitions and further explanations to aid public understanding of technical language and concepts. The concepts require a paraphraser to be familiar with articles in their reference list as well as others that they don’t cite. Some explanations have made the passages longer than their denser originals.

Throughout, I aimed to maintain the original order of sentences, paragraphs, and sections. Some paragraphs and sentences have been combined or divided to provide further clarity and emphasis. Comprehension can be aided by making paragraphs shorter.

I engage in adaptive paraphrase of this article and insert images from scientific publications within the terms of Canadian and US copyright “fair dealing” and “fair use” for purposes of education and review: See copyright law info

The abstract, paraphrased

In the healthy euthyroid state, thyroid hormone concentrations are maintained through appropriate stimulation by the pituitary gland’s secretion of thyroid-stimulating hormone (TSH).

This is a dynamic system under constant high pressure from metabolic demand for thyroid hormone supply, so it is vital to guard against overstimulation by TSH and oversecretion by the thyroid gland.

Therefore, several defensive mechanisms protect against accidental overstimulation, such as

  • the protein binding of thyroid hormones in blood plasma (bound vs. free hormone),
  • the conversion of T4 into the more active hormone T3,
  • the active transportation of T4 and T3 across cell membranes (thyroid hormone transmembrane transport),
  • the counter-regulatory activities of Reverse T3 (RT3) and thyronamines (the many derivatives of thyroid hormones), and
  • the control of TSH levels via the negative hypothalamic-pituitary-thyroid feedback loop (the power of T4 and T3 to reduce TSH concentrations).

Unfortunately, TSH has gained a dominant but misguided role in the interpretation of thyroid function.

The dominance of TSH is based on the incorrect assumption that its exceptional sensitivity as a hormone and as a laboratory test translates into superior diagnostic performance in all situations.

However, thyroid disease classifications that depend only on TSH values are heavily influenced by statistical analysis techniques. The TSH reference range is itself a statistical phenomenon based on a very diverse population of persons who are judged to be free of thyroid disease and in a state of health. A change in the mathematical interpretation of the TSH result can change the clinical interpretation significantly. “Normality” in thyroid hormone status is defined very differently based on univariate (one-variable) calculations based on TSH only, and multivariate (multi-variable) calculations involving two or three hormone levels (TSH + FT4, or all three, TSH + FT4 + FT3).

This difference necessitates a separation between two roles of TSH, in screening and in diagnosis:

  1. TSH plays one role as a sensitive screening test when its concentrations are far outside of reference range, and
  2. TSH plays another role to diagnose a person’s hormone status when its concentrations are within the laboratory reference range.

Thyroid hormones achieve a “homeostatic equilibrim” in health.

(“Homeostasis” is the concept of a healthy dynamic equilibrium achieved by adaptive systems in an organism’s biology, rather than a constant, unchanging state. The homeostatic “set point” is another a term that some people have used to describe the homeostatic equilibrium or the temporarily stable range of levels of thyroid hormones and TSH.)

This homeostatic equilibrium is less variable among individuals in a state of health than in a state of disease.

But there is variability even among healthy people’s TSH, FT3 and FT4 hormone relationships.

These variations between people do not follow a pattern of random genetic variation. Instead, their pattern indicates there is variation in homeostatic control among the hormones across the entire euthyroid ranges of TSH, FT4 and FT3. The body adjusts hormone levels in response to early and progressive changes in the system, for example, as a thyroid gland dies from autoimmune attack.

In the event of imminent thyroid gland failure causing a reduced secretion of FT4 per unit of TSH, the efficiency of conversion of T4 into T3 increases in the attempt to maintain FT3 stability.

The body compensates for lower T4 levels by increasing T3 concentrations, shifting the T4:T3 ratio in blood. In such situations, T3 stability takes priority over the maintenance of the prior set point of TSH and FT4. Achieving a healthy Free T3 supply is the goal of the system’s restabilization. The shifted TSH-FT4 relationship enables the new adaptive Free T4:T3 ratio.

This well-known example of the rise of T3 in mild early thyroid failure suggests the concept of “relational stability,” rather than a static and unchanging state of hormone health. The currently optimal state of stability shifts.

Healthy TSH-T4-T3 relationships are not the same across members of a population, and they are not the same within an individual person over time. It is a “relational” form of stability because it is not a system determined by a single hormone in isolation from the others.

These scientific findings about the adaptive nature of the HPT axis have significant implications for TSH reference limits as well as treatment targets for patients on levothyroxine (LT4) therapy.

We even propose using a patient’s own archival markers of hormone levels (when available) to facilitate the interpretation of relational stability among all parameters, TSH, T4, and T3.

All parts of the paraphrase

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