Ubiquitination: The glass ceiling of T4 monotherapy

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


Scientists recently explained how D2’s gene (DIO3) is inactivated by rising levels of T4:

“Although DIO2 expression is only weakly downregulated by T3, D2 activity is greatly decreased by T4

D2 protein and catalytic activity are lost upon interaction with T4 as a result of conjugation to ubiquitin. [‘ubiquitination”]

This explains why D2 exhibits a variable half-life that depends on whether its natural substrate T4 is available.

In the presence of T4, D2 is inactivated with an ~20-minute half-life,

whereas in the absence of T4 its half-life is prolonged to hours.

This provides a mechanism through which the production of T3 can be regulated according to the availability of T4.”

(Bianco et al, 2019)

This system of reducing T4-T3 conversion rate works well when you have a variable rate of thyroid gland T3 secretion that can compensate for lost D2 activity.

Unfortunately, the loss and of “UBIQUITINATION” of the enzyme Deiodinase type 2 (D2) means that a significant percentage of hypothyroid patients on the standard T4 therapy will live the rest of their lives with lower Free T3 levels in bloodstream.

This is because T4 levels are usually significantly higher than average (high-normal or mildly above reference) during full thyroid “replacement” doses, when adjusted to merely normalize TSH levels according to current policy.

This T4-induced lower T4-T3 conversion rate is a more serious problem than most doctors realize, and are likely the cause of ongoing hypothyroid symptoms. (3. Abdalla & Bianco, 2014; 4. Larisch et al, 2018)

The health problem with this T3 “glass ceiling” is that some of us have bodies that require a Free T3 near the top of the reference range to maintain healthy T3 tissue supply and symptom relief.

Human variation in T4-T3 conversion rate via D2

Our need for an individually-optimized FT3 level within reference is partly due to genetic differences in thyroid hormone transport, Deiodinase Type 2 genes, and/or reduced thyroid receptor sensitivity (5. Carle et al, 2017).

Because of human biological variation in the strength of our D1 and D2 enzymes, some patients are very “poor converters” of T4 hormone at the doses needed to normalize TSH (6. Midgley et al, 2015).

When D2 is less efficient at converting T4 to T3, you need more T3 in circulation to “top up” this slower T4-T3 conversion rate in cells. (See “How do we get enough T3 into thyroid hormone receptors?“)

In LT4 monotherapy studies in people without thyroids, most patients are freed from hypothyroid symptoms as FT3 rises past the midpoint of range (Hoermann et al, 2019; Larisch et al, 2018; see ” 2018 study shows T3 in upper half of reference range relieves hypothyroid symptoms” ).

At the point of complete TSH suppression, in people with no thyroid, the diversity of FT3 levels is huge, with some people having a very low T3 and a few having excess T3. (4)

The data show that a certain percentage of patients can’t even achieve that FT3 midpoint, even as one escalates the T4 dosage higher while lowering the TSH below reference range.

Some of us will not be able to use LT4 alone to bring our serum Free T3 levels up to the level of the average healthy human being, much less achieve our own potentially higher-normal Free T3:T4 ratio set point.

If you are in this category as a patient, and you experience worsening symptoms and insufficient FT3 despite escalating your LT4 dose, you’ll likely need to dose at least some T3 hormone, whether through desiccated thyroid (NDT / DTE) or synthetic LT3 liothyronine (such as Cytomel brand), to boost FT3 levels until they rise to mid-point or mildly higher. Dosing T3 during LT4 therapy can help by keeping down the level of FT4 in blood as well.

The science of D2 activity

Scientists currently theorize that at normal levels, the enzyme responsible for the majority of our body’s T4-T3 conversion is Deiodinase Type 2 (D2).

The problem is that 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.

Metaphor: The T4-processing office worker

You can imagine that D2 is like an office worker, busy at his desk processing T4 paperwork into T3 paperwork. Then a bunch of people bring boxes of extra T4 into his office.

D2 gets discouraged. Overloaded. He takes more coffee breaks. He becomes ubiquitinated (progressively inactivated).

As T4 levels get higher and higher, even in reference range, a lower and lower percentage of that T4 will become T3 when it lands on Mr. D2’s desk.

Now the metabolism of T4 has to depend more on D1, the other enzyme that converts thyroid T4 hormones into T3. Where is most of your D1? your thyroid, then your liver, then your kidney. If D1 is weak too, you don’t get much help. Your Free T3 levels drop.

If you continue to dose T4 at the same level, excess T4 will continue to inactivate D2 even in situations where there’s not enough Free T3 getting into cells.

Imbalance as a result of T4 dominance

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 — partly because of ubiquitination of the D2 enzyme.

Therefore, when Free T3 levels are low and Free T4 is higher, this imbalance can result in a T3 deficiency in brain, bones, fat cells … true tissue hypothyroidism within D2-dominant locations in your body.

Scientists understand “ubiquitination” as one of the major biological reasons why T4 monotherapy results in symptoms for so many patients.

It creates an unnaturaly low T3:T4 ratio — 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. Werneck de Castro et al, 2015)

Can we measure D2 activity? Yes, indirectly.

D2 does its job of conversion secretly within cells, where blood tests can’t measure it. Some doctors think that means D2 activity is unmeasurable.

Not true. The net effect of all three deiodinases is measurable, and during health, D2 is likely to be responsible for most deiodinase activity.

In patients maintained on T4 who don’t have a thyroid secreting T3, the Free T3:T4 ratio in blood is a good measure of the efficiency of both D1 and D2 combined, everywhere in their body.

Fortunately, every cell that converts T4 into T3 hormone also transports a lot of that T3 back into bloodstream where it CAN be measured.

Transport is 2-way: we transport hormones into cells, and we transport hormones out of cells. That’s the only way T3 appears in blood in people who get 100% of their T3 from T4 medication.

We are not all statistically average.

Doctors like to proclaim that “80% of your T3 supply gets produced beyond the bloodstream and only 20% is secreted from your thyroid.”

Wait a minute. Whose thyroid are you talking about, Bob’s or Susan’s?

Check your facts. This is an average that is not representative of the diverse data set from 14 people in Pilo’s 1990 classic study.

This is the study where the 80/20 average comes from.

The average estimate of 80% assumes you are a statistically average person with normal thyroid physiology and healthy T4-T3 converting deiodinases.

Only one person in this set of 14 people (the orange bar above) came close to the statistical average of 20% T3 supplied from the thyroid gland. (See “Meet a person with the perfect T3:T4 thyroid secretion ratio“)

What if you’re subject #3 who obtained more than 40% of T3 from their thyroid in health? That person’s thyroid was likely compensating for weak deiodinase efficiency beyond the thyroid. What if that person loses their thyroid? Now the weak deiodinases can’t supply the T3 secretion that was lost.

How TSH boosts T4-T3 conversion in the healthy thyroid via D1 and D2

The human thyroid gland expresses most of our body’s D1 enzymes, and a lot of our D2 enzymes (see Tissue RNA expression of DIO1, DIO2, and DIO3).

TSH stimulates more than just T4 and T3 “de novo” synthesis from raw materials. TSH also enhances the rate of T4-T3 conversion in the thyroid gland, so that as TSH rises, you get more T3 out of the thyroid. As TSH-containing blood flows through our thyroid, it gets into D2 and D1-expressing cells, where a lot of our T4 gets converted to T3 during transit, before secretion.

Even in an individual human being, there is no such thing as a static T4-T3 conversion rate because TSH fluctuates.

Every day the thyroid hormone axis is in a continual state of flux. TSH rises and falls in a circadian rhythm, and the large TSH wave induces a distinct, gentle T3 rhythm, while T4 rhythms are random. Most healthy-thyroid people get to take a “dose” of T3 every night. (See graphs and an explanation of the science in Circadian rhythms of TSH, Free T4 and Free T3 in thyroid health )

In normal thyroid physiology, your TSH-receptor signals and thyroid gland cooperate to fine tune your bloodstream’s T4 and T3 supply so that a proper ratio and amount gets into cells. When T4-T3 conversion fall short outside the thyroid and T3 levels are at risk of falling low, the TSH-regulated healthy thyroid steps up to maintain the ideal T3 level and T3:T4 ratio for our individual body. (See a review of the science on thyroidal compensation: Thyroid T3 secretion compensates for T4-T3 conversion.)

The thyroid gland’s secretion rate and ratio (supply) vs. the ratio of T4 and T3 in bloodstream (metabolism + supply) will change under higher and lower TSH-receptor stimulation in thyroid-healthy patients. Secretion ratio changes in untreated hyperthyroidism, and in untreated hypothyroidism.

Problems in T4 monotherapy

If you take away healthy thyroid tissue, you take away its D2 (and its D1), and its TSH-guided potential to boost T3 secretion.

  • That causes D2 (and D1) enzyme loss.
  • That causes TSH to lose thyroid-mediated regulatory control over T3 levels.

Things change further once you add T4 monotherapy, which supplies an unnatural 0:100 ratio of T3 to T4.

  • People on LT4 monotherapy carry an unnecessarily high FT4 supply (65-90% of reference range) compared to healthy thyroid people (average around 30-40% of reference range). (4)
  • That dominant T4 level causes a higher rate of D2 inactivation via ubiquitination.
  • D2 enzyme loss + D2 ubiquitination = lower T3:T4 ratio in blood

How the TSH can be T3-blind in T4 therapy

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

This is because of the loss of the “feed-forward” role of TSH. It no longer regulates a thyroid’s T3 and T4 secretion rate and ratio. It no longer boosts the thyroid’s T4-T3 conversion rate via D1 and D2.

Doctors have been overly enthusiastic about the fact that as T4 levels rises, the TSH’s response to thyroid horomone negative feedback is still there.

To patients, having a “normal” TSH negative feedback loop without a “normal” TSH feedforward loop can be a curse.

If you use only “normal” TSH to guide therapy, the negative feedback at the pituitary pays attention to the dominant hormone in circulation and ignores the relatively depleted hormone.

TSH may be normal but the T3:T4 ratio is abnormal. TSH does not express the ratio, only its local rate of T4-T3 conversion plus blood T3 supply to its own tissues. TSH is blinded to the loss of T3 in people on T4 monotherapy. (See the science in The TSH-T3 disjoint in thyroid therapy )

As a result of T4 dominance in blood, TSH cannot rise to signal T3 depletion!

The obvious solution for thyroid patients

What can you do if you’ve hit the glass ceiling of T4 monotherapy and can’t raise your FT3 to eliminate symptoms? Rebalance your FT3:FT4 bloodstream ratio by rebalancing your T3:T4 dosing ratio.

TSH-stimulated thyroid secretion is no longer driving your thyroid hormone health. Instead, your strategic dosing partners with your deiodinases.

What a real thyroid gland does as it customizes its T3:T4 secretion ratio to the individual. So, customize.

Combine both T4 and T3 in therapy (either via synthetic combo or by desiccated thyroid NDT, or by a combination of both synthetic and animal-derived). Lowering T4 moderately and incorporating T3 intake can finally give many patients access to euthyroid levels of T3 tissue supply.

Because of ubiquitination, your T4 will now convert more efficiently to T3 via D2 when T4 is somewhat lower in reference. (Optimizing D1 and preventing D3 excess are for other posts.)

So be nice to your D2 enzyme, and stop overloading it into ubiquitination. Help your D2 give you as much T3 out of your T4 as it can!


Click to reveal reference list

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

6. 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

22 thoughts on “Ubiquitination: The glass ceiling of T4 monotherapy

  1. I wish I could give every endocrinologist that doesn’t understand this stuff my Hashimotos. I wish they could feel how terrible I feel when I’m on any other protocol than T3 only.

    1. I know, Dan. It’s a common sentiment many hypothyroid patients feel. I’ve been there. It seems totally logical to say “You have no idea what you are doing to me because you don’t have my disease. Why don’t you try living with this disease for a while.” Here’s the sad part. Even if they did have Hashimoto’s, not everyone’s Hashimoto’s is the same. They might make the mistake of thinking their Hashi’s is like yours. But just because you share high TPO antibodies wouldn’t mean you are the same. Some have simple & mild Hashi’s with a gland that is only half-damaged, and they are the kind who does very well on 50 mcg/day of T4 alone. Those people might ask us “what are you whining about? It’s not so bad.” Others have “Hashi’s plus X” and almost no thyroid function left, and it makes their Hashi’s a nightmare like nobody else’s. Hashi’s plus fluctuating Graves’ antibodies. Or Hashi’s plus another chronic disease or three. Or Hashi’s plus metabolism-warping genetic mutations that scientists haven’t yet discovered. Each of us is unique, and the “best” therapy is the one that meets our unique needs. – TSS

  2. This makes sense as to why I can’t raise my FT4 above the 30-40% range without developing debilitating symptoms. Still leaves me with low T3. My body makes very good use of that 30-40% but it doesn’t make up for the loss of thyroid tissue and additional T3.

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