Thyroid T3 secretion compensates for T4-T3 conversion

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How does TSH affect T3 secretion and conversion rate?

This study’s data shows that TSH is by no means a proxy for T3 secretion and conversion rate, even in the healthy.

You can see it in this table — now re-sorted by FT3 in pg/ml, which they measured before the 8 days of iodine dosing and injection of the radioiodine-tagged T4 and T3.

As you can see, there is no pattern in relationship to this middle FT3 column that ranges from 2.6 to 5.7.

The T3 secretion/conversion ratio in the final two columns used to show that smooth gradation from dark to light colors.

Now when you re-sort by the TSH column, the TSH does not correlate with T3 secretion or T3 conversion ratios at all.

The lack of a pattern is metabolically significant.

Why doesn’t TSH fully regulate the T3 portion of thyroid metabolism? Because our T3 supply doesn’t all depend on TSH.

  • Deiodinase enzymes D1, D2, and D3 in tissues throughout our bodies are in control of peripheral thyroid hormone conversion.
  • Deiodinase type 2 (D2) can be upregulated by TSH, but it will still function when TSH is suppressed.
  • Deiodinase enzymes D2 and D1 in the hypothalamus and pituitary control TSH secretion locally by negative feedback. The T4-T3 conversion rate in these central organs is different from the conversion rate in other organs.
  • Powerful feed-forward mechanisms can signal TSH to take a leading role in shifting metabolic rate higher or lower, such as during adaptation to cold, or recovery from nonthyroidal illness (NTIS).

Central regulation of TSH is just as complex as thyroid metabolism; it is not just a passive hormone regulated by thyroid hormone feedback.

Instead of trying to understand the complex systems that regulate Free T3 levels, the old paradigm of thyroid therapy decided to focus on TSH and ignore Free T3 altogether.

The body never ignores FT3.

It’s foolish to ignore what we don’t understand.

Even though T3 is not the most abundant hormone, it is the most important and powerful thyroid hormone. In health, it is so important that Free T3 blood levels are individually customized.

T3 is not singlehandedly regulated by the TSH level, but by the complex metabolic dance between thyroidal secretion and peripheral conversion seen in the graphs above this one.

This individual variation in FT3 levels accords with the phenomenon observed since Anderson and team published an article in 2002 showing that each individual has an unique “optimal” level and ratio for FT3 and FT4 thyroid hormones in blood, and their individual ranges are much narrower than the population-wide reference range.

A later study by Ankrah-Tetteh in 2008 in ten healthy people discovered how carefully each individual’s body regulated their FT3 supply.

Overall,

Ankrah-Tetteh found that each individual’s TSH and FT3 pair was unique and tightly controlled.

The image from Ankrah-Tetteh below shows individualized FT3 levels in relationship to TSH.

You can see by the varying sizes and heights of the rectangles of data that in each of these 10 patients,

  • the TSH levels are generally flatter and in the lower half of the reference range. They don’t seem to relate to the FT3 levels in a consistently inverse way as one may expect.
  • The TSH was not inversely related to FT3 as one would expect, but rather mildly positively related to FT3 in some patients.
  • the Free T3 levels are highly varied in different positions across the full reference range for the population.
  • Each individual does not wander far from their TSH and FT3 anchor points over time, and each stays within a narrow range.

Based on mathematical calculations, the “index of individuality” (IOI) for FT3 was 0.38.

This is low, and the result is statistically significant in an interesting way. According to Petersen et al, 1999,

  • Any low IOI below 0.6 makes the width of the population reference range significantly wider than the range of variation for each individual.
  • Such a low IOI means that individuals’ levels are not tightly clustered around an average, but vary significantly from each other within the population.
  • A low IOI also makes the FT3 level in health very dependable, with not much change expected from one test result to the next. The FT3 level is just as dependable as FT4 in health, since the IOI for FT4 was 0.41.

In contrast to FT3, the IOI for the TSH in Ankrah-Tetteh’s study was significantly higher, at 0.68, according to their calculations. This is because TSH lab results in the population were more tightly clustered around a mean of 1.58 mU/L, which is consistent with the average TSH in larger populations.

Therefore, Pilo’s data are consistent with the modern research on TSH and thyroid hormone level differences between individuals.

All Pilo’s study could not do was measure change over time, data which studies like Ankrah-Tetteh et al’s and Andersen et al’s now provide.

Human variation within a wider population range is the principle of thyroid hormone economy.

Optimal FT3 thyroid hormone levels and FT3:FT4 ratios are highly individualized.

A FT3 level anywhere within the population reference range is not precise enough for the health of the individual.

Unfortunately, basic flaws of Pilo’s study prevent us from understanding how TSH influenced T3 secretion, T4-T3 conversion, and overall thyroid hormone supply:

  • No reference ranges were given for TSH, FT3 or FT4, so we cannot see how levels varied across the reference range.
  • Nobody in Pilo’s study had a TSH level outside the narrow range of 1-2 mU/L, so it was impossible to see how TSH variation could affect the results.
    • We now know that higher TSH levels seen in untreated hypothyroidism can push a failing thyroid to secrete and convert relatively more T3 than T4 (Citterio et al, 2017; Hoermann et al, 2020).
  • Pilo’s study could not account for huge circadian rhythms seen in TSH, and their article did not specify the time of day at which baseline TSH was measured.

How do sex and age influence these rates?

Next, let’s look at a fundamental feature of Pilo’s data–their unbalanced selection of 14 young, old, male, and female participants.

In a study of only 14 people, it’s difficult to come to conclusions about how sex may or may not be a variable in secretion and conversion rates of T4 and T3.

However, we can notice the bias in selection of participants:

  • the smaller number of women (5) were generally older (43-59, average 49.4)
  • the larger number of men (9) were generally younger (19-65, average 35.7).

Does the sex bias in participants bias the calculated averages in Pilo’s study?

Let’s take a look.

The table below is sorted primarily by sex and secondarily by age.

The younger women had more T3 coming from their thyroid gland, and the oldest woman had the least thyroidal T3 secretion rate among all subjects in the study.

Hmm, why did the older women have the lowest T3 secretion rates?

Among women, the secretion/conversion ratio was 16% / 84%,

  • but if you remove one outlier, the youngest 43-year-old patient #2 with a high T3 secretion of 36.2%, the ratio would be 11% / 89%.

Among men, the secretion/conversion ratio was 24.1% / 75.9%,

  • but if you remove the highest outlier, the 31-year old male patient #3 with a high T3 secretion of 42%, the ratio would be 21.8% / 78.2%

This next table was sorted by Age, allowing Sex to fall where it may:

There is clearly an age pattern in the secretion/conversion ratio. The older participants between 44 and 59 years of age had less T3 coming from their thyroids, according to Pilo’s team’s estimates.

Exceptions existed in a few men, such as the 36-year-old male and the 20-year-old male who had significantly lower T3 secretion ratios than the rest of their cohort, and I’ve already explained why these anomalies exist.

Surprisingly, the oldest patient in the cohort, a 65-year-old male, had quite a robust thyroidal T3 secretion of 24.9%.

What are the implications of this imbalanced group?

Older women represent the majority of patients with thyroid disease.
They are the people whose thyroid therapy is being influenced by misrepresentations of Pilo’s findings.

The younger men’s data compensated for the older women’s data, making the study’s averages less applicable to older women.

Middle-aged women’s health problems during thyroid therapy can too easily be blamed on stress, diet, exercise, and sex hormones.

One can only wonder how different the “average” 20/80% ratio estimate would have been with improvements in sampling and interpretation:

  • a larger sample size,
  • a balance of both sexes,
  • a balance of ages, and
  • the choice to specify age- and sex- specific ranges of thyroidal secretion and conversion.

What about health factors?

Finally, let’s ponder how health factors may have influenced the wide human diversity seen in Pilo’s estimates.

Pilo’s article gave no information about how they screened their 14 patients for health factors.

Many factors could lower T3 secretion, such as:

  • Mild central hypothyroidism. TSH secretion rate may be too low in people with genetic handicaps in pituitary TSH signalling, permanent damage to the central glands, and even degenerative diseases such as “empty sella” and autoimmune pituitary disease. Central hypothyroidism varies in severity from person to person and will hinder both T4 and T3 secretion.
  • An undiagnosed nonthyroidal illness. Measuring Reverse T3 would have revealed whether any of these people were having even a mild case of “Low T3 syndrome” in which the TSH is normal but T3 drops while RT3 rises above the healthy mean.
  • Iodine excess. Perhaps some patients with lower body weight had a more extreme reaction to the drops of Lugol’s iodine that all patients were forced to take during the 8 days of the study.
  • Substances that limit T4-T3 conversion.
  • DIO1 and DIO2 genetic handicaps that changed peripheral conversion rate.

Unfortunately, this study showed only biochemistry, not health outcomes.

It did not measure biomarkers that are sensitive to circulating T3 thyroid hormone and are commonly used to verify tissue euthyroid status, such as

  • heart rate,
  • body temperature,
  • cholesterol,
  • ankle reflex,
  • creatine kinase,
  • liver health,
  • bone metabolism biomarkers,
  • kidney health,
  • mental health, or
  • cardiovascular health.

(Ito et al, 2017; Meier et al, 2003)

Solutions?

1. Respect T3 flexibility and diversity.

Spread awareness of Berberich et al’s 2018 update on Pilo’s study, which acknowledges the wide flexibility of thyroid homeostasis.

“the HPT axis is a much more dynamic system than has been previously thought. In particular, the interrelationships between FT3FT4, and TSH are less constantly fixed, rather conditional and contextually adaptive.”

(Berberich et al, 2018)

2. change the mantra.

State the wide range!

3. Study how to optimize each thyroid patient’s FT3 and FT4

This study by Pilo is not focused on thyroid therapy.

It’s about the “normal, healthy” TSH- and thyroid-gland-driven thyroid hormone economy.

In thyroid therapy, each patient has unique thyroid gland disabilities.

Each patient has unique thyroid metabolism handicaps.

Only recently have researchers begun to study how to optimize FT3 levels during thyroid therapy to achieve tangible health outcomes:

  • Hoermann, R., Midgley, J. E. M., Larisch, R., & Dietrich, J. W. (2019). Individualised requirements for optimum treatment of hypothyroidism: Complex needs, limited options. Drugs in Context, 8, 1–18. https://doi.org/10.7573/dic.212597
  • 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
  • Ito, M., Kawasaki, M., Danno, H., Kohsaka, K., Nakamura, T., Hisakado, M., Yoshioka, W., Kasahara, T., Kudo, T., Nishihara, E., Fukata, S., Nishikawa, M., Nakamura, H., & Miyauchi, A. (2019). Serum Thyroid Hormone Balance in Levothyroxine Monotherapy-Treated Patients with Atrophic Thyroid After Radioiodine Treatment for Graves’ Disease. Thyroid: Official Journal of the American Thyroid Association. https://doi.org/10.1089/thy.2019.0135
  • 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

If we really want to respect natural human diversity, flexibility and adaptation in thyroid hormone economy, we have to give doctors the tools to optimize Free T3 to the individual using FT3 and FT4 evidence.

We don’t need to do fancy genetics studies to identify why some people do not fare well on TSH-normalized therapy using LT4 alone or fixed ratios of T3-T4 combination therapy that supply limited T3.

All we need to understand is that some individuals require more T3 than others, and that our T3 needs can change over time as our bodies and metabolic demands change throughout life.

Let’s respect that the individualized thyroid hormone economy may require a wide diversity of thyroid therapy approaches, just as each person’s T3 secretion and T4-T3 conversion rate adapts to challenges like iodine supply, childhood, pregnancy, cold climates, and nonthyroidal illness.

References

Andersen, S., Pedersen, K. M., Bruun, N. H., & Laurberg, P. (2002). Narrow Individual Variations in Serum T4 and T3 in Normal Subjects: A Clue to the Understanding of Subclinical Thyroid Disease. The Journal of Clinical Endocrinology & Metabolism, 87(3), 1068–1072. https://doi.org/10.1210/jcem.87.3.8165

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

Berberich, J., Dietrich, J. W., Hoermann, R., & Müller, M. A. (2018). Mathematical Modeling of the Pituitary–Thyroid Feedback Loop: Role of a TSH-T3-Shunt and Sensitivity Analysis. Frontiers in Endocrinology, 9. https://doi.org/10.3389/fendo.2018.00091

Citterio, C. E., Veluswamy, B., Morgan, S. J., Galton, V. A., Banga, J. P., Atkins, S., Morishita, Y., Neumann, S., Latif, R., Gershengorn, M. C., Smith, T. J., & Arvan, P. (2017). De novo triiodothyronine formation from thyrocytes activated by thyroid-stimulating hormone. The Journal of Biological Chemistry, 292(37), 15434–15444. https://doi.org/10.1074/jbc.M117.784447

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

Hoermann, R., Pekker, M. J., Midgley, J. E. M., Larisch, R., & Dietrich, J. W. (2020). Triiodothyronine secretion in early thyroid failure: The adaptive response of central feedforward control. European Journal of Clinical Investigation, 50(2), e13192. https://doi.org/10.1111/eci.13192

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

Jeon, M. J., Lee, S. H., Lee, J. J., Han, M. K., Kim, H.-K., Kim, W. G., Kim, T. Y., Kim, W. B., Shong, Y. K., & Ryu, J.-S. (2019). Comparison of Thyroid Hormones in Euthyroid Athyreotic Patients Treated with Levothyroxine and Euthyroid Healthy Subjects. International Journal of Thyroidology, 12(1), 28. https://doi.org/10.11106/ijt.2019.12.1.28

Jonklaas, J., Bianco, A. C., Bauer, A. J., Burman, K. D., Cappola, A. R., Celi, F. S., Cooper, D. S., Kim, B. W., Peeters, R. P., Rosenthal, M. S., & Sawka, A. M. (2014). Guidelines for the Treatment of Hypothyroidism: Prepared by the American Thyroid Association Task Force on Thyroid Hormone Replacement. Thyroid, 24(12), 1670–1751. https://doi.org/10.1089/thy.2014.0028

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

Petersen, P. H., Fraser, C. G., Sandberg, S., & Goldschmidt, H. (1999). The Index of Individuality Is Often a Misinterpreted Quantity Characteristic. Clinical Chemistry and Laboratory Medicine (CCLM), 37(6), 655–661. https://doi.org/10.1515/CCLM.1999.102

Pilo, A., Iervasi, G., Vitek, F., Ferdeghini, M., Cazzuola, F., & Bianchi, R. (1990). Thyroidal and peripheral production of 3,5,3’-triiodothyronine in humans by multicompartmental analysis. The American Journal of Physiology, 258(4 Pt 1), E715-726. https://doi.org/10.1152/ajpendo.1990.258.4.E715

Rendell, M., & Salmon, D. (1985). “Chemical hyperthyroidism”: The significance of elevated serum thyroxine levels in L-thyroxine treated individuals. Clinical Endocrinology, 22(6), 693.

Wiersinga, W. M., Duntas, L., Fadeyev, V., & Nygaard, B. (2012). 2012 ETA Guidelines: The Use of L-T4 + L-T3 in the Treatment of Hypothyroidism. European Thyroid Journal, 1(2). https://doi.org/10.1159/000339444


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Categories: Healthy thyroid axis

2 replies

  1. I have this in my blood test. All the symptons of low thyroid whit above range TSH but my Free T3 is also high on the range. No Hashimoto and my thyroid gland is perfect in the ultrasoud.

    • Dear Lucas, if your TSH is above range and your FT3 is high within range, it makes sense that you have a healthy thyroid gland pushing T3 higher. Your case looks like one of two things that come immediately to mind:

      1) the higher T3 seen in obese patients with “metabolic syndrome,” and

      2) people with Resistance to Thyroid Hormone often have the paradox of higher TSH along with higher T3 and T4.

      In your case I would suspect #1 before #2. Metabolic syndrome is MUCH more common. “Resistance to Thyroid Hormone” requires a genetic mutation.

      I wish I could link to articles on our blog on these two topics, but I haven’t had time to cover them yet, so all I can do is refer you to literature.

      Here is a reference for you on higher T3 + TSH in metabolic syndrome:

      Kim, H. J., Bae, J. C., Park, H. K., Byun, D. W., Suh, K., Yoo, M. H., Kim, J. H., Min, Y. K., Kim, S. W., & Chung, J. H. (2016). Triiodothyronine Levels Are Independently Associated with Metabolic Syndrome in Euthyroid Middle-Aged Subjects. Endocrinology and Metabolism (Seoul, Korea), 31(2), 311–319. https://doi.org/10.3803/EnM.2016.31.2.311

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