Winter T3 loss: Why it matters to thyroid patients

It’s April. You’re a thyroid-hormone treated person with a thyroid disability on a fixed budget of thyroid hormone. Have you been feeling hypothyroid in the past few months?

If so, you’re not alone.

If not, thank your thyroid, or your thyroid doctor.

Scientific studies show a winter-season loss of Total or Free T3 (FT3) in hypothyroid levothyroxine (LT4) -treated patients, followed by a spring or summer FT3 return to baseline.

Long ago, in 1984, a study performed in Osaka, Japan revealed that treated hypothyroid patients’ T3 and T4 hormones fell and TSH rose in winter compared to healthy controls. They reasoned that:

“the dose required for replacement of thyroid hormone in patients with hypothyroidism may be higher in winter than in summer.”

(Hamada et al, 1984)

More recently, in 2017, Gullo and team performed research on seasonal TSH, FT4 and FT3 variations in thousands of treated hypothyroid patients and healthy controls in Sicily, Italy.

I’ve featured Gullo’s research data in a previous post: “In Winter, everyone gains T3 except thyroidless patients on LT4 therapy.” but here I would like to focus more on the potential health significance of winter Free T3 losses for the individual patient, despite the apparently small average changes across a population.

Gullo’s article title emphasized changes in TSH. However, the winter rise in TSH was powerless to prevent Free T3 loss in winter in people with severe hypothyroidism who were on a fixed dose of thyroid hormone all year.

The relative FT3 loss in winter ought to have been the focus of Gullo’s study because it has the potential for significant and severe physiological effects, depending on a patient’s individual vulnerability.

In undiagnosed, untreated, severe hypothyroidism, winter time T3 loss can be deadly. A hypothyroid emergency, called “myxedema coma” — or more appropriately, “myxedema crisis,” since it rarely involves a comatose state — has a high mortality rate of 25–60% (Mathew et al, 2011). It is associated with winter months, especially in zones that have colder winters:

“Myxedema coma mostly develops during winter months. … Look for cold exposure. … The typical patient is an older woman with altered consciousness, presenting in wintertime.”

(Wiersinga et al, 2018)

As expected, on the opposite side of the spectrum, the hyperthyroid emergency of “thyroid storm” is slightly more frequent (29% of cases) in the summer months (Ono et al, 2016).

Seasonal T3 fluctuation is something that observant thyroid patients learn from each other when they share their laboratory results with each other in private online support groups. I’ve noticed some thyroid patients’ results in March showed a loss of Free T3, but no significant change in TSH or FT4. The lost FT3 clearly fell below their individual therapeutic window as crippling symptoms appeared.

The body charges a winter T3 tax, but not everyone can afford to pay it.

Some hypothyroid people are more vulnerable to winter T3 losses than others. A wide variation exists among individuals’ thyroid gland disabilities, thyroid treatment paradigms, and thyroid metabolism handicaps.

Many variables can affect responses to thyroid hormone treatment to render a thyroid-disabled person vulnerable to a decline in health over the winter that goes hand in hand with perhaps a small but significant fall in FT3.

The most vulnerable patients may have little to no thyroid function and/or may already be close to the bottom of their FT3 therapeutic window before winter arrives. Some may be fragile people struggling with other health problems beyond a thyroid disability, like anemia, diabetes, or heart failure, and they can’t afford to lose FT3.

Other hypothyroid people may still have some partial thyroid function, may be good converters of their T4 hormone pharmaceutical, or may have enough supply from their T3 hormone pharmaceutical before and during the cold months of winter.

In this post, I discuss the significance of Winter T3 loss to thyroid patients’ health.

  • I show that all thyroid patients may experience the winter T3 loss featured in Hamada’s and Gullo’s research.
  • I review the scientific evidence showing that even small seasonal losses in FT3 within the normal range can result individually insufficient FT3 hormone levels.
  • I give practical tips on using T4, desiccated thyroid, or synthetic combination therapy to cover winter T3 loss.

The mechanisms of T3 loss, involving thermogenesis, will have to be covered in a separate article going over the science. Yet other articles will have to cover individual cases.

With knowledge, patients and physicians can overcome T3-blind thyroid treatment paradigms and work together to cover winter T3 demands.

The metabolic contexts of winter T3 loss

Some basic background knowledge is necessary to interpret studies on winter T3 loss:

  1. T3 inequity exists between thyroid-disabled and thyroid-healthy people at the same TSH, year round, and it just deepens in winter.
  2. With a healthy thyroid, TSH and T4 hormone levels can stabilize and defend circulating T3, year round.
  3. With a healthy thyroid, each person maintains FT3 at an unique, individualized healthy level within approximately 20% of the reference range, year round (see graphs below, within this article).
  4. With a healthy thyroid, flexible and individualized thyroid gland secretion ratios defend FT3 year round.
  5. With a healthy thyroid, circadian TSH rhythm supports FT3 rhythm, year round.
  6. With a healthy thyroid, there are serious consequences for chronic T3 loss during severe illness, year round.

I’ve discussed each of these principles in previous posts. But if you would like a review of them, here they are, each briefly expanded and sometimes illustrated with a visual:

Click to review the six contexts

1. T3 inequity exists between thyroid-disabled and thyroid-healthy people at the same TSH, year round, and it just deepens in winter.

Over many decades, studies have shown that T3-inequity exists between the severely thyroid-disabled, LT4-treated population and the healthy-thyroid population, on average.

At the same level TSH, severely thyroid-disabled people get less FT3 and more FT4 than the healthy-thyroid population. (Ingbar et al, 1982; Liewendahl et al, 1987; Alevizaki et al, 2005; Gullo et al, 2011).

Read more at “Gullo: LT4 monotherapy and thyroid loss invert FT3 and FT4 per unit of TSH

These are the averages year-round, not yet accounting for seasonal losses. As one can see in the image, Gullo’s 2011 graphs show that as TSH increases within range, people without thyroids get less FT3, but the healthy population maintains theirs, on average.

Normalizing our TSH does not stabilize our FT3 like it does in the healthy-thyroid population.

In winter, the context of a limited hormone budget takes its toll. LT4-treated populations that are T3-poor year round become even more T3-poor in winter.

2. With a healthy thyroid, TSH and T4 hormone levels can stabilize and defend circulating T3, year-round

Scientific review of the HPT axis (hypothalamus – pituitary – thyroid hormone relationships) reveals that the untreated human body targets and defends circulating FT3.

Abdalla and Bianco in 2014 explained that in the HPT axis, TSH and FT4 will adjust as necessary to maintain T3 concentrations.

“That the level of serum T3 is a main target around which serum T4 and TSH are adjusted constitutes a shift in the paradigm traditionally accepted for the function of the hypothalamus–pituitary–thyroid axis.”

(Abdalla & Bianco, 2014)

Appropriately, the title of Abdalla & Bianco’s scientific review was “Defending Plasma T3 is a Biological Priority.” (Learn more: “Infographic: T3 paradigm vs. TSH paradigm.”)

Hoermann and team’s review translated this to the concept of flexible TSH-FT4 setpoints to protect the stability of FT3 concentrations, reasserting it twice:

maintaining stable FT3 positions takes priority over set point fixation in expressing the TSH–FT4–FT3 relationship.” …

“Where conflicts between the two regulatory elements [TSH and FT4] may arise, T3 stability takes priority over set point maintenance.”

(Hoermann et al, 2016)

TSH and FT4 must move in order to keep circulating T3 levels stable at the individual’s target. T3 is the natural biological target of thyroid hormone equilibrium, or “homeostasis.”

In Winter, the HPT axis uses a TSH-stimulated healthy thyroid gland to defend the individual’s target FT3.

A longitudinal study of 328 people in South Korea over 5 years found that relative to each healthy individual’s range of TSH values, the TSH increased when the average monthly temperature fell below 10 degrees Celsius (Kim et al, 2014). As a result of their thyroid’s ability to fill the TSH prescription, there was no significant Total T3 or Total T4 loss.

3. With a healthy thyroid, each person maintains FT3 at an unique, individualized healthy level within approximately 20% of the reference range, year round.

Each person with healthy TSH-driven thyroid hormone secretion has a unique FT3 setpoint.

In the untreated population, a significant clinical difference can occur with a change of only 0.7 pmol/L of Free T3 between two laboratory tests (Ankrah-Tetteh et al, 2008, discussed in more detail below).

The thyroid hormone that changes the least over weeks or months in a person with a healthy thyroid is FT3.

The individual’s physiological requirement for a narrow, customized FT3 level does not disappear in people with a thyroid disability.

However, their ability to find their optimal FT3 naturally and automatically has been compromised. Merely normalizing their TSH won’t optimize their FT3.

In winter, an LT4-treated person’s FT3 may fall below their therapeutic window. In fact, researchers have recently discovered that small changes in FT3 levels within the reference range can cause hypothyroid or hyperthyroid symptoms (Hoermann et al, 2019, discussed in more detail below).

4. With a healthy thyroid, flexible and individualized thyroid gland secretion ratios defend FT3 year-round.

Although the statistical average thyroidal secretion ratio in a famous study of 14 healthy people was 1:14 (one unit of T3 for ever 14 units of T4), a highly variable ratio of T3 and T4 is secreted from the thyroid gland in each individual in the study (Pilo et al, 1990).

The famous study estimated that

  • in one person, 6.5% of their daily T3 supply came from their thyroid gland,
  • while in another, 42% of their T3 came from their thyroid.

The statistical average T3 secretion was not representative of any individual.

(See “Thyroid T3 secretion compensates for T4-T3 conversion.”)

The main purpose of the TSH-driven thyroid gland’s flexible secretion rate and ratio in each individual is to counterbalance peripheral T4-T3 conversion rates to maintain FT3 at the individual’s optimal level.

People with disabled thyroids do not have the equipment to support this degree of metabolic flexibility to counterbalance peripheral T3 losses.

During winter, it is not known whether some people’s healthy thyroid glands rely more on thyroidal secretion or peripheral conversion to defend FT3. Nevertheless, the data from Hamada’s and Gullo’s studies, discussed below, shows that in mild winter climates, the healthy thyroid gland can compensate for winter peripheral T3 losses.

5. With a healthy thyroid, circadian TSH rhythm supports FT3 rhythm, year round.

By allowing TSH to fluctuate in a wide circadian rhythm, the healthy HPT axis supports a narrower FT3 rhythm.

Beyond the steady average TSH measured between 8AM and 5PM are continual daily adjustments in individuals as TSH peaks at 3AM and falls to its lowest level by 3PM. (See “Circadian rhythms of TSH, Free T4 and Free T3 in thyroid health.”)

The hormone that varies the most within its range over the 24 hour cycle is TSH (1.4 to 2.3 mU/L), not FT3 (5.2 to 5.6 pmol/L).

(See “Circadian rhythms of TSH, Free T4 and Free T3 in thyroid health“)

The wide daily rhythm of TSH initiates a smaller, gentler circadian rhythm in FT3 that has its highest concentrations as we sleep. Meanwhile, FT4 has no distinctive circadian rhythm. As TSH rises, it boosts the FT3 more than the FT4, elevating the FT3:FT4 ratio during sleeping hours as the pink line rises above the blue line.

Research associates health and longevity with a wider TSH-FT3 rhythm (Jansen et al, 2015). The FT3 rhythm is likely meaningful for sleep-wake cycles and other hormones’ circadian rhythms that peak at night.

However, FT3 circadian rhythms are eliminated in LT4 monotherapy, creating a flat line for FT3 over the 24 hours post-dose (Saravanan et al, 2007).

During winter, a person’s inability to raise FT3 at night may be more problematic than in summer. Studies of seasonal change often overlook the fact that the peak night-time level may adjust in ways that daytime laboratory testing cannot reveal.

6. With a healthy thyroid, there are serious consequences for chronic T3 loss during severe illness, year round.

Every organ and tissue, including the brain, depends on circulating FT3 for a certain percentage of its required thyroid receptor occupancy rate, and some tissues like the liver depend significantly on FT3, and less so on local conversion of T4 to T3 (Bianco et al, 2019).

“Nonthyroidal illness syndrome” (NTIS) demonstrates how important the individual’s optimal FT3 is to their health. A significant loss of FT3 can occur during the acute phase of a severe illness. Meanwhile, TSH remains normal or falls low, permitting short term T3 depletion.

Acute T3 loss differs from chronic T3 loss. It may be inevitable or adaptive for FT3 to drop during the acute phase of an injury or illness, but non-recovery of FT3 is a serious health risk. During recovery from severe illness, if a person’s body cannot recover T3 in a timely manner by elevating TSH to enrich thyroidal T3:T4 secretion ratios, it can put their life at risk or significantly hinder recovery (Van den Berghe, 2014).

In a fragile body, low Total or Free T3 is associated with mortality. Having a higher FT4 level at the same time as a low FT3 is not a metabolic compensation, but a metabolic burden. (See “Ataoglu: Low T3 in critical illness is deadly, and adding high T4 is worse.“)

In large population studies, the highest prevalence rates for many diseases correlate with a FT3 measurement below range while TSH and FT4 remain normal. A milder, yet significant risk also exists for certain chronic health conditions with TSH and FT4 in the upper half of their ranges. (See “Prevalence rates for 10 chronic disorders at various FT4, TSH and FT3 levels“).

Therefore, with a healthy thyroid, the body can maintain optimal FT3 despite cold stress in winter.

Cold environments pose a challenge for the HPT axis’ defense of circulating T3.

To maintain body heat, the body makes changes to thyroid hormone metabolism and clearance rates. The body tries to generate more T3 locally in our metabolic furnace, our brown fat tissue. Various mechanisms require continuous replenishment of circulating T3 thyroid hormone during a time of increased T3 urinary losses. With the enhancement to enzymes that convert T4 to T3, comes the potential enhancement of enzymes that convert T3 to T2 (I’ll explain the mechanisms in a separate post; here I’m just illustrating the fact of T3 loss, the extent of T3 loss on average, and its potential physiological significance to those who suffer it.)

Clearly, the research discussed below shows FT3 loss occurring in thyroid-disabled LT4-treated patients in the mild winters of Sicily (Gullo et al, 2017) and the moderate winters in Osaka, Japan (Hamada et al, 1984).

In contrast, in people with healthy thyroids, a slight gain in FT3 (Gullo), or no significant difference in FT3 (Santi et al, 2019) may occur in winter.

However, to prove that cold stress poses a genuine metabolic challenge, FT3 losses in healthy-thyroid people do become noticeable in extremely cold environments like northern Finland (Hassi et al, 2001).

Hamada’s 1982 study

Hamada’s study was titled “Is It Necessary to Adjust the Replacement Dose of Thyroid Hormone to the Season in Patients with Hypothyroidism?”

It was performed in 7 female patients aged 27-66 who had “impalpable thyroid glands” and were diagnosed with

  • “chronic thyroiditis” in five, [this is a synonym for Hashimoto’s Thyroditis]
  • “idiopathic myxedema” [unknown cause] in one, and
  • post-radioiodine treatment for Graves’ disease.

Five out of seven patients had a Total T3 loss of 10 ng/dL in winter compared to summer, and five out of seven had a loss of Free T4 of 0.2 to 0.4 ng/dL. (Note: These were relatively new laboratory tests in 1984, and no reference ranges were given, so one cannot calculate the loss as percent of the range).

  • Hamada even found that the Reverse T3 concentration dropped in 6 out of 7 patients in the winter, so conversion to RT3 is not the cause of T3 loss.
  • In Hamada’s study, healthy controls had no significant difference in any of their values. Free T3 was not measured.

The treated hypothyroid patients’ basal metabolic rate (BMR) decreased from 11.2 in summer to -0.7% winter, while the healthy controls gained BMR from 0.3 in summer to 19.0 in winter. Even the change in TSH after a TRH injection revealed that the treated patients were not truly euthyroid.

Fortunately, in Hamada’s patients back in 1984, dosage was not adjusted by targeting a TSH range, but by clinical assessment. The removal of clinical signs and symptoms of hypothyroidism was the target of therapy, and as a result, their patients were dosed at robust levels averaging 2.09 mcg/kg of levothyroxine per day, whereas today the average dose is estimated at 1.6 mcg/kg per day in persons with no thyroid function when a normalized TSH is the overruling therapeutic target.

Since Hamada and team’s treatment paradigm was so generous to their own patients, they concluded that seasonal dose changes were “not yet necessary” for their own cohort, but “may be advisable” for others:

“In our patients, there were no distinct clinical signs or symptoms of hypothyroidism, even in winter.

We can not yet conclude that it is necessary to change the replacement dose of thyroid hormone according to the season.

Such a course may be advisable for residents of places with severe seasonal variations of temperature or for people moving to a different climate.”

(Hamada et al, 1984)

Where are the studies on winter FT3 losses in Edinburgh, Calgary, and Helsinki?

Gullo’s 2017 research on seasonal FT3 variation

Gullo’s study was a large retrospective analysis that did not assess symptoms, BMR, or the TSH response to TRH. Interestingly, most of their results paralleled the findings of Harada back in 1982.

Gullo’s team conducted their study on patients living in Sicily (Italy), an island with rather mild winters.

Over ten years (2004 to 2014), they analyzed thyroid laboratory data for

  • 11,806 untreated people with normal TSH and
  • 3,934 patients with total thyroidectomies with TSH below 4.0 mU/L.

After exclusions for health status, and dosage stability, they were left with a cleaner data set that could reveal seasonal variation:

  • LT4-treated patients: 1,315 people’s data from Dec-March lab tests and 1,241 people’s data for June-September, and an average of 328 people’s lab data for each month of the year.
  • Healthy controls: 3,819 people’s data from Dec-March lab tests and 3,703 people’s data for June-September lab tests, and an average of 984 people’s lab data for each month of the year.

After seeing the strong evidence of seasonal variation in this data from thousands of people, Gullo’s team performed a deeper retrospective longitudinal analysis. They chose a smaller group of patients who had both summer and winter season lab tests over consecutive seasons on the same LT4 dose and brand. They selected age-matched controls, since age makes a significant difference to thyroid metabolism.

This focused analysis involved:

  • LT4-treated patients: 119 of the patients with richer data sets
  • Healthy controls: 156 age-matched controls with richer data sets

How much difference was there in winter vs summer FT3?

First, the data from Gullo’s large-scale cross-sectional study:

  • Healthy controls: December to March FT3: 4.47 pmol/L; June to September, 4.34 pmol/L, a seasonal gain of 0.13 in winter (+ 4.2% of reference)
  • LT4-treated patients: December to March FT3: 3.86 pmol/L; June to September, 4.00 pmol/L, a seasonal loss of 0.14 in winter (- 4.5% of reference).
  • Winter T3 Inequity: The treated patients had 0.61 pmol/L less FT3 than healthy controls in winter, on average. (-19.6% of reference)

This graph below shows the Winter vs. Summer FT3 and FT4 from 156 matched controls on the left, and the levels of 119 LT4-treated thyroid patients on the right.

NOTE: I’ve presented the graph scaled to “Percent of reference” for visual comparison because the FT3 and FT4 have different quantities in blood and different reference range widths.

In this narrower population, the results showed a more extreme seasonal FT3 loss in LT4 patients:

  • Healthy controls had a seasonal gain of 0.09 pmol/L in winter. (+ 2.9% of reference)
  • LT4-treated patients had a seasonal loss of 0.27 pmol/L in winter. (- 8.7% of reference)

The T3 inequity between controls and LT4 patients in winter was just as significant as it was in the cross-sectional study:

  • Winter T3 Inequity: The treated patients had 0.60 pmol/L less FT3 than healthy controls in winter, on average. (- 19.4% of reference)

The thyroidless patients’ year-round low FT3:FT4 ratio sets the stage for their FT3 loss in winter, as I’ll explain below.

A financial analogy: “Winter T3 Tax”

Gullo’s research adds to the TSH-T3 disjoint knowledge of the seasonal FT3 deficit, or what I call the Winter T3 Tax. Using a financial analogy, here’s what happens.

If a thyroid patient with little to no thyroid function stays on the same dose of thyroid hormone all year round,

  • In winter, they pay a Winter T3 Tax to generate body heat (thermogenesis) in response to cold stress. If they can’t afford it, they may carry a T3 debt.
  • In spring or summer, they get a T3 Tax Refund, returning them to their baseline T3 level.
  • If treated with T4 only, their baseline is lower than the healthy population’s baseline T3 all year round.

In contrast, transactions can happen in the opposite direction in people with healthy thyroids:

  • In winter, the healthy-thyroid population also pays the Winter T3 Tax, which they can afford. They can invest thyroidal T3 to make up for any losses.
  • They even earn minor Winter T3 Dividends on average.
  • Their TSH and FT4 remains constant, on average.

Unfortunately, the thyroid-disabled population is often T3-poorer than anyone else, all year round, due to FT3-blind treatment policies and traditions.

The T3-poor get T3-poorer. The T3-rich get T3-richer.

Lucky people with healthy thyroid glands who have more T3 to invest will earn Winter T3 dividends from their thyroid gland’s investments and will have the ability to to turn up their body’s furnaces.

Winter T3 loss can happen in any treated hypothyroid patient to some degree

Gullo’s 2017 study was performed on patients with total thyroidectomies after thyroid cancer at least one year after their surgery, once they were on stable LT4 dosing.

But this doesn’t only affect people with total thyroidectomies. Hamada’s study included people with autoimmune thyroid disease. Any treated hypothyroid patient can experience Winter T3 Loss.

  • The most important variable in weathering winter T3 loss is remnant thyroid gland function, since this fundamental functional loss underlies the increasing TSH-T3 disjoint seen as increasing doses become necessary during thyroid therapy (Hoermann et al, 2013, 2018).
  • The second most important variable is the therapeutic paradigm (medical guidelines and choices regarding the type of thyroid hormone pharmaceutical and therapeutic targets), which can set the stage for year-round T3 poverty, not just winter T3 loss.
  • The third variable is global T4-T3 conversion efficiency, which is variable even among people with total thyroidectomies (Midgley et al, 2015).

A study of patients with total thyroidectomies, such as Gullo’s, is informative about the first variable in the extreme — the complete loss of thyroid gland function. It enables the study of people whose thyroid gland volume is known, and whose thyroid volume is neither variable from person to person nor variable over time as long as no thyroid cancer regrowth occurs.

However, a complete loss of thyroid function can and does occur in some people of any age with autoimmune thyroid disease (Hashimoto’s, Atrophic thyroiditis, or hypothyroidism caused by radioactive iodine ablation for Graves’ hyperthyroidism).

With little to no thyroid function, a person is completely at the mercy of the strengths and weaknesses of their net metabolic T4-T3 conversion efficiency in tissues beyond the thyroid gland, as shown in research by Hoermann (2015) and Ito (2015).

In hypothyroid patients who may still have a small amount of functional thyroid tissue, such as people with partial thyroidectomies or partial autoimmune thyroid failure, TSH receptor stimulation can still coax T4 and T3 from the gland, and the remaining functional D1 and D2 enzymes in the thyroid can still convert some T4 to T3.

Due to diverse treatment paradigms and diversity in thyroid hormone metabolism, one cannot say that people with total thyroidectomies are always “more hypothyroid” than people with thyroid gland volume.

  • Some people treated by physicians who accept high-normal TSH as a sign of “adequate” dosing may be clinically hypothyroid year-round in symptoms and other measurable signs, no matter what their thyroid gland volume or thyroid function status may be.
  • Some people without thyroid glands have very efficient metabolism of T4 to T3 hormone and may be T3-richer than many of their colleagues with autoimmune thyroid disease or partial thyroidectomies.

When autoimmune thyroid patients and partial thyroidectomy (“benign goiter”) patients are on full-replacement doses of LT4 monotherapy, their FT3:FT4 ratios and TSH-T3 relationships can overlap with people who have no thyroid tissue at all (Midgley et al, 2015; Larisch et al, 2018; Hoermann et al, 2019; Ito et al, 2019). We share the same broad clinical spectrum, despite our differences.

Can 8.7% of the FT3 reference range matter to health?

Yes, if you’re close to the bottom of your FT3 therapeutic window, or below it, before winter arrives.

In Gullo’s study, the average FT3 dropped by -8.7% of the reference range, 0.27 pmol//L.

However, statistical averages conceal vulnerable individuals. It is well within reason to imagine that some individuals lost far more than 8.7% of their FT3 between Winter and Summer.

Unfortunately, Gullo provided no examples of representative individuals’ losses.

Even more unfortunately, Gullo did not study symptoms or health outcomes correlated with seasonal FT3 loss. For that level of evidence, we often have to resort to case studies, or to longitudinal studies of symptom-hormone correlations like Hoermann and team’s studies (Larisch et al, 2018; Hoermann et al, 2019), but they have not yet provided an analysis of seasonal FT3 loss in their data set — perhaps in future they will.

However, we do know that reference ranges for thyroid hormones are unlike many other substances in the human body. The population’s range is a poor fit for the individual.

No healthy human being’s FT3 setpoint spans the entire reference range.

Each person’s FT3 or Total T3 (TT3) in a state of thyroid gland health and overall health is customized to fit into a narrow band covering only 10-30% of the reference range width.

Some people’s average FT3 is at 20% of range, most people’s is at 50% of range, some at 90% of range (Andersen et al, 2002; Karmisholt et al, 2008a; Ankrah-Tetteh et al, 2008).

Let’s see how 6-week stability (no seasonal change data) compares to 13-month stability that incorporates the seasonal change.

Thyroid setpoint stability over 6 weeks

A period of only 6 weeks cannot show seasonal change, but it can reveal the degree of overall stability within individuals and significant uniqueness among individuals in a group of healthy people.

Ankrah-Tetteh performed a standard statistical analysis to discover the “critical difference” in hormone levels. (I recommend Trefor Higgins’ 2013 DynaLife PowerPoint slides, “When are Test Results Significantly Different?”)

The following changes in hormone levels were considered clinically significant:

  • TSH: a change of 1.2 mU/L (23% of the width of its reference range)
  • FT4: a change of 2.3 pmol/L (20.9% of reference)
  • FT3: a change of 0.7 pmol/L (21.9% of reference)

Individuals have different metabolic demands, and each individual has a unique “homeostatic setpoint.”

Person #7 may encounter severe hypothyroid symptoms in their brain or cardiovascular system if they were forced to live with Person #1’s lower FT3, because that FT3 level is necessary to top up their T4-T3 conversion rate to maintain nuclear thyroid hormone receptor occupancy in each organ and tissue.

Some people have a wider range of healthy FT3 levels, others have a very tightly controlled FT3.

Thyroid setpoint variability over 13 months

Now look what happens when you take monthly measurements over 13 months in stable subclinical hypothyroid patients.

Now this includes any seasonal change in FT3.

In these 15 people, TSH was high because it was needed to compensate for mild thyroid function loss, but thyroid therapy was not needed yet. The researchers did not mention symptoms, but the true definition of “subclinical” would mean no symptoms or signs of hypothyroidism had appeared yet.

In this graph, an individual’s setpoint for FT3 was approximately 20 to 30% of the width of the reference range (the pink bar on the right) when including winter and summer months from May 2004 to July 2005.

In the graph above you can see that their FT3 hovered around mid-reference range, just like the healthy controls in Gullo’s 2017 study.

In Karmisholt’s study, the TSH fluctuated more widely than it does in healthy people, since it needed to make frequent thyroid secretion adjustments in order to stabilize FT3 and FT4 where the body needed them to be:

“Variation in TSH increased with increasing thyroid failure, while variation in thyroid hormones was unaltered in these patients.”

(Karmisholt et al, 2008a)

Karmisholt and team emphasized FT3 and FT4 as the most efficient tests for monitoring these patients’ progression from subclinical hypothyroidism toward either overt thyroid failure or euthyroid status:

“To be 90% confident of a significant difference requires a median
• 40% difference between two TSH tests and
15% difference between two tests of fT4 or fT3.

(Karmisholt et al, 2008a)

In other words, a mean 15% change of FT3, such as of 5.0 to 4.25 pmol/L, (which constitutes 20% of the reference range) could potentially change “subclinical” status to overt hypothyroid. For these people, it would make the difference between requiring no treatment or requiring thyroid therapy.

Given the narrow setpoints found in untreated people whose bodies naturally ensure FT3 is just right for health, why should thyroid function loss and thyroid therapy suddenly make a lower-normal FT3 level within range acceptable to the average human body?

The loss of TSH-regulated thyroid function reduces, not increases, one’s ability to stabilize FT3 at a level acceptable for health.

During therapy, FT3 remains the body’s highest-priority hormone level with a narrow range of acceptable individual values.

Either T4 treatment or T3 treatment, or a combination, can help prevent winter T3 loss.

In winter, the full range of thyroid hormone pharmaceuticals offers many choices to meet the demand of individualized FT3 setpoints and seasonal FT3 requirements.

1. LT4 monotherapy dose adjustments may help some people

Treating hypothyroidism with levothyroxine (LT4) alone can provide many people with mild or moderate thyroid function loss with enough FT3 in circulation year round. However, a seasonal dose increase in LT4 may be helpful in some people with more severe thyroid function loss and peripheral metabolic handicaps, especially in climates with more severe winters.

Hoermann and team discovered that FT3 at mid-range or higher was necessary to reduce the probability of hypothyroid symptoms in people with total thyroidectomies. A mere reduction in TSH (a normal response to a higher FT4) could not remove hypothyroid symptoms if the FT3 was still insufficient for the individual (Larisch et al, 2018; Hoermann et al, 2019).

Adjustment of dose discovers the range of FT3 levels that remove hypothyroid symptoms in the individual, since each person’s therapeutic window is uniquely placed within the reference range.

In Hoermann and team’s graph below, the red dots indicate the average FT3 levels at which hypothyroid symptoms were present, and blue dots represent their absence, over an average of 5.25 years of therapy and 9 physician visits per patient.

However, not everyone has a wide therapeutic window, as one can see in some patients whose red and blue dots for “symptomatic” status and “asymptomatic” status almost overlapped.

As shown in cases where the red dots (symptoms present) are at higher levels of FT3 than the blue dots (symptoms absent), some patients develop symptoms that are conventionally categorized as “hypothyroid” after increasing the dose.

  • This can occur because higher-normal levels of FT4 can make T4-T3 conversion less efficient via D2 enzyme, through the process of ubiquitination.
  • In addition, higher FT4 levels can also enhance the activity of D3 enzyme, which not only converts T4 to RT3 at a higher rate within cells, but can also convert T3 into an inactive form of T2. As a result, FT3 may rise higher in bloodstream while being inactivated in D3-expressing cells.

2. Advantages of T3-inclusive therapies

In the end, regardless of seasonal change, treatment with LT4 alone does not always raise FT3 sufficiently at dosing levels that normalize TSH, since some people are “poor converters” of T4 (Midgley et al, 2015), and some patients remain symptomatic no matter what the dose. Some people may be unable to access the FT3 their bodies need without a low or suppressed TSH and/or T3-T4 combination therapy (Larisch et al, 2018; Hoermann et al, 2019).

Due to its faster-acting and faster-clearing pharmaceutical profile, the easiest way to respond to or prevent winter T3 losses is to gradually add a little synthetic liothyronine (LT3, Cytomel) hormone or a little desiccated thyroid extract (DTE/NDT) for two or three months and then gradually remove it when it’s not needed.

While LT4 changes can take 2 to 6 weeks to achieve a new equilibrium, LT3 or desiccated thyroid takes only a few days or a week to boost baseline FT3 levels, and the same amount of time to return to the former baseline. Pill-splitting can aid the transition phases.

3. Some tips for T3-inclusive therapies

The downside of T3 treatment is its complexity because of its fast absorption and clearance, but its inconvenience is a price patients may feel is worth paying to prevent disabling symptoms.

  • FT3 blood tests should be done 12 hours post dose to avoid the volatile post-dose peak FT3 levels, during which a delay of 20 minutes can make a difference in results. During the transient peak, much of the FT3 in blood will be quickly converted to T2 within cells anyway (See “Free T3 peaks and valleys in T3 and NDT therapy”).
  • Splitting the daily prescribed T3 dose can minimize the height of peaks and depth of valleys and approximate a circadian FT3 rhythm. Patients who are competent enough to be entrusted with micromanaging their T3 or NDT dosing can consult online peer support groups and books.
  • In combination therapies or desiccated thyroid, optimal FT3 will usually need to rise higher in range (12 hours post dose) to compensate for FT4 levels at mid- to low range. In addition, FT3 may need to be higher than it was pre-thyroid loss or pre-thyroidectomy if peripheral metabolic handicaps cause “poor converter” status while on LT4 (Midgley et al, 2015).

Whether a person uses T4 alone or a combination of T4 and T3, the key to any thyroid therapy’s effectiveness is to safely and gradually sneak up to an optimal dose or combination while monitoring TSH, FT3 and FT4, as well as symptoms and signs, tracking key variables along the way. If the physician and patient are systematic, they will not speed past the optimal dose and/or dosing ratio. Symptoms to monitor include, but are not limited to, cold intolerance.

Conclusion: Support Winter T3 sufficiency

First, some words to suffering thyroid patients.

Have hope: If you are among those who lost FT3 and it fell below your therapeutic window, spring may bring you a “Winter T3 Tax” refund.

Take a look at your thyroid lab history and consider your thyroid lab test’s time of year.

If you’re on a yearly calendar for thyroid checkups, and if you have a physician who tends to underdose you because they feel compelled to follow TSH-centric, FT3-blind guidelines, February or March may be the best month of the year to get a lab test and a prescription that can accommodate year-round levels.

If you need more assistance with accommodating a TSH-centric physician, check out our tips on “7 ways to raise TSH without reducing thyroid dose.”

April may be a bit too late for a lab test revealing FT3 loss, but there’s time to plan ahead for next winter. Self advocate to get Free T3 tested, and if your doctor can’t or won’t do it, try to find a patient-pay testing service that will draw blood at a reputable lab nearby. Get a baseline lab test in August, and another one in January or February.

If your seasonal FT3 losses map onto your symptoms and health crises, consider sharing this evidence with your physician. You could even make detailed records with dates if you want to be scientific about tracking your own body’s response.

Hopefully your physician will have the scientific evidence they need from the scientific research and reviews cited here, plus the compassion and foresight, to consider a prescription that accommodates your payment of Winter T3 Tax in future years.

Don’t wait until you have a serious health crisis that happens to occur during winter, since “nonthyroidal illness syndrome” (NTIS) can worsen your T3 loss. It is unfortunate that Thyroid patients are routinely excluded from low T3 syndrome (NTIS) research, since treated patients are not immune to even greater losses during NTIS (See “Low T3 syndrome in thyroid therapy: THREE studies“).

For physicians, policy makers, and scientists:

The hormone level that the healthy HPT axis defends (FT3) should be the hormone(s) we defend and optimize during thyroid therapy. This is the logical way to defend health in people whose HPT axis can no longer defend or optimize FT3 due to thyroid function loss.  (Read more: “The thyroid gland is a T3 shield. Defend the unshielded.”)

Medical compassion and therapeutic success is fostered by connecting FT3 laboratory test evidence and clinical signs and symptoms, as supported scientific studies that connect FT3 to clinical outcomes.

Hoermann and team’s research in 2018 and 2019 gives hope that each patient’s unique FT3 therapeutic window can be discovered and maintained by monitoring symptoms, signs and FT3 levels. Seasonal change is an opportunity to learn from patients where the boundaries of their individual therapeutic windows of FT3 levels are located.

Scientists discovered decades ago that symptom severity does not correlate with TSH levels, only with thyroid hormone levels, even among untreated hypothyroid patients with high TSH (Meier et al, 2003).

No one’s health outcomes change the minute they step over a TSH or FT4 reference range boundary. Scientists have attempted, and failed, to map symptom scores onto TSH-FT4 diagnostic categories pre- and post- therapy (Karmisholt et al, 2008b).

TSH-centric therapy-monitoring policies hide from physicians the seasonal hormone level changes that correlate with symptoms. If physicians don’t measure FT3 and seek to optimize it within the therapeutic window of a vulnerable thyroid-disabled person, they won’t know how much FT3 their patient has lost between December and March, or how poor a converter of T4 their patient is. They might think the patient’s thyroid symptoms are all in their heads, or that all they need is a cup of hot chocolate, a cuddly partner, or a head-to-toe sweater.

Patients should not be coaxed to accept hormone levels too low for their body when they have to pay the price. The consequences are not limited to cold intolerance. During years of living on the edge of one’s therapeutic window, a winter loss of T3 can cost a patient’s mental health, employment, or family ties.

Our health care systems now have the ability to measure FT3 with the same degree of technical precision as FT4. Both assays are accurate enough to be used in research and clinical settings.

Our societies can, if they so choose, also provide a wide range of bioidentical synthetic and animal-derived T3 and T4 hormone pharmaceuticals to meet individual and seasonal demands, without financial extortion.

Instead of offering bandaid solutions, let’s work together to understand, measure and treat the core of the problem that shows up in FT3 hormone levels and tissue FT3 effects.

  • Tania S. Smith, PhD
    President, Thyroid Patients Canada
    Thyroid patient and Thyroid science analyst

References

Click to view reference list

Abdalla, S. M., & Bianco, A. C. (2014). Defending plasma T3 is a biological priority. Clinical Endocrinology, 81(5), 633–641. https://doi.org/10.1111/cen.12538

Alevizaki, M., Mantzou, E., Cimponeriu, A. T., Alevizaki, C. C., & Koutras, D. A. (2005). TSH may not be a good marker for adequate thyroid hormone replacement therapy. Wiener Klinische Wochenschrift, 117(18), 636–640. https://doi.org/10.1007/s00508-005-0421-0

Ankrah-Tetteh, T., Wijeratne, S., & Swaminathan, R. (2008). Intraindividual variation in serum thyroid hormones, parathyroid hormone and insulin-like growth factor-1. Annals of Clinical Biochemistry, 45(Pt 2), 167–169. https://doi.org/10.1258/acb.2007.007103

Bianco, A. C., Dumitrescu, A., Gereben, B., Ribeiro, M. O., Fonseca, T. L., Fernandes, G. W., & Bocco, B. M. L. C. (2019). Paradigms of Dynamic Control of Thyroid Hormone Signaling. Endocrine Reviews, 40(4), 1000–1047. https://doi.org/10.1210/er.2018-00275

Gullo, D., Latina, A., Frasca, F., Le Moli, R., Pellegriti, G., & Vigneri, R. (2011). Levothyroxine Monotherapy Cannot Guarantee Euthyroidism in All Athyreotic Patients. PLoS ONE, 6(8). https://doi.org/10.1371/journal.pone.0022552

Gullo, D., Latina, A., Frasca, F., Squatrito, S., Belfiore, A., & Vigneri, R. (2017). Seasonal variations in TSH serum levels in athyreotic patients under L-thyroxine replacement monotherapy. Clinical Endocrinology, 87(2), 207–215.
https://doi.org/10.1111/cen.13351

Hamada, N., Ohno, M., Morii, H., Jaeduk, N., Yamakawa, J., Inaba, M., Ikeda, S., & Wada, M. (1984). Is it necessary to adjust the replacement dose of thyroid hormone to the season in patients with hypothyroidism? Metabolism: Clinical and Experimental, 33(3), 215–218. https://pubmed.ncbi.nlm.nih.gov/6420646/

Hassi, J., Sikkilä, K., Ruokonen, A., & Leppäluoto, J. (2001). The pituitary-thyroid axis in healthy men living under subarctic climatological conditions. The Journal of Endocrinology, 169(1), 195–203.

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. (2019). Functional and Symptomatic Individuality in the Response to Levothyroxine Treatment. Frontiers in Endocrinology, 10. https://doi.org/10.3389/fendo.2019.00664

Ingbar, J. C., Borges, M., Iflah, S., Kleinmann, R. E., Braverman, L. E., & Ingbar, S. H. (1982). Elevated serum thyroxine concentration in patients receiving “replacement” doses of levothyroxine. Journal of Endocrinological Investigation, 5(2), 77–85. https://doi.org/10.1007/BF03350495

Ito, M., Miyauchi, A., Hisakado, M., Yoshioka, W., Kudo, T., Nishihara, E., Kihara, M., Ito, Y., Miya, A., Fukata, S., Nishikawa, M., & Nakamura, H. (2019). Thyroid function related symptoms during levothyroxine monotherapy in athyreotic patients. Endocrine Journal, 66(11). https://doi.org/10.1507/endocrj.EJ19-0094

Jansen, S. W., Roelfsema, F., van der Spoel, E., Akintola, A. A., Postmus, I., Ballieux, B. E., Slagboom, P. E., Cobbaert, C. M., van der Grond, J., Westendorp, R. G., Pijl, H., & van Heemst, D. (2015). Familial Longevity Is Associated With Higher TSH Secretion and Strong TSH-fT3 Relationship. The Journal of Clinical Endocrinology and Metabolism, 100(10), 3806–3813. https://doi.org/10.1210/jc.2015-2624

Karmisholt, J., Andersen, S., & Laurberg, P. (2008a). Variation in thyroid function tests in patients with stable untreated subclinical hypothyroidism. Thyroid: Official Journal of the American Thyroid Association, 18(3), 303–308. https://doi.org/10.1089/thy.2007.0241

Karmisholt, J., Andersen, S., & Laurberg, P. (2008b). Interval between tests and thyroxine estimation method influence outcome of monitoring of subclinical hypothyroidism. The Journal of Clinical Endocrinology and Metabolism, 93(5), 1634–1640. https://doi.org/10.1210/jc.2008-0101

Kim, S. S., Lew, D. H., Choi, J. Y., Lee, E. J., Kim, M. G., Kim, K. Y., Kim, S. K., Jung, J. H., Jung, J. H., & Hahm, J. R. (2014). The Change of Thyroid Stimulating Hormone Values of Healthy Subjects According to Temperature and Aging. Kosin Medical Journal, 29(2), 125–134. https://doi.org/10.7180/kmj.2014.29.2.125

Larisch, R., Midgley, J. E. M., Dietrich, J. W., & Hoermann, R. (2018). Symptomatic Relief is Related to Serum Free Triiodothyronine Concentrations during Follow-up in Levothyroxine-Treated Patients with Differentiated Thyroid Cancer. Experimental and Clinical Endocrinology & Diabetes: Official Journal, German Society of Endocrinology [and] German Diabetes Association, 126(9), 546–552. https://doi.org/10.1055/s-0043-125064

Liewendahl, K., Helenius, T., Lamberg, B. A., Mähönen, H., & Wägar, G. (1987). Free thyroxine, free triiodothyronine, and thyrotropin concentrations in hypothyroid and thyroid carcinoma patients receiving thyroxine therapy. Acta Endocrinologica, 116(3), 418–424. https://pubmed.ncbi.nlm.nih.gov/3687325/

Mathew, V., Misgar, R. A., Ghosh, S., Mukhopadhyay, P., Roychowdhury, P., Pandit, K., Mukhopadhyay, S., & Chowdhury, S. (2011). Myxedema Coma: A New Look into an Old Crisis. Journal of Thyroid Research, 2011. https://doi.org/10.4061/2011/493462

Meier, C., Trittibach, P., Guglielmetti, M., Staub, J.-J., & Müller, B. (2003). Serum thyroid stimulating hormone in assessment of severity of tissue hypothyroidism in patients with overt primary thyroid failure: Cross sectional survey. BMJ, 326(7384), 311–312. https://doi.org/10.1136/bmj.326.7384.311

Midgley, J. E. M., Larisch, R., Dietrich, J. W., & Hoermann, R. (2015). Variation in the biochemical response to l-thyroxine therapy and relationship with peripheral thyroid hormone conversion efficiency. Endocrine Connections, 4(4), 196–205. https://doi.org/10.1530/EC-15-0056

Ono, Y., Ono, S., Yasunaga, H., Matsui, H., Fushimi, K., & Tanaka, Y. (2016). Factors Associated With Mortality of Thyroid Storm. Medicine, 95(7). https://doi.org/10.1097/MD.0000000000002848

Santi, D., Spaggiari, G., Brigante, G., Setti, M., Tagliavini, S., Trenti, T., & Simoni, M. (2019). Semi-annual seasonal pattern of serum thyrotropin in adults. Scientific Reports, 9(1), 10786. https://doi.org/10.1038/s41598-019-47349-4

Saravanan, P., Siddique, H., Simmons, D. J., Greenwood, R., & Dayan, C. M. (2007). Twenty-four hour hormone profiles of TSH, Free T3 and free T4 in hypothyroid patients on combined T3/T4 therapy. Experimental and Clinical Endocrinology & Diabetes: Official Journal, German Society of Endocrinology [and] German Diabetes Association, 115(4), 261–267. https://doi.org/10.1055/s-2007-973071

Van den Berghe, G. (2014). Non-thyroidal illness in the ICU: A syndrome with different faces. Thyroid: Official Journal of the American Thyroid Association, 24(10), 1456–1465. https://doi.org/10.1089/thy.2014.0201

Wiersinga, W. M. (2018). Myxedema and Coma (Severe Hypothyroidism). In K. R. Feingold, B. Anawalt, A. Boyce, G. Chrousos, W. W. de Herder, K. Dhatariya, K. Dungan, A. Grossman, J. M. Hershman, J. Hofland, S. Kalra, G. Kaltsas, C. Koch, P. Kopp, M. Korbonits, C. S. Kovacs, W. Kuohung, B. Laferrère, E. A. McGee, … D. P. Wilson (Eds.), Endotext. MDText.com, Inc. http://www.ncbi.nlm.nih.gov/books/NBK279007/



Categories: T3 hormone, Thyroid therapy

7 replies

  1. Continuing from comment on a previous article – going back to an article published 27th March 1920:

    Kendall found that during the months of January, February, and March the glands contain only a slight percentage of thyroxin, whereas during the summer months there is an increase amounting to 400 per cent., and this is the time when the glands should be used for the extraction of their thyroxin.

    Page 74/75

    https://archive.org/details/b19974760M2188/page/n75/mode/2up?q=kendall

    • Thanks for another helpful historical quotation! Interesting that porcine glands have more thyroxine in summer. It comes with quite a detailed description of the chemical process of extracting thyroid hormone from fresh porcine thyroid glands. They didn’t know at that time that triiodothyronine (T3) was in those glands alongside T4, so it’s not quite clear whether it was 100% pure thyroxine they yielded by their chemical processing. I’ve added this to my library and it may come handy in future posts.

  2. I live in the tropics. It’s in the 20s & 30s every day of the year. Thermogenesis might not apply to Canucks elsewhere!

    However, I wonder if any other factors may create a ‘T3 debt’ in winter. Winter is opposite to ours south of the Equator. Any NZ or Australia studies?

    • Yes it’s bound to be different with temperatures in the 20s and 30s. I’m in the process of writing the “mechanisms of winter T3 loss” post. It really does seem to be depend on ambient temperature and thyroid gland function, though nutrient deficiencies like anemia can worsen the T3 loss. There’s a sex difference in some studies, too. Yes the winter months are not January or February in the southern hemisphere, as I see the month names denoting the season of “winter” change in studies of cold stress and thyroid hormones in Antarctica. I haven’t yet seen a study in NZ or Australia.

  3. I like your content in general, but I’d like to see more articles that talk to things other than T3. It’s a bit of a T3 focused blog. While that is the answer for a portion of thyroid patients. It’s not always the case. In fact, I’d guess only 30% or so of folks would need T3 in some way (just guessing no hard data on that).

    • Hi Mike, this article’s research sources mainly focused on LT4 therapy, meaning people dosing only T4. Our concern is that all thyroid patients have enough to cover the T3 they lose in winter whether they are on LT4 therapy, combo, or desiccated thyroid. T3 is the hormone that is active at most receptors where thyroid hormones have activity, no matter what you dose.

Trackbacks

  1. Focusing on T3: The T3 hormone or the LT3 pharmaceutical? – Thyroid Patients Canada

Leave a public reply here, on our website.

This site uses Akismet to reduce spam. Learn how your comment data is processed.

%d bloggers like this: