Rationale: Low TSH vs. thyrotoxicosis

Updated 2018-11-27

In thyroid therapy, it is possible for patients to have a low TSH and NOT be hyperthyroid or have thyrotoxicosis from being overdosed on thyroid medication.

True thyrotoxicosis is caused by T3 excess of any cause. Hyperthyroidism, however, is thyroidal in origin.

Werner and Ingbar’s Thyroid, 9th edition, 2005 is the most recent edition to include 14 chapters that specified the effects of thyrotoxicosis on the body. Chapter 22, which opens this section, explains its definition:

We use the term thyrotoxicosis to mean the clinical syndrome of hypermetabolism and hyperactivity that results when the serum concentrations of free thyroxine (T4), free triiodothyronine (T3), or both, are high.

The term hyperthyroidism is used to mean sustained increases in thyroid hormone biosynthesis and secretion by the thyroid gland.

Thus, the terms thyrotoxicosis and hyperthyroidism are not synonymous. (p. 454)

Although T4 excess is mentioned as present in the bloodstream in thyrotoxicosis, T4 causes thyrotoxicosis as it is converted to T3 hormone.

Only T3 hormone and its metabolite T2 can hyper-stimulate cells and tissues by initiating powerful “genomic” effects in the thyroid hormone receptor. As of 2018, T4 hormone has no known “genomic” effects in the thyroid hormone receptor and limited non-genomic effects.

Whether or not T4 excess exists in bloodstream, only a state of T3 excess in cells can cause thyrotoxicosis.

Low TSH is not a requirement in thyrotoxicosis. Werner and Ingbar’s Thyroid explains that it can be induced by excess TSH stimulation of a thyroid gland (Chapter 24).

Signs of thyrotoxicosis

In thyrotoxicosis, the following signs are present, not just low TSH:

“Increases in heart rate are characteristic of thyrotoxicosis; more than 90% of patients have resting tachycardia, and many have heart rates of 120 beats per minute or higher.”

“Systemic vascular resistance is 50-70% lower.”

“Cardiac output” increases by “200-300%”

Systolic blood pressure increases while diastolic pressure decreases. (p. 560)

If hyperthyroid status persists,

  • Body temperature will be elevated
  • Muscle catabolism will cause weakness and tremors in limbs
  • Total and LDL cholesterol will be low
  • Sex hormone binding globulin (SHBG) will be high

A hyperthyroid state affects the entire body, not just the pituitary gland that secretes TSH.

Therefore whenever TSH is low, one should examine whether a patient is truly hyperthyroid by measuring Free T3 levels and by looking for classic physiological effects of high T3 beyond low TSH.

How high does T3 need to be to cause true hyperthyroidism?

Each person has a different serum Free T3 level at which hyperthyroid physiologic responses appear.

Some patients’ thyroid hormone receptors are less sensitive to T3 hormone. “Thyroid hormone resistance” is usually caused by a genetic defect in the THRB gene. It means that person requires more T3 than normal to achieve a truly euthyroid state.

On the other hand, some patients are extremely sensitive to even small Free T3 fluctuations and rises in bloodstream. These patients may have classic hyperthyroid responses 2-4 hours after taking a dose of T3 medication, when Free T3 peaks in bloodstream.

The Free T3 reference range is based on statistical norms. Each laboratory may adjust its range to adapt to the population that regularly tests Free T3. In regions where more hypothyroid than hyperthyroid patients are tested, the range can be biased to lower numbers.

On T3-based therapy, Free T3 could be slightly above reference range without causing hyperthyroidism if Free T4 levels are low-normal or low. This is because additional Free T3 molecules are required to replace the Free T4 molecules that would have converted to Free T3 beyond the bloodstream. It’s simple math.

Does peak T3 from the “T3 dosing effect” harm the body? Not likely.

Every cell, tissue, and organ expresses Deiodinase Type 3 (D3), the enzyme that keeps a lookout for high T3 and is always ready to convert excess T3 into T2.

In early tests of T3 effects, patients were given enormous doses of T3 (even as high as 1000 micrograms!) but their bodies did not experience adverse effects, only a slightly raised heart rate. The liver, which expresses D3, can clear out a lot of excess T3 from circulating blood.

Our bodies are well equipped to deal with much smaller “T3 mountains” in well-managed long term T3 therapy. In full thyroid-replacement T3 monotherapy, a daily dose averaging 60-80 mcg is usually divided into 3-4 smaller doses per day.  Cytomel T3 is usually taken in tiny doses of 5-10 mcg each in T3-T4 combination therapy.

This “T3 dosing effect” of TSH suppression therefore does not necessarily reflect a state of persistent excess T3, either when judged by Free T3 levels in blood or by patients’ metabolic rate.

The paradox of Low TSH and suboptimal T3

TSH can be suppressed by T4 alone, by medications, by fasting, by critical or chronic illness, or by minor temporary peaks in Free T3 during T3-T4 combination therapy.

  • In TSH-suppressive therapy after thyroidectomy for thyroid cancer, T4 monotherapy is often used to suppress TSH, and in this state, 15% of patients can maintain a Free T3 level below reference range.[61, 62]
  • In “non-thyroidal illness” — a critical or chronic illness can cause Low T3 even if the thyroid gland is healthy; TSH and T4 will often drop low following the T3. If T3 stays too low for too long, the patient is at high risk of death.
  • In T3/T4 combination therapy or desiccated thyroid therapy, the ingestion of T3 hormone by the oral route, rather than by gradual secretion and conversion, can suppress TSH even if Free T3 levels fluctuate below the optimal range.

Low TSH = Not hyperthyroid

A patient on thyroid therapy can be HYPOthyroid with a low TSH.

Hypothyroidism is caused by suboptimal T3 levels, not by TSH or T4 levels.

A person’s TSH will respond to the most abundant thyroid hormone, which could be either T4 or T3, depending on the form of therapy you are taking.

Low TSH in L-T4 monotherapy

In L-T4 monotherapy, TSH can be completely suppressed by a high T4 alone. This is what happens when Thyroid Cancer patients are put on “TSH suppressive therapy.” They take a higher dose of T4 than other patients in order to suppress the TSH, because TSH can stimulate the regrowth of cancer.

Here’s the problem with suppressing TSH with T4 pills:  Your TSH can be utterly blind to low serum T3.

How and why does this happen?

The pituitary gland doesn’t completely depend on T3 from bloodstream.  It has a safety net. It is equipped to survive temporary, mild, low T3 levels in blood. In a person who has a normal thyroid gland, their T3 naturally goes low when they are sick, when the body needs to slow down its metabolic rate — to lower the heart rate, energy expenditure, etc.

Whenever blood T3 is very low, the pituitary gland converts more T4 into T3 locally within its own tissues, using the enzyme called Deiodinase type 2. From your pituitary gland’s point of view, nothing’s wrong with low Free T3 in blood. (Sadly, some doctors are trained to trust the pituitary report more than your FT3 data.)

When the pituitary is very satisfied by the T3 levels within its own tissues, it reduces TSH or stops producing TSH.

This patient is not HYPER-thyroid due to low TSH.  The pituitary gland itself is protected from true T4/T3 hyperthyroidism by the other enzyme, Deiodinase type 3 (D3), which inactivates excess T4 and T3 as necessary. Your pituitary will be just fine with its internal T3 levels, even if it’s not producing any TSH at all. It’s definitely not in a hyperthyroid state while it’s using D2 to convert its T4 into T3. As proof of this, your pituitary will still produce all its other hormones your body needs, it’s just not producing as much TSH.

But if the T3 is low, the rest of the patient’s body is very likely hypOthyroid from low T3.

Whenever T3 in bloodstream is low, our organs that depend on bloodstream T3, the organs that don’t convert internally as well as the pituitary does —  organs like your heart muscle — could be anywhere between slightly deficient and absolutely starving!

Low TSH in T3-based therapy

In L-T3-based thyroid therapies such as desiccated thyroid extract (NDT / DTE),  T3-T4 combination therapy, and T3 monotherapy, low-normal and suppressed TSH can be a benign side-effect of oral dosing.

This is what we call L-T3 dosing effects.

The hypothalamus and pituitary are not programmed for oral dosing. They are more accurate at interpreting and responding to “endogenous” T3 and can make mistakes when interpreting data from “exogenous” T3.

In healthy thyroid hormone physiology, T3 appears in the body at a smooth, constant rate. There’s a small circadian rhythm in Free T3 that echoes the TSH’s circadian rhythm.

But on T3 medication, there can be huge mountains in Free T3 after each dose, followed by deep valleys because T3 has a short half-life in bloodstream.

One 50 mcg dose of T3, tested in pharmokinetic study by Jonklaas et al (2015) suppresses TSH within an hour, long before Free T3 peaks in the bloodstream around two and a half to three hours post dose.

TSH stays suppressed for a very long time after a dose, even if T3 levels can fall very low before the next dose of T3. The loss of T3 from bloodstream can be more swift in a person whose ratio of “Free T3” to “bound T3” is high, due to lower levels of “thyroxine binding globulin.” Free T3 is available to enter cells and can be cleared out more quickly than bound T3.

Because of the short half-life of T3, the TSH can be suppressed in T3-based therapy long before a patient achieves a dose that sustains their Free T3 levels within an “optimum” range for their body.

To put it simply, when dosing T3 orally, the hypothalamus and pituitary overreact to the HIGH points in the fluctuations of T3. They assume that this level of T3 will persist because it is coming from a thyroid gland.

When the TSH overreacts, the doctor may also overreact by lowering the patient’s dose.

Sadly, many T3-based therapy patients are UNDERdosed for this reason. The doctor’s guidelines and flowcharts say they cannot let TSH go below reference range.

When the TSH reference range is applied without qualifiers and conditions, it can prevent a doctor from applying critical thinking and looking for further confirming evidence.

Can low TSH damage your health?

Recently, low TSH alone has been “associated” with a higher risk of osteoporosis and heart disease.

These population studies have established a TSH-disease association without measuring the most powerful thyroid hormone, Free T3. They have focused on a confounding variable, because low TSH is often, but not always, present with a high Free T3.

They have been unable to establish an independent cause-effect relationship between low TSH and disease.

Fear of heart disease with low TSH

As for heart disease and cardiac events, low TSH simply cannot be the direct or independent “cause.”

In 2015, an article’s title strongly asserted that TSH is a distraction: “Free triiodothyronine [T3], not thyroid stimulating hormone [TSH], should be focused on for risk stratification in acute decompensated heart failure.” [85

Research has shown that both high T3 and low T3 are risk factors for adverse cardiac events. [82, 83]

When articles focus on the topic of “thyroid and heart,” they often use the term “thyroid hormone” as a synonym for T3 hormone. They are more concerned with T3 than T4 or TSH.

Some cardiologists recommend measuring T3 in diagnosis and treatment of cardiac disease regardless of whether the patient has a risk of thyroid disease.[84]

Fear of osteoporosis with low TSH

In 2014, a review of research aptly concluded that “it is still unclear if bone changes observed in state of thyrotoxicosis are related to lack of TSH or to excess of thyroid hormones or both of them.” [94

Four years later, in 2018, some observant researchers studying this TSH – bone association stated “we found no evidence for a causal effect of circulating TSH on BMD [bone mineral density].” [99]

Research long ago in the 1990s on 1,180 thyroid patients compared these two cohorts — patients who had suppressed TSH and those who did not.

Even though they did not measure T3 (unfortunately) but only measured TSH and T4, the study found

  • “There was no increase in risk for overall fracture, fractured neck of femur or breast carcinoma in those on thyroxine with suppressed or normal TSH.” — No matter how much or how little TSH they had, there were no clear risk associations.
  • “There was no excess of fractures in patients on L-thyroxine even if the TSH is suppressed.” Low TSH did not “cause” fractures. [86]

The key role of T3 in bone health

Reviews of research on “thyroid and bone” explain bone turnover slows down with insufficient T3 and bone turnover speeds up with excess T3.

Speed is an important factor in research, because researchers aim for quick turnover of published articles.

Within the time frame of most research studies, science has discovered that speedy loss of bone mineral density is caused by excess T3. Even short-term excess T3 can be harmful because the damage happens so quickly.

Therefore, studies can easily observe the effects of high T3 and/or high T4 levels on bone mineral density loss and fracture. [89, 90]

It takes a longer time to see harm to bones from low T3. But it can make bones brittle, and during aging, fractures can happen due to long-term low T3.

Normal T3 levels cancel out the “Low TSH” risk

A novel research methodology in 2015 divided patients’ T3 levels into tertiles (3 levels) rather than just averaging all of the T3 data into a single number.

Researchers found low TSH was only associated with bone loss when T3 was in the highest tertile (above reference range).

Unexpectedly, “normal”-range T3 (rather than excess T3) was found to reduce bone loss despite low TSH. [97]

TSH is a difficult variable to understand because it has an indirect effect on T3. In this study’s discussion section, researchers cited a previous study that had shown TSH administration to increase osteoblast cells’ expression of Deiodinase type 2 (which converts T4 to T3 in tissues). Therefore, they reasoned, “TSH may indirectly promote bone turnover by increasing local T3 availability in osteoblasts in addition to its direct action on bone remodeling.” [128 (p.7)In other words, TSH can upregulate D2, and thereby stimulate T4 to convert to T3 within bone cells, thus “increasing local T3 availability” in bones.

To resolve the debate on TSH versus T3, we have to supplement “observational studies” of humans with studies of the molecular action of hormone in bone cells in the laboratory setting.

Lab studies are capable of explaining the causal mechanisms of each hormone by studying cells under a microscope and measuring levels of substances associated with bone activity.

Lab studies _can_ distinguish between TSH and T3 hormone effects. [92, 93]

The clear chain of “indirect” TSH influence (by means of enhancing D2 to stimulate conversion to T3)  and “direct” T3 causation has repeatedly been clarified in molecular biology articles over the years; in 2005,[95] and then again in 2008.[96]

In laboratory literature, you have to carefully take notice of where T3 is being measured, in the blood, or in the cells. The scientists’ distinction between measures of “serum” (blood) thyroid hormone and “cellular” thyroid hormone is crucial, since earlier research found that “serum” levels of thyroid hormone (T3/T4) were not as statistically significant as “serum” TSH.

Heemstra et al’s 2009 study analyzed bone mineralization markers from patients with temporarily very low T3 in Thryoid Cancer (DTC) patients during medication withdrawal who had been injected with very high levels of bovine recombinant TSH, to see if the TSH protected their bones from the effect of low T3 on slow bone turnover.  They found that if a patient lacks T4 and/or T3 in serum (true hypothyroidism) regardless of TSH level, they can experience harm to their bones:

  • “In summary, bone turnover is decreased during hypothyroidism due to thyroxine withdrawal in DTC patients. As rhTSH did not impact on bone turnover, we conclude that the low thyroid hormone levels instead of the increased TSH levels are responsible for the decreased bone resorption during hypothyroidism in DTC patients.” [98]

In this research paper, their discussion section directly addressed the “proposal” (an untested theory) that high TSH can protect bones from harm. They cited past research, including their own, to cast serious doubt on this proposal.

In 2010, a study of patients on TSH-suppressive L-T4 therapy after thyroid cancer showed that Free T3, but not TSH, was the independent risk factor for decreased osteocalcin levels in bone. [91]

Thus, a TSH deficiency appears not to cause any harm to bones at all, as long as a patient concurrently has neither excess T3 nor low T3 levels.

Implications for thyroid therapy: Measure T3!

Why do hypothyroidism treatment guidelines in Canada continue to make frighteningly vague warnings such as “Patients on thyroxine therapy with TSH < 0.2 mU/L may have increased health risk”? [15]

The real truth, according to the scientific evidence, is that patients with Free T3 above or below the normal range will have increased health risk.

That’s why measuring Free T3 is important in thyroid therapy.

The pituitary indicator, TSH, is not capable of interpreting this complex relationship in treated patients. An unknown number of patients who remain symptomatically and biologically hypothyroid from low T3 with a “normal TSH” is being condemned to live for years, even decades, with thyroid hormone deficiency from the perspective of their body.


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