Gullo: LT4 monotherapy and thyroid loss invert FT3 and FT4 per unit of TSH

In 2011, Gullo’s research team published a landmark study in thyroid therapy titled “Levothyroxine Monotherapy Cannot Guarantee Euthyroidism in All Athyreotic Patients.”

Gullo and colleagues examined the TSH, FT3 and FT4 levels and the FT3:FT4 ratios of 1,811 thyroidless patients on levothyroxine (LT4) monotherapy and compared them with 3,875 healthy controls.

Gullo’s study shook the foundations of dogma by looking at distortions to thyroid hormone levels within the TSH reference range. It questioned the assumption that “euthyroid” status was achieved merely by normalizing TSH to the range of the thyroid-healthy population. Since it was published in 2011, the article has inspired researchers and patients. I hope to reignite that inspiration.

Gullo’s team found several inequities between the two populations at the same TSH levels:

  1. The healthy controls’ relative position of FT3 and FT4 within their reference ranges was inverted by thyroid loss and LT4 monotherapy.
  2. The FT3 hormone, after being lowered in treated people, behaved abnormally in yet another way: FT3 fell further as TSH rose within reference range, while healthy subjects’ average FT3 did not fall as TSH rose within reference.
  3. The separation between the lower FT3 and higher FT4 in the treated population was a significant contrast with controls. As a result of this relative FT3 shortfall per unit of FT4, the average FT3:FT4 ratio in treated people fell significantly lower, with 29.6% of LT4-treated patients below the ratio’s reference range in controls.
  4. Women and older persons were more likely to have the lower FT3 levels and FT3:FT4 ratios, but the absolute FT3 loss was far more significant in the LT4-treated group.

In this post, I review and critique a set of FT3 and FT4 graphs by Gullo et al, 2011. They show general trends in average FT3 and FT4 relationships in blood at various levels of normal TSH.

I provide several ways of re-visualizing these graphs’ data so that we can see them enhanced by color coding and overlaid on top of each other.

Gullo’s original graphs’ Y-axes (vertical axis) didn’t show the full reference ranges, which means there’s a vertical distortion. Therefore, I provide visual adjustments that show the hormones’ relative positions within their ranges.

I also provide further commentary in light of other scientific research. What is the implication for health throughout the body, given that T3 hormone plays the vast majority of essential signaling, while T4 and TSH hormones have very different effects on the body? Why does the healthy HPT axis appear to maintain average circulating FT3 levels as TSH rises within range, and why can’t treated patients maintain their FT3 as TSH rises in range? Finally, what does this inequity mean for our treatment guidelines and testing policies?

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Step 1. Gullo’s original graphs

This pair of graphs separate FT4 trendlines in one graph from FT3 trendlines in another graph.

Both graphs have the same horizontal X axis — TSH from 1 to 10, on a logarithmic scale.

In the two original graphs, notice that:

  • dotted lines represent treated patients, with higher FT4 than controls.
  • bold lines represent euthyroid controls, with higher FT3 than treated patients.

Step 2. Gullo’s graphs overlaid, hormones in color

If one were to overlay the graphs as-is and turn FT3 trendlines pink, FT4 trendlines teal blue-green, you would get this image:

This image drives home the point that the TSH reference range 0.4 to 4.0 is the same, but the hormone levels differ considerably.

Step 3. Gullo’s graphs with full reference ranges adjusted to midpoints

Next, there’s a visual distortion that needs to be corrected. The Y axes (vertical) are not showing the full reference ranges.

  • Both the top and bottom of the FT4 range is missing (9.0 – 20.6 pmol/L).
  • The FT3 reference range is shortened at its top (2.9 – 6.0 pmol/L)

In addition, the center of the graphs are not adjusted to the mathematical mid-points of each of the reference ranges.

  • The midpoint of the FT4 range is 14.8 pmol/L
  • The midpoint of the FT3 range is 4.45 pmol/L

Now that full ranges are shown, and midpoints of the two reference ranges are aligned across the horizontal gray line, the FT4 trendlines in teal are positioned much higher in relationship to the two pink FT3 trendlines.

Now the graphs visually align with Gullo’s findings regarding the FT3:FT4 ratios in treated vs. untreated individuals.

The scales of injustice: Illustration

The injustice in the illustration above is that the two scales are evenly balanced in TSH concentration but they are very unequal in hormone concentrations of FT3 and FT4. Even if there are fewer pmol/L of FT3 in circulation, signaling potency of FT3 and its active T2 metabolite makes each pmol/L of FT3 worth many times the weight of a pmol/L of FT4. The person with the healthy thyroid is richer.

The injustice potentially becomes a sex-specific prejudice by means of research neglect of women’s health outcomes. Most of the FT3-deficient persons in Gullo’s study were women. “The percentage of athyreotic patients with FT3 serum levels lower than the normal range was 8.6% in males and 16.4% in females.”

For many decades, scientists have neglected to study the health risks of the population rendered FT3 deficient by thyroid disability and therapy, so we are still unable to determine whether women’s health suffers more than men at these lower levels of FT3 after complete thyroid tissue loss.

Data visualization critique

Of course, these two trendline graphs still have handicaps in communicating the true shape of the data.

  • Their strength is that they oversimplify, making the “bare bones” of a complex system stand out boldly.
  • Their weakness is also that they oversimplify, focusing only on the linear trends among statistical averages, failing to characterize the diversity and central tendency of data within the populations sampled.

Averages vs. distributions

By means of their focus on averages, the simple trendline graphs fail to identify the extent to which outliers exist with far higher FT4 levels beyond reference or far lower FT3 levels beyond these hormones’ reference ranges.

Fortunately, Gullo’s additional graphs revealed the distribution of FT4 and FT3 within LT4-treated populations, with a shaded area representing the controls’ range and a dotted line showing the mean among healthy controls.

Gullo’s research revealed that 29.3% of people with no thyroid function who are forced to live on T4 supply alone obtain a FT3:FT4 ratio below the reference range. In addition, 15.2% of this population is forced to suffer a FT3 below reference range merely for the sake of TSH normalization as a policy target.

Gullo’s study did not provide distribution graphs for healthy subjects alongside the LT4-treated patients’ distribution graphs, above.

Fortunately, Ganslmeier et al, 2014, provided a set of graphs using some of the most carefully-vetted data sets yet published. They even screened for mild thyroid failure using thyroid ultrasound and TRAb (anti-TSHR) antibody tests.

Notice that in the healthy FT3 distribution, two bars at the mid-point of range almost achieve 25%. This means that almost 50% of the healthy population attains mid-range FT3.

In the TSH-driven healthy controls, both low-normal and high-normal FT3 is rare. This data pattern echoes the FT3’s role as a metabolic target, in contrast with TSH, which is a metabolic tool, only one of several means of adjusting and maintaining euthyroid FT3 levels for the individual.

Separate hormone trends vs. individuals’ FT3:FT4 ratios

By isolating the two hormones’ averages, the simple trendline graphs do not express the FT3:FT4 ratios found within individuals, such as people with an extremely low ratio (top-of-range FT4 and a mid-range FT3, or mid-range FT4 with a bottom-of-range FT3).

Since the human body engages in continual 2-way transport of hormones in and out of cells where T4-T3 metabolism occurs, the ratio is a good representation of global T4-T3 conversion efficiency as well as thyroidal supply in healthy controls. In the thyroidless person who has been barred from access to both thyroidal and pharmaceutical T3 supply, the ratio purely represents metabolic efficiency.

Fortunately, Gullo provided a distribution graph for the LT4-treated patients’ ratios. They show a larger percentage of the treated population below reference in their ratio (29.7%) than for the FT3 levels below reference (15.2%):

Within the TSH reference range vs. below it

Populations that depend on TSH receptor signaling to stimulate 100% of their T3 and T4 hormone supply are different from populations whose TSHR signaling stimulates 0% of their thyroid hormone supply.

In the latter population, bloodstream FT3 and FT4 ratios that are not generated by TSHR signaling in a healthy thyroid gland will interfere in the natural feedback loop and imbalance TSH response, creating a TSH-T3 disjoint. (Hoermann et al, 2013; See “The TSH-T3 disjoint in thyroid therapy“).

The higher levels of FT4 found in T4 monotherapy have a more powerful TSH-suppressive effect, partly due to tissue-specific T4-T3 conversion rates in the hypothalamus and pituitary. This renders TSH secretion rates insensitive to lower FT3 levels in blood.

By focusing only on hormones within the TSH reference range, the trendline graphs failed to express what happened to FT3 levels as TSH response fell below the statistical parameters of the healthy TSH-coregulated population.

Gullo’s study did not examine these hormone configurations at all, leaving it as a fruitful topic of study for other researchers characterizing the untreated HPT axis vs. the LT4-treated HPT axis.

More recent research not only confirmed the trendlines within the TSH reference range, but demonstrated that lower-than-mean FT3 levels continue to be found in other populations of LT4-treated people, even at the extreme of TSH suppression.

To the left of the pink box in Larisch’s scatterplot, it is difficult to maintain that patients with low or suppressed TSH could suffer from thyrotoxicosis while they have a low or low-normal FT3. Such FT3 levels, which are largely responsible for genomic signaling in the receptor, are inconsistent with both thyroxicosis and euthyroidism. In fact, patients with lower FT3 are far more likely to suffer from the very opposite condition — hypothyroidism — in their extrapituitary tissues, which conflicts with their low or suppressed TSH and higher-than-average FT4. When hormone signals conflict, the most powerful signaling hormone, FT3, has the loudest voice when determining tissue thyroid status.

To confirm patients’ suffering at lower FT3 levels, one must go beyond Gullo’s study. Larisch et al, 2018 and Hoermann et al, 2019 have now demonstrated that the likelihood of hypothyroid symptoms increases as FT3 levels drop below the mid-range healthy FT3 population mean, even if TSH concentrations drop and FT4 rises.

These populations were carefully screened to be free from non-thyroidal illness, so neither their symptoms nor their FT3 levels could be blamed on non-thyroidal illness. They were both induced by hormone dosing and its inefficient metabolism in some patients, because adjustment in hormone levels removed the symptoms.

Discussion

To what degree do FT3 and FT4 in blood represent global hormone supply, transport and metabolism?

T4-T3 and T3-3,5-T2 conversion occurs within cells expressing D1 or D2 enzymes, and T4-RT3 and T3-3,3-T2 conversion occurs within cells expressing D3 or D1 enzymes.

These three enzymes are expressed at different rates in different tissues. Thyroid hormone transport and metabolic activities occur at different rates within each tissue to customize the bloodstream supply to local needs.

Science informs us that each tissue and organ converts T4 to T3 at a different rate, and that biochemistry can’t tell us how much T3 only the brain is getting into its thyroid hormone receptors, or how much T3 only the liver is getting.

Nevertheless, since thyroid hormone transport in and out of cells is a 2-way exchange that continually occurs throughout the body over time, the FT3 and FT4 in the bloodstream is a representation of the body’s global metabolic rate, as well as thyroidal (and/or pharmaceutical) supply.

Biochemical measurements of hormone concentrations are a useful estimate of overall thyroid hormone metabolic efficiency. Unless a scientist is performing a study of one specific organ or tissue’s metabolic rate and T3 receptor occupancy, one doesn’t need to estimate tissue-specific T3 supply and metabolic rates.

Bloodstream levels reflect metabolic rates because the same transporters that carry T4 and T3 into a cell are capable of transporting them out again. A variety of transporters can serve a single tissue, like the liver. The net quantity of hormone influx will equal the efflux. Some of the T4 that enters cells will also exit those cells as T4 (unconverted to T3), and some T3 will exit the cell as T3 (without being converted to a form of T2). Cells will donate much of their hormone metabolites RT3, T3, T2 and T1 to the bloodstream, and yet any thyroid hormone can be re-used by many cells until it is metabolized or excreted.

In particular, Free T3 consists of both the product of global T4-T3 conversion rates and any T3 supply from the thyroid or pharmaceuticals. In persons who cannot secrete T3 from a thyroid and are only dosed with synthetic T4 hormone, 100% of their T3 quantity is dependent on global T4-T3 metabolism rate, while subtracting global T3 losses due to T3 metabolism and clearance rate.

Therefore, the FT3:FT4 ratio can be used as a biomarker for “global deiodinase efficiency” (D1 + D2 + D3) (Dietrich et al, 2016). This ratio can be interpreted in light of a particular ratio and rate of supply from a thyroid and/or pharmaceuticals.

According to Pilo et al, 1990, in 14 healthy people whose thyroids were stimulated by a TSH between 1.0 and 2.0, an average of 27.3% T4 converted to T3 every day. But this average rate varied widely from person to person. The lowest global T4-T3 conversion rate was 16.9% and the highest T4-T3 conversion rate was 42.9%.

Therefore, in healthy people, thyroidal T3 secretion rates, and the thyroid’s T3:T4 secretion ratio, attempts to adjust to make up for shortfall in the body’s global T4-T3 conversion rates, and this obtains an appropriate level of FT3 and FT4 in bloodstream.

But in T4-dosed people without thyroids, there is no way to make up for a global T4-T3 conversion rate shortfall.

What potential harm? Imbalanced T3 and T4 hormone signaling.

Both T4 and T3 have signaling activity in the human body. However, each hormone has a different signaling pathway and a different affinity or potency at various thyroid hormone receptors.

A shortfall in FT3 supply and excess of FT4 will have implications for metabolism and signaling.

  • FT3 is necessary to top up local T4-T3 conversion rate in any tissues that do not convert T4 as efficiently.
  • FT3 is also necessary in tissues that may have a higher rate of T3 than T4 influx via transporters and may require a higher quantity of T3 receptor occupancy than others.

T3 hormone performs the vast majority of signaling in the three known locations for thyroid hormone receptors 1) in the nucleus, 2) in mitochondria, and 3) at the integrin αvβ3 receptor on the cell membrane.

For advanced readers: click to read more

1. Nuclear receptors

In these images below, T3 and its metabolite 3,5-T2 are derived via intracellular conversion by enzymes D1 (T3 in blue) and by D2 (T3 in pink).

In addition to the T3 obtained from D1 and D2 conversion rates, a healthy level of T3 occupancy is provided by Free T3 entering cells directly from circulation (T3 in black text). Some FT3 will not undergo conversion via D1 or D2 enzymes in a cell before binding to a receptor in the nucleus.

T4 hormone has 10-15% affinity to nucleus receptors, but T4 activity in this receptor is not yet confirmed by scientists, only theorized by a small minority based on indirect evidence by recruitment of cofactors (Schroeder, 2014).

It is undisputed among scientists that T3 hormone signaling maintains healthy function in organs and tissues throughout the human body, since genomic signaling in the nucleus receptors is essential.

2. Mitochondrial receptors

Healthy mitochondria are essential to intracellular energy supply and many other functions. T3 is essential to mitochondrial health, since T4 is not known to bind to mitochondria’s special receptors.

But T3 is not the only hormone that supports mitochondrial function. One of the three forms of T2 hormone, an active T2 metabolite derived from T3 (3,5-T2) is also very active in mitochondria, exerting a more immediate effect than T3 (Goglia, 2005).

Cells that express D1 or D2 enzyme can perform both T4-T3 and T3-T2 conversion activity, and this provides not only T3 but also an active form of 3,5-T2 hormone to the mitochondria floating in the cytosol of the cell.

The half-life of T2 hormone is shorter than that of T3, so it is likely that local T3-T2 conversion within a cell provides the basis of most T2 signaling at mitochondria, rather than Free T2 in circulation entering cells. Therefore, circulating levels of FT3 are significant in providing T2 to mitochondria.

3. Integrin αvβ3 thyroid hormone receptors

Meanwhile, T4 hormone has confirmed signaling activity in only one of the three receptors for thyroid hormone, the non-genomic “integrin αvβ3” receptor located on the cell membrane (Davis et all, 2018).

Integrin αvβ3, expressed in
• malignant cells [cancers],
• osteoclasts [bone cells], and
• dividing endothelial and vascular smooth muscle cells, 
binds ECM [extracellular matrix] components (eg, vitronectin [a glycoprotein involved in cell adhesion, migration, proliferation & differentiation]) and is also the membrane receptor for thyroid hormones (THs).”

(Cayrol et al, 2015)

In other words, even in health, everywhere our body has blood vessels next to endothelial cells, and in our bones, this thyroid hormone receptor is expressed and T4 has some activity.

T3 signaling at the integrin receptor is qualitatively different from that of T4, because T3 binds primarily to one site on the receptor while T4 binds to another site on the receptor. T3 on its binding site sends a different signal into the cell than T4 does from its binding site. Overall, the receptor has a higher affinity for T4 (Davis et all, 2018).

Because this receptor is located on the cell membrane, it is largely activated by bloodstream levels of free hormone.

Based on bloodstream levels, the healthy population has more T3 signaling capacity at the cell membrane, while the treated population will have more T4-dominant signaling at the cell membrane.

A ratio imbalance causing T4 to dominate at the integrin receptor is not necessarily benign. Within the FT4 reference range, even high-normal levels of T4 signaling at this receptor can be pathological in certain disorders, such as cardiovascular disease and cancers. Cancer tumor cells express these integrin receptors in far greater quantity. New research shows that RT3 joins with T4 at this receptor, and RT3 levels are often significantly higher in patients with cancer (Davis et al, 2018; See our research review “Cancer scientists point finger at T4 & RT3 hormones.”) Therefore, some patients with concurrent non-thyroidal illnesses have a greater susceptibility to health problems when FT4 is closer to the top of reference range.

Nevertheless, in both healthy controls and treated patients without these non-thyroidal disease susceptibilities, higher-normal FT4 levels may be benign if a person can convert their T4 supply to support a level of FT3 that is sufficient for their health.

Why doesn’t TSH receptor signaling have a similar effect in both populations?

TSH is not just a response to thyroid hormone, but is itself a signaling hormone. It sends signals at its own TSH-receptor on the cell membrane.

People with healthy thyroids get a lot more out of their TSH-receptor signal than people with damaged or missing thyroids. Healthy thyroids also drive and maintain FT3 and FT4 supply by means of more than just their TSH concentrations, since healthy thyroid function depends on sufficient iodine, iron, and other substances.

When the thyroid gland is in good health, benign TSH signaling does more than just enhance the rate of T4 and T3 synthesis within living thyroid tissue. It also shifts the ratio of thyroid hormone synthesis to enhance the FT3:FT4 ratio in blood. As TSH rises within reference, thyroidal T3 synthesis will be stimulated relatively more than T4 synthesis (See review: “T3 is not always converted from T4: De novo T3 synthesis.”), unless TSH is blocked at its receptor by TSH-receptor blocking antibodies (TBAb).

TSH receptors are expressed not only in the thyroid gland, but in tissues throughout the body, where their signal can upregulate D1 and D2 enzymes. A higher TSH will enhance T4-T3 conversion rates 1) within the thyroid and 2) in tissues beyond the thyroid.

For advanced readers: click to read more

When TSH hormone (or the TSH-receptor stimulating antibody, TSAb) sends a signal at the TSH receptor (TSHR), it enhances the cAMP-dependent pathway in the cell, which upregulates the activity of D1 or D2 enzymes within a cell, raising the rate of T4-T3 conversion within that cell. Much of the T3 created within a cell will exit the cell as 2-way hormone transport carries hormones continually in and out of cells.

Among all tissues and organs in the human body, the thyroid gland expresses the largest amount of Dio1 and Dio2 mRNA (See our review “Tissue RNA expression of DIO1, DIO2, and DIO3“). Because of the thyroid’s strong mRNA expression, the healthy thyroid gland is capable of tremendous sensitivity and flexibility in its TSHR-stimulated secretion rates and T3:T4 ratios. In Pilo’s 1990 study, at a TSH level between 1 and 2 mU/L, TSHR-driven T3 secretion from the thyroid ranged widely across the 14 healthy subjects, providing between 6.5% to 42.0% of the daily T3 supply.

In the healthy daily circadian rhythm, TSH is the most volatile hormone, since it is the main “lever” that adjusts thyroid secretion rates, and it also influences metabolic rates in health. Therefore, high-normal levels of TSH secretion are usually only achieved during the nightly apex in circadian rhythm and in older populations with aging thyroids (See “The significance of the TSH-FT3 circadian rhythm“). The median TSH level in healthy populations during the day found across many large populations is 1.5 – 1.6 mU/L, which is usually approximately 25-30% of the reference range.

Within reference range, chronically high-normal levels of TSH receptor signaling can have pathological effects, making it potentially harmful to “normalize” TSH at the higher end of the range. In metabolic syndrome, which drives higher-normal TSH levels, overstimulated TSH receptors in blood vessels can drive endothelial dysfunction, lowering serum nitric oxide (NO), a vasodilator, and raising serum endothelin-1 (ET-1), a potent vasoconstrictor. (Ahirwar et al, 2017). No wonder high-normal TSH was the second-most pathological hormone level after low FT3, as illustrated in Anderson’s 2020 prevalence rate data set, which emphasized cardiovascular disorders (See “Prevalence rates for 10 chronic disorders at various FT4, TSH and FT3 levels“)

  • Note: The TSH concentration does not always represent the level of TSHR signaling in people with autoimmune thyroid disease. In Graves’ hyperthyroidism, when TSH is low, TSHR signaling by TSAb stimulating antibodies is high throughout the body. Graves’ disease antibodies overstimulate the thyroid gland through TSHR receptors, and the antibodies are also involved in osteoporosis, heart diseases, and can cause thyroid eye disease. At the opposite end of the spectrum, in blocking hypothyroidism and atrophic thyroiditis, even if TSH is extremely elevated, TBAb antibodies can block TSHR signaling, preventing TSH from stimulating thyroid tissue and cells throughout the body, causing hypothyroidism (Tagami et al, 2019; McLachlan & Rapoport, 2013; Takasu & Matshishita, 2012).

Since higher-normal levels of TSHR stimulation can be pathological, it’s best to have a thyroid gland that can respond efficiently to low-normal levels of TSHR signaling and a metabolism that can convert T4 to T3 with a minimal push from TSHR signals. The thyroid’s response to 1.0 mU/L of TSH varies from person to person because thyroid glands vary in volume and efficiency, and because receptors in addition to TSHR can enhance the cAMP-dependent pathway that upregulates D1 and D2 in cells.

In the healthy HPT axis, TSH is a tool, not a target. TSH hormone, by signaling in the TSH receptor, is a co-regulator of thyroid hormone supply and metabolism. TSHR signaling modulates cardiovascular health, and excess signaling can have pathological effects.

Of course, TSHR signaling is not the only factor; thyroid gland health and responsiveness is essential. Moreover, variable, individualized TSH-driven T3 and T4 supply is only half of the thyroid economy. Metabolism is the other half. Metabolism is not only regulated by TSHR signaling but by thyroid hormone levels in blood, and other health factors.

Why the steady FT3 in health?

In thyroid health, the thyroid gland’s T4 and T3 secretion rate and ratio is nature’s method of counterbalancing the TSH’s stimulation of the metabolic rate of T4-T3 conversion in cells throughout the body.

The two counterbalancing systems maintain a homeostatic equilibrium in blood levels of FT3 and FT4 that support healthy tissue-level T3 and T4 hormone signaling (See “Relational Stability, part 4: The new thyroid paradigm“).

The ultimate metabolic target of this system is to maintain the individual’s circulating FT3 supply from day to day, week to week, and month to month (Abdalla & Bianco, 2014), in relationship to a fluctuating FT4 and TSH that respond to the current metabolic demand in order to adjust FT3.

Average trendlines do not represent individuals, and thyroid therapy must be individualized.

In thyroid hormone metabolism and signaling, “optimal” FT3 and FT4 concentrations in blood are highly individualized.

The healthy thyroid metabolism keeps FT3’s circadian rhythm fluctuating narrowly within that person’s uniquely optimized area inside the wider reference range. (See our research review “Thyroid T3 secretion compensates for T4-T3 conversion“)

Thyroid hormone concentrations must maintain a state of metabolic homeostasis between hormone supply, metabolism and signaling, given each person’s unique metabolic strengths and handicaps, and their body’s current metabolic demands.

In thyroid health, each individual’s optimal FT3 and FT4 is located at a uniquely narrow band within reference range. (See our review “Individual thyroid ranges are far narrower than lab ranges.”)

In health, this FT3 and FT4 homeostatic setpoint is achieved by TSH-receptor stimulation of a thyroid gland and the person’s global metabolic rate of T4-T3 conversion across all tissues.

But in thyroid-disabled people on therapy, the FT3 and FT4 are not primarily influenced by TSH-receptor stimulation and thyroidal secretion. Instead, they are powerfully manipulated by dosing and deiodinases (D1, D2, D3) that convert hormones. TSH has a very limited influence on secretion and metabolism in those with limited thyroid function, and therefore TSH negative feedback response is an insufficient biomarker of sufficient thyroid hormone signaling.

Individualization of FT3 and FT4 concentrations continues to exist in thyroid therapy. Moreover, in therapy, the diversity of “optimal” of FT3 and FT4 levels is more extreme due to the severity of overlapping thyroidal and metabolic disabilities for which FT3 must compensate, and FT4 and TSH must adjust to accommodate.

The fact that each individual has “optimal” levels does not mean that measuring FT3 and FT4 hormones is pointless in therapy. It means the opposite. It would be harmful for a person who needs FT3 near the top of reference to suffer with a FT3 level below mid-reference. In people who convert T4 poorly, more FT3 will be needed per unit of FT4 to make up for poorer T4-T3 conversion rates in tissues. Over time, blood measurements are an objective guide that helps one to interpret symptoms and signs of imbalance, as well as alleviate them.

Correlations between symptoms and thyroid hormone levels are strong, even before treatment begins, while TSH is elevated. For example, Meier et al in 2003 performed a study that correlated thyroid symptoms with FT3, FT4 and TSH, and found

“In contrast to the good correlations with both circulating thyroid hormones, we found no correlation or only weak correlations with serum TSH.”

In the context of standard LT4 monotherapy, most people, even the thyroidless, have the metabolic strength to achieve optimal FT3 levels — but only if the LT4 dose is raised until FT3 levels remove symptoms and measurable tissue biomarkers of thyroid hormone signaling (Ito et al, 2012-2019; Hoermann et al, 2013-2019; Larisch et al, 2018)

However, a strategy of LT4 dose escalation will not work for up to 33% of individuals after a thyroidectomy, whose FT3 remains below reference range even at the point of TSH suppression:

“Even when escalating LT4 dose as a treatment strategy to suppress TSH levels below its reference range during early follow-up of the carcinoma patients, FT3 concentrations remained below the lower part of its reference range in one third of the presentations.”

(Larisch et al, 2018)

Note: Despite this metabolic handicap in 1/3 of the patients studied, the scatterplot graph by Larisch et al, 2018, shown above, reveals FT3 levels within reference. It is likely, therefore, that for these metabolically handicapped individuals, the compassionate physicians raised their LT4 dose further past the point of TSH suppression to raise their FT3 into reference range, and to alleviate symptoms.

This extreme metabolic diversity is why effective LT4 thyroid hormone therapy must be adapted to the individual, not only in terms of permitting a higher dosage and FT4 levels in some people (if their T4-dominant signaling at the integrin receptor does not cause health problems), but in terms of permitting TSH response to fall lower for the sake of global FT3 and FT4 metabolism and T3 signaling. (Midgley et al, 2015; Hoermann et al, 2013, 2017, 2019)

For the patients who remain symptomatic or ill with FT3 levels below the mid-range population mean, and especially those who remain below range in FT3 even at a suppressed TSH and elevated FT4 level, T4-T3 combination therapy is the logical metabolic solution (Hoermann et al, 2018, 2019).

Despite the failures in research methods in T3-T4 combination therapy, no studies have shown that the incorporation of T3 is any more dangerous than T4 monotherapy as long as doses are reasonable.

Overall, the methodologically faulty T3-T4 combination therapy trials demonstrate that combination therapy was equally effective (on average) compared to LT4 monotherapy when both were just as poorly optimized. In these studies, even LT4 monotherapy was not optimized, being blindly normalized only to the TSH rather than to FT3 levels. These trials averaged results from diverse thyroid patients, and their results were not representative of the poorest T4 converters, those who lack thyroid function and suffer from thyroid metabolism handicaps.

For poor converters of LT4 monotherapy (Midgley et al, 2015), combination T3-T4 therapy at a dosing ratio that suits the individual is the ethical, compassionate option.

Moreover, optimization of T3 and T4 signaling is an absolute necessity to protect health of all organs and tissues for the remainder of the person’s life.

In the context of flexible T3-T4 combination therapy, virtually any combination of FT3 and FT4 concentrations becomes possible. To prevent thyroid hormone excess at a global level, FT4 intake will need to drop to accommodate rising FT3 levels from T3-containing pharmaceuticals. The lower the FT4 falls, the more FT3 in blood is necessary to compensate for the lower T4-T3 conversion rate. Overall, as a patient’s thyroid hormone therapy is adjusted to their individual needs, their suffering or improvement can be objectively correlated with their changing FT3 and FT4 levels and ratios over time, when a physician understands the various factors involved in metabolism and signaling. (See “Flexible-Ratio T3, T4, and NDT Combination Thyroid Therapy“)

Conclusions

Gullo’s descriptive study was significant enough to be reviewed in sections of the 2012 and 2014 American Thyroid Association (ATA) guidelines for treatment of hypothyroidism (Garber et al, 2012; Jonklaas et al, 2014). Both sets of writers attempted to throw a wet blanket on the revolutionary implications.

The 2014 ATA guidelines by Jonklaas admitted decades of neglect and ignorance within the endocrinology community regarding the clinical significance of this shift, claiming that the health outcomes were as yet “unknown.”

Instead of admitting that the FT3 and FT4 levels and ratios were extreme shifts in levels of the most powerful signaling hormone, Jonklaas’ ATA 2014 guidelines called them mere “perturbations” of FT3 because they occurred within the reference range. They also shrugged at FT3 levels that were “mildly low,” when most studies of nonthyroidal illness have been honest enough to acknowledge even “mildly low” T3 levels as major drivers of mortality and morbidity (For example, see “Ataoglu: Low T3 in critical illness is deadly, and adding high T4 is worse.“)

These guidelines used verbal rhetoric to justify and minimize decades of scientific neglect and ignorance of the human cost of T3 deficits in the LT4-treated population.

It has always been thyroid endocrinologists’ professional mandate to answer such questions that are essential to the health of thyroid-disabled people, instead of presuming that human metabolism will always convert “enough” T4 to T3 in cells throughout the body.

Worldwide, potentially millions of patients suffer poor thyroid hormone metabolism. Policy-mandated T3-less therapy, merely normalized to TSH and not optimized, combines with general scientific complacency toward investigating their supposedly “unknown” health outcomes at lower-than average FT3 levels.

But the clinical significance of insufficient T3 signaling in tissues has not been unknown to patients or compassionate doctors. Symptoms that agree with FT3 and FT4 levels are far more clinically significant than a mere “surrogate” endpoint like TSH in isolation. Health outcomes in T3-aspects of chronic illnesses are strong endpoints that TSH cannot usurp as a mere surrogate.

By making only the TSH’s negative feedback loop into the sole target and the only surrogate endpoint of therapy, policy has ignored the TSH’s broken feedforward loop on T3 secretion that can make up for shortfalls in T4-T3 conversion. The potency of the TSH’s feedforward loop in a state of thyroid gland health is the main reason that a negative feedback loop exists; the brakes are only necessary when the gas pedal is functional. Thyroid therapy policy today is like a car being driven by brakes. Health can’t be driven by a negative feedback loop.

In 2014, the ATA’s guideline writers attempted to straitjacket researchers from pursuing the argument stated in Gullo’s 2011 title. They tried to make reasonable scientific questioning of the concept of TSH-based euthyroid status seem ridiculous and unethical (See “2014 ATA therapy guidelines: 5. Research“). Instead, the very idea of misapplying the untreated population’s TSH-based euthyroid status to the thyroid-damaged population ought to be ridiculous and unethical. The FT3 and FT4 inequity per unit of TSH between the two populations renders “normal” TSH an unfair judge of euthyroid T3 signaling beyond pituitary and hypothalamus tissues.

Japanese scientists Ito and team saw this FT3 inequity result in clinically-significant symptoms and had the courage to critique the ATA’s TSH-targeting policy directly in their discussion section (See “Japanese thyroid scientists examine symptoms in relation to FT3 and TSH“).

The major hindrances to thyroid hormone health during therapy consist of inappropriate apathy, inappropriate fear, prejudice, and reluctance. They are

  • Inappropriate apathy toward mildly lowered FT3 and signs and symptoms of lower T3 signaling in tissues that are less efficient at local T4-T3 conversion,
  • Inappropriate reluctance to measure and adjust the most vital hormone’s concentrations to alleviate symptoms and improve health,
  • Fear of mildly higher FT3 levels and intermittent, short-term post-dose peaks that drives unreasonable prejudice against T3 hormone pharmaceuticals, when research shows they can fill a T3 deficit without causing measurable harm to health, and
  • Reluctance to perform research that associates FT3 levels and FT3:FT4 ratios with long term health outcomes in the most vulnerable thyroid-disabled, treated populations.

A few groups of scientists like those led by Gullo, Hoermann, and Ito have led the way for cardiologists, kidney, lung, and liver specialists to follow when they are ready to study treated thyroid patients. We’re ready for them and waiting to be recruited and heard.

References

Click to reveal references

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Hoermann, R., Midgley, J. E. M., Larisch, R., & Dietrich, J. W. (2013). Is pituitary TSH an adequate measure of thyroid hormone-controlled homoeostasis during thyroxine treatment? European Journal of Endocrinology, 168(2), 271–280. https://doi.org/10.1530/EJE-12-0819

Hoermann, R., Midgley, J. E. M., Larisch, R., & Dietrich, J. W. (2015). Homeostatic Control of the Thyroid–Pituitary Axis: Perspectives for Diagnosis and Treatment. Frontiers in Endocrinology, 6. https://doi.org/10.3389/fendo.2015.00177

Hoermann, R., Midgley, J. E. M., Larisch, R., & Dietrich, J. W. (2017). Recent advances in thyroid hormone regulation: Toward a new paradigm for optimal diagnosis and treatment. Frontiers in Endocrinology, 8. https://doi.org/10.3389/fendo.2017.00364

Hoermann, R., Midgley, J. E. M., Larisch, R., & Dietrich, J. W. (2018). Lessons from Randomised Clinical Trials for Triiodothyronine Treatment of Hypothyroidism: Have They Achieved Their Objectives? Journal of Thyroid Research, Article ID 3239197. https://doi.org/10.1155/2018/3239197

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Hoermann, R., Midgley, J. E. M., Larisch, R., & Dietrich, J. W. (2019b). Individualised requirements for optimum treatment of hypothyroidism: Complex needs, limited options. Drugs in Context, 8, 1–18. https://doi.org/10.7573/dic.212597

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Ito, M., Miyauchi, A., Hisakado, M., Yoshioka, W., Ide, A., Kudo, T., Nishihara, E., Kihara, M., Ito, Y., Kobayashi, K., Miya, A., Fukata, S., Nishikawa, M., Nakamura, H., & Amino, N. (2017). Biochemical Markers Reflecting Thyroid Function in Athyreotic Patients on Levothyroxine Monotherapy. Thyroid, 27(4), 484–490. https://doi.org/10.1089/thy.2016.0426

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Categories: Free T3 test, Free T4 test, FT3:FT4 ratio, Healthy thyroid axis, T4-monotherapy

11 replies

  1. Great post, Tania. So interesting also about the T2 metabolite. If I should make a suggestion, it would be to make a very simplified abstract, for those who don’t read long posts. They are many. I will post it right away in a Norwegian group, where someone just today posed a question about why we thyroid sick need such different doses. This is a strong candidate for translation, very important info. The form just doesn’t take my websiteadrs, no matter how I enter it. Just so you know.

    • Thanks Liv. yes T2 is an important metabolite, and I’d like to make a separate post that features the science on the three forms of T2. Thanks for the suggestion about the abstract. I’ve reorganized the post since it was first published. Now, after the introduction provides an outline and raises questions, the images build an argument, and then the discussion answers questions (summaries are above the “click to read” sections that provide technical details). I’ve kept the main points of instruction outside the “click to read” sections. The main points of patient advocacy come out in the conclusion.

      • I will be looking foreward to that post. When we don’t convert T4 into T3 well, do we also have issues with convertering into T2? Or is that something the body must do, as otherwise TH cannot be excreted? Or can they be excreted even with iodine atom attached? I have been thinking a lot about this since reading your post.

        I think making this kind of abstracts are a good idea. Many thyroid patiens suffer from fatigue, or even brain fog. A long article is too much for them. But they still need to learn as much as possible. And we want to share what we know with everybody.

  2. Another excellent piece of work . Your many blogs have helped me understand so much about all things thyroid, and you seem to be getting better all the time. I’m so very impressed by your work . just wanted to say ‘thanks a million’

    • Thanks for your appreciation! Some excellent research is scattered all over the vast literature of thyroid science. It’s my aim to feature this knowledge and point out its ethical applications for improving thyroid therapy. – Tania S. Smith

  3. Tania, it would be so helpful to us thyroid advocates if there were a convenient way to download your thorough articles as PDFs which may then be printed & passed to our doctors. Hope this is easily accomoplished. TIA!

    • Thanks, CJ. Good idea. I’ve been talking with our team about this. It might take a little labor now that some posts have “click to reveal” sections in them that might not get captured in a “Save to PDF” tool. Some pages will need some manual PDFs created by volunteers recruited from among our members. Thanks for putting the idea forward. Cogs and wheels are moving. – Tania S. Smith

  4. does thyroid gland with non autoimmune hypothyroidism like iodone deficiency have normal or prefrential T3 thyroidal secretion as compare to gland destroyed by hashimotos or any other cause that destroy thyroid gland?

    • Dear Ali, that’s a good and insightful question. Usually iodine deficiency does not damage thyroid cells unless it leads to autoimmune response. After treating the iodine deficiency, the thyroid cells should recover.

      Yes, if one has enough healthy thyroid tissue, a rising TSH ought to enhance the FT3:FT4 ratio even as both hormones rise in bloodstream. Carpi et al, 1979 studied this in some patients who had had a thyroid nodule removed but their thyroid gland was otherwise healthy and they did not have autoimmune thyroid disease. Only a small subset of their test patients had an autoimmune thyroid disease. They found in all patients that “endogenous TSH can induce a preferential secretion of T3 over T4 by the human thyroid.” https://pubmed.ncbi.nlm.nih.gov/494987/
      – Tania S. Smith

      • What I found is that my high TSH is only due to T4 deficiency as calculated by free t4 and total t4 before and after starting levothyroxine therapy and I also have negative antibodies but I have some antibodies but in normal range .Anti tpo 45 u ml (less then 60 u ml normal range) so I get confused weather I have autoimmune or simple hypothyroidism.Does Hashimotos patient have neck swelling or thyroid swelling majority of times?

      • Hello Ali. Yes in Hashimoto’s, the thyroid swelling (goiter) often occurs not only with an elevated TSH but also with thyroid inflammation together with high TPO antibody values. Prior to treatment, Hashimoto’s is so commonly seen together with goiter that it used to be categorized as “goitrous hypothyroidism.”

        However, if your TPO is in normal range and you have no goiter with higher TSH levels >10, you may still have autoimmune hypothyroidism, but it may be of another type.

        “Non-goitrous hypothyroidism” is what they used to call Atrophic Thyroiditis (autoimmune thyroid atrophy). Also, now some scientists also talk about “blocking hypothyroidism” (TSHR-blocking without gland atrophy). This is the third type of autoimmune thyroid disease that blocks TSH receptors in the thyroid and disables high TSH from causing goiter. This subtype of autoimmune thyroid disease counts for about 10% of people incorrectly classified as either Hashimoto’s or non-autoimmune. It often escapes diagnosis nowadays because doctors and patients don’t know what signs to look for.

        The TBAb antibody does not require the TPO antibody to cause hypothyroidism or gland atrophy. TBAb may be present even if TPO is normal (not elevated).

        Yes, it sounds like your low FT4/T4 is the main reason for your high TSH, but if your TSH is far more elevated than normal people’s at the same FT4 level, the extra elevation in TSH may be caused by the TBAb antibody interfering with TSH-receptor signaling in the pituitary.

        See this post to learn about the full spectrum of thyroid autoimmunity: https://thyroidpatients.ca/2020/04/12/the-spectrum-of-thyroid-autoimmunity/

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