A Second Opinion

A novel approach to treating hypothyroidism shifts the focus from TSH levels.

Rudolf Hoermann, MD, PhD, a consulting endocrinologist based in Australia, talks to Endocrine News about a new approach to treating patients with hypothyroidism. Hoermann counters that regulating the HPT axis from a T-3-inclusive perspective as well as considering other factors aside from TSH levels could lead to a “rebirth of endocrinology as a unique regulatory discipline” beyond statistical analysis.

A few years ago, an article appeared in BMC Endocrine Disorders titled, “Time for a reassessment of the treatment of hypothyroidism.” With this relatively direct title, the article served as a call to action for those who treat hypothyroidism, pointing to the “consequential historical shift in the treatment of thyroid disease, driven by an over-reliance of a single laboratory parameter [thyroid stimulating hormone].”

The authors go on to point out that this singular focus on TSH has resulted in almost dogmatic treatment guidelines, resulting in the pendulum swinging from fear of drug-induced thyrotoxicosis to undertreated hypothyroidism. The paper came on the heels of a 2018 American Thyroid Association report that found many patients were dissatisfied with their thyroid treatments or their doctors. Many patients who responded to this satisfaction survey expressed “a strong desire for the development of additional hypothyroidism treatment options.” 

“Given the existence of the thyroidal T3 shunt, the diagnostic reliance based solely on TSH leads to misclassification and consecutive dissatisfaction of patients,” says Rudolf Hoermann, MD, PhD, former head of the Department of Endocrinology at Klinikum Lüdenscheid, Germany (and a consulting endocrinologist based in Yandina, Queensland, Australia.) “Serious correction of scientific evidence is not unprecedented in medicine, and we explained why this may be necessary in the treatment of hypothyroidism.”

Then, last year, Hoermann and his co-authors published a paper in Frontiers in Endocrinology, using a proof-of-concept mathematical model to elucidate the principles of the hypothalamic-pituitary-thyroid (HPT) axis in the treatment of thyroid disease. “We’ve believed for quite some time that it is essential to re-consider effective system regulation of the HPT axis from a T3-inclusive perspective,” he says.

Here we’ll look at this work, and how a re-examination of the treatment of hypothyroidism, especially through the lens of T3, could improve outcomes for patients and their physicians.

“Subclinical Hypothyroidism”

Hoermann tells Endocrine News that he and his co-authors wanted to find why the balance point is so heavily guarded for optimum thermodynamic efficiency, yet under certain conditions, the system can change quite dramatically from its previous state, with its own system of regulation. He explains that the endocrine system is designed to protect a state of integrity and inner workings of the system when faced with adverse conditions and challenges arising outside of the system, which means, in HPT axis regulation, FT4, and even more so FT3, are maintained in a tight concentration range, to allow for the proper functioning of the many dependent metabolic processes.

“However, if the previous homeostatic level becomes indefensible it may be advantageous to adapt it to a new level,” he says. “This flexibility to choose between the preservation of homeostasis and its adaptation (allostasis) supports optimum resilience in stressful situations. Since the classical HPT model of TSH-FT4 regulation does not account for such properties, we came to the conclusion that HPT axis regulation needs to include T3.”

Since hypothyroidism was first clinically described in 1870, TSH emerged as the predominant marker, mainly under the wrong assumption that a person’s own pituitary may be best suited to accurately reflect the peripheral thyroid state of that person. Hoermann says that this assumption led to “subclinical hypothyroidism,” diagnosed when the TSH value exceeds its reference range, but FT4 concentration is within range.

“The endocrine mechanisms of the HPT control should be extended to address important aspects of T3 physiology, together with the predominance of presentation and uniqueness of each patient’s biochemistry. This offers a chance of a rebirth of endocrinology as a unique regulatory discipline beyond the predominant statistical area of research.”

Rudolf Hoermann, MD, PhD, consulting endocrinologist, Yandina, Queensland, Australia

TSH can rise in response to seasonal change, cold exposure, fasting, weight gain, infectious disease, and psychological stress. “Many clinical studies have obscured a clear distinction between these different entities, reporting conflated statistical outcomes,” Hoermann says. “Given the thyroidal T3 shunt and its influence on HPT regulation — namely that TSH feedforward controls T3 secretion and T4-T3 conversion efficiency — TSH cannot be regarded as passively responsive and reflective, rather acting pro-actively and correctively.”

Therefore, according to Hoermann, “subclinical hypothyroidism” does not define an entity or disease in need of treatment. The distinction lies not so much in the moderate TSH increase, but in its etiology and whether its corrective action is successful in preserving FT3 homeostasis. “The therapeutic goal can no longer be defined by TSH and its ‘normalization’ but shifts to restoration of FT3 homeostasis. The latter is more closely associated with symptom relief according to recent clinical studies. That way, a better understanding of the regulatory mechanisms translates to improved patient care.”

Four Hormones of the HPT Axis

To get a better understanding of these regulatory mechanisms, Hoermann and his co-authors developed the aforementioned proof-of-concept mathematical model, which allowed them to gain theoretical insights into the effective system control of the HPT axis. The authors describe the model as four nonlinear, parameterized, first-order ordinary differential equations (ODEs) that account for the interactions of the four hormones TRH, TSH, FT4 and FT3 in the HPT axis regulation.

The extended system incorporated FT3 homeostasis as a system goal, including feedforward of TSH on FT3 at the lower level and feedback of FT3 on TSH and TRH at the upper levels. One of the mechanisms examined was thyroidectomy, and the authors found that thyroidectomy breaks T3 homeostasis, and the loss of the intra-thyroidal T3 shunt shifts the balance between TSH, FT4 and FT3 levels, compared to that prior to surgery. “Together with other clinical studies, it explains why their former TSH level is no longer indicative of the euthyroid state, and these patients may continue to suffer from residual symptoms,” Hoermann says.

The findings further bolster the need to account for the conditionality of FT3/FT4 levels when aiming for them in treatment. Hoermann says the FT3/FT4 ratio in thyroid disease will alter from the healthy state in raising the ratio in subclinical hypothyroidism (relational stability), and also in nonthyroidal disease (low T3 syndrome) but lowering it in hypothyroidism in the absence of a functioning thyroid gland. “We should therefore reconsider the importance of measuring FT3,” he says. “It is the chief biologically active thyroid hormone and more integral to HPT axis regulation than previously thought.”

Overlapping Symptoms

Still, it seems some physicians have a habit of dismissing patient symptoms because of a seemingly normal TSH value. Hoermann sees TSH as too respected a diagnostic tool for both hypothyroidism and T4 treatment. “If the thyroid is failing, then FT3/FT4 ratio changes in favor of T3’s bigger contribution stimulated by more TSH,” he says. “In therapy, a satisfactory outcome may require more T4 to optimize FT3. The interpretation of a given TSH value should be conditional, as appropriate to the condition and the resulting FT4 and FT3 levels.”

“Denying these patients T3 normalization does not help their symptoms. We should not place a TSH value, which we may yet have to fully understand, over patient complaints we understand well as a doctor.”

Rudolf Hoermann, MD, PhD, consulting endocrinologist, Yandina, Queensland, Australia

And again, not recognizing the limitations and conditionality of isolated sensitive TSH measurements has resulted in many patients complaining about residual hypothyroid symptoms. In the case of a thyroidectomy, Hoermann says, to get the FT3 to the same level it had been prior to thyroidectomy, many patients on LT4 would need a suppressed TSH after surgery to achieve this goal, which per se does not mean hyperthyroidism to them if their balance point has shifted in the absence of TSH feedforward onto FT3.

“Denying these patients T3 normalization does not help their symptoms,” Hoermann says. “We should not place a TSH value, which we may yet have to fully understand, over patient complaints we understand well as a doctor. This is not to say all is easy — there are non-specific and overlapping symptoms with other diseases, and over-treatment must be avoided. However, it is equally clear there are residual symptoms in the presence of a ‘normal’ TSH.”

Hoermann goes on to say that in realizing each patient achieves a unique balance between their FT3, FT4 and TSH levels, we must avoid inappropriate generalization and a one-size-fits-all approach, again pointing to the importance of personalized medicine. “This is important since the amalgamation of dissimilar subgroups (whose members do not share the same average or optimum) in clinical studies results in a statistical error (collider stratification bias),” he says. “We also suggest to blindly study patient satisfaction against FT3/FT4 and TSH values in different subgroups of patients on differing treatment modalities.”

In January, Endocrine News spoke with Antonio Bianco, MD, PhD, about his book Rethinking Hypothyroidism, in which he argues that the current approach to treating hypothyroidism is failing many patients. Hoermann says he and his co-authors were grateful for Bianco’s insight, and they hope that this growing chorus will soon be reflected in the guidelines.

Clinical presentation should have predominated over biochemistry to resolve the conflict, Hoermann continues. The guidelines have a role in standardizing patient care, but in doing so they tend to marginalize patients that do not fit in. They were meant to provide general guidance only but not to be instrumentalized as a legal imperative to treat everybody the same.  “The endocrine mechanisms of the HPT control should be extended to address important aspects of T3 physiology, together with the predominance of presentation and uniqueness of each patient’s biochemistry,” he says. “This offers a chance of a rebirth of endocrinology as a unique regulatory discipline beyond the predominant statistical area of research.”

Bagley is the senior editor of Endocrine News. In the June issue, he wrote about the ENDO 2023 oral presentation touting a potential new treatment for pediatric growth deficiency that would eliminate injections.

[Editor’s note: This post has been updated with “FT3/FT4,” since FT3 is relatively more produced.]