Ubiquitination: The glass ceiling of T4 monotherapy

UBIQUITINATION: This is the “Glass ceiling” of T4 monotherapy — there is a biological limit on how much T3 you can get out of treatment with T4 thyroid hormone alone (Synthroid, levothyroxine).


The enzyme responsible for the majority of our body’s T4-T3 conversion is Deiodinase Type 2 (D2), and it does its job of conversion secretly within cells, where blood tests can’t measure it.

The problem is, D2 is an unstable enzyme. It is capable of being inactivated (transformed into “ubiquitin”) in the presence of T4 hormone. This is a biological “failsafe” that is meant to protect our body from perceived T4 excess.

However, excess T4 will continue to inactivate D2 even in situations where there’s not enough Free T3 getting into cells. Therefore, when Free T3 levels are low and Free T4 is higher, this imbalance can result in a T3 deficiency in brain, bones, joints… true tissue hypothyroidism.


Scientists understand “ubiquitination” as one of the major biological reasons why T4 monotherapy results in symptoms for so many patients. It creates an unnatural T4:T3 relationship — a higher Free T4, nurtured by continual T4 dosing, results in a simultaneously lower Free T3 in bloodstream at the same TSH when compared with healthy controls. (1)

You simply can’t FORCE the body to convert more T4 into T3 by increasing the T4 dose, or it will backfire and you will paradoxically get less T3 out of it — because of ubiquitination of the D2 enzyme.

Doctors like to proclaim that “80% of your T3 supply gets produced beyond the bloodstream.” This is a falsely static percentage that is not true to biology. The estimate of 80% is assuming you have normal thyroid physiology that enables your TSH and thyroid gland to fine tune your bloodstream’s T4 and T3 supply so that a proper ratio and amount gets into cells.

In reality, the thyroid hormone axis is in a continual state of flux, and the ratio and percentage of T4 and T3 in and beyond bloodstream will change under higher and lower TSH stimulation in thyroid-healthy patients, and it changes in untreated hyperthyroidism, and in untreated hypothyroidism, AND under T4 therapy.

The “80% peripheral conversion” is a mathematical model and guesstimate made in 1990 in a single study of 14 “normal” (not T4-treated) subjects (likely all male), back when we could not accurately measure tissue T3 and D2 activity in lab rats, much less in human beings.(2) We now know better. There is no such thing as a static T4-T3 conversion rate beyond the bloodstream.


Unfortunately, “UBIQUITINATION” means that a large percentage of hypothyroid patients on the standard therapy will live the rest of their lives with lower Free T3 levels in bloodstream, which is a more serious problem than most doctors realize, and likely the cause of ongoing hypothyroid symptoms. (3) (4)

The problem with this T3 “glass ceiling” is that many of us require a Free T3 near the top of the reference range for full health and symptom relief, partly due to genetic differences in thyroid hormone transport, Deiodinase Type 2 genes, and/or reduced thyroid receptor sensitivity.(5)

Because of human biological variation, some patients are very poor converters of T4 hormone and will NEVER be able to bring their serum Free T3 levels up to the level of the average healthy human being while on T4 monotherapy, much less achieve their own potentially higher Free T3 set point near top of range.

The optimal T4:T3 balance in serum doesn’t happen autoimatically during thyroid therapy.

Merely obtaining a “normalized TSH” is not going to magically squeeze enough T3 out of your static T4 dose.


What can you do if you’ve hit the glass ceiling of T4 monotherapy and can’t raise your FT3 to eliminate symptoms?

Simply combine both T4 and T3 in your therapy (either via synthetic combo or by desiccated thyroid) and adjust the ratio and doses while monitoring both Free T3 and Free T4 until you are able to attain a Free T3 result in the upper part of reference range. Combination therapy may require a lower FT4 level, which is appropriate to prevent both hyperthyroidism and peripheral T3 loss due to ubiquitination.


1. Werneck de Castro, J. P., Fonseca, T. L., Ueta, C. B., & McAninch, E. A. (2015). Differences in hypothalamic type 2 deiodinase ubiquitination explain localized sensitivity to thyroxine. Journal of Clinical Investigation, 125(2), 769–781. https://doi.org/10.1172/JCI77588

2. 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

3. 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

4. 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

5. Carlé, A., Faber, J., Steffensen, R., Laurberg, P., & Nygaard, B. (2017). Hypothyroid Patients Encoding Combined MCT10 and DIO2 Gene Polymorphisms May Prefer L-T3 + L-T4 Combination Treatment – Data Using a Blind, Randomized, Clinical Study. European Thyroid Journal, 6(3), 143–151. https://doi.org/10.1159/000469709

Categories: Deiodinase Type 2, Deiodinases, FT3:FT4 ratio, T4-monotherapy

13 replies


  1. Dosing by TSH results in FT3 inequity and health discrimination – Canadian Thyroid Patients Campaign
  2. The pituitary response is abnormal. Stop TSH worship. – Canadian Thyroid Patients Campaign
  3. As of 2019, still no proof that low TSH causes harm to bones – Canadian Thyroid Patients Campaign
  4. Several fallacies in the TSH-T4 paradigm of thyroid therapy – Canadian Thyroid Patients Campaign
  5. Thyroid therapies: What my life is like in the T3-monotherapy wheelchair – Canadian Thyroid Patients Campaign
  6. Thyroid therapies: Managing the T3-T4 combo “walker” – Canadian Thyroid Patients Campaign
  7. Targeting TSH? It’s not as specific or as sensitive as people claim. – Thyroid Patients Canada
  8. Thank you, good thyroid doctors! – Thyroid Patients Canada
  9. The TSH-T3 disjoint in thyroid therapy – Thyroid Patients Canada
  10. Visualizing thyroid hormone activity in cells: T3 and RT3 in context – Thyroid Patients Canada
  11. Deiodinase Type 3 plays a T3-blocking function – Thyroid Patients Canada
  12. Principles & Practical tips for Reverse T3, FT3, FT4 – Thyroid Patients Canada
  13. What can prevent T3 from getting into thyroid receptors? – Thyroid Patients Canada

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