Free T3 peaks and valleys in T3 and NDT therapy

Lack of knowledge about Free T3 peaks and valleys contributes to failure and frustration in T3-based therapies, including desiccated thyroid and T3-T4 combination therapy.

On patient support groups, I often see conversations that go like this:

• “My FT3 result was over reference range, FT4 low in range, and my TSH was low, so my doctor reduced my Cytomel T3 dose. Now I feel horribly hypothyroid.”
• Another patient replies to ask, “How many hours post-dose did you do your lab test?”
• She answers, “My doctor didn’t say. I think it was about 3 hours after my AM dose. Why, does it matter?”

Another common patient exchange usually goes like this:

• “I am taking ## mg of NDT (Desiccated Thyroid) but I still feel tired for half the day.”
• Another patient replies to ask, “Are you splitting your daily dose into two doses?”
• She answers, “My doctor didn’t say I needed to split my dose. Why, should I?”

So many times, I’ve thought to myself, “I really wish all doctors who prescribe T3 or NDT medication understood the science behind the T3 dosing effect.”

In fact, even thyroid patients taking T3 or NDT should know the Free T3 dosing curve because it strongly influences their symptoms and lab results. Yes, you might be hypothyroid for half the day or more, and your lab tests might tell an uninformed doctor you’re thyrotoxic when you’re not.

This post displays one graph of normal TSH, FT4 and FT3 circadian rhythms, and then six graphs showing Free T3 fluctuations after doses of T3.

You can learn a lot just by simply scrolling through and eyeballing these graphs.

To help intelligent thyroid doctors interpret and apply them, I summarize their research context and give some commentary.

Once you understand how T3 behaves in isolation, you can apply your knowledge to various T3-T4 combinations and NDT dosing.

Therefore, most of the thyroid therapy images and notes (after the first two images) focus on T3 monotherapy because it isolates the dynamics of T3 dosing in the body.

OUTLINE:

• NORMAL Circadian rhythm, no thyroid medication (“click to reveal” section)
  • Russell, 2008 – the natural TSH, FT3 and FT4 curves
• When does a thyroid patient need T3 dosing? (“click to reveal” section)
• The T3 Dosing curve
  • Saravanan et al, 2007 – Combination T3-T4 therapy, hypothyroid result
  • Hershman, 2009 – The different timing of peak T3 in NDT
  • Jonklaas et al, 2015 – A single overdose of 50 mcg T3 in euthyroid people
  • Saberi & Utiger, 1973 – A single dose of 50 mcg T3 in hypothyroid people
• T3 Dose-splitting effects on FT3 / T3 levels
  • Ben-Shachar et al, 2012 – 1x a day versus 2x a day, 3x a day
  • Busnardo et al, 1980 – 3 times a day, euthyroid with suppressed TSH
  • Celi et al, 2010, 2011 – 3 times a day, hypothyroid with normal TSH
• Blood test timing
• Lessons learned

NORMAL Circadian rhythm, no thyroid medication

When does a thyroid patient need T3 dosing?

The T3 dosing curve

Saravanan et al, 2007

CONTEXT: This is a study of 10 hypothyroid patients on synthetic T3/T4 combination therapy and 10 hypothyroid patients on T4 alone. They were treated autoimmune thyroid disease patients with Hashimoto’s thyroiditis or Graves’ patients after radioactive iodine therapy who were rendered hypothyroid. Judging by the Free T3 baseline around mid-reference, these were fairly good converters of T4 hormone who were already getting good value out of their T4 dosing. They likely had some functional thyroid gland tissue helping them to convert T4 into T3.

Laboratory reference ranges:

• fT3: 2.8 – 7.1 pmol / L | fT4: 10.0 – 24.0 pmol / L, | TSH: 0.3 – 4.0 mU / L.

Why the higher TSH in T3/T4 combo therapy?

Saravanan’s T3/T4 combo used an incorrect pharmaceutical equivalence ratio that rendered some patients quite hypothyroid.

The combination therapy group had been on T3/T4 therapy for 3 months. They had been taking more than 100 mcg of T4 only. Then they had 50 mcg of their T4 dose taken away and replaced by only 10 mcg of T3 (a substitution ratio of 1:5). As a result, when the FT4 dropped by 6-8 pmol/L down to 12, close to bottom of range, the extra FT3’s temporary rise did not do enough to compensate for the FT4 loss.

• The T3 should have replaced T4 at a ratio of at least 1:3, 1 mcg LT3 per 3 mcg LT4.
• They needed at least 16.5 mcg of T3 (not 10 mcg) to replace their 50 mcg of T4.

Observations on circadian rhythm during thyroid therapy

Hershman, 2009

In an endocrinology textbook chapter, Jerome Hershman expressed his opinions of the various thyroid hormone preparations available on the market, steering readers away from all except synthetic T4 monotherapy.

One very useful piece of information on the T3 post-dose peak is highlighted by the pink bars in the margin of this quotation:

For those whose resolution does not permit reading the fine print, here are the relevant sections:

“2. Desiccated thyroid extract, USP … Approximately 4 to 8 hours after ingestion, T3 levels may rise to the supranormal range.”

“3. Synthetic T3 … Patients taking T3 therapy have elevated T3 concentrations for several hours after ingestion, which gradually fall to much lower levels 24 hours later.”

(Hershman, 2009)

I cite this rather biased piece of scholarship for the reason that I have yet to find a scientific source with a graph. Hershman gave no citations to research publications to back up his claims regarding the 4-8 hour post dose peak for NDT.

If the 4-8 hour time to peak is indeed the case, it confirms what some patients experience, a gentler and more delayed post-dose peak in desiccated thyroid (NDT/DTE) dosing. This may also be the reason why some thyroid patients (based on anecdotal evidence) who do not respond well to the fast FT3 peak in synthetic are able to tolerate the T3 obtained from NDT.

In theory, a T3 peak that is placed 4-8 hours post NDT dose may be partly due to the fact that its thyroid hormone molecules T4 and T3 are bound to thyroglobulin, which is a protein. The GI tract must separate the protein from the hormone molecules before they can pass into circulation. In contrast, synthetic T3 is bound to sodium.

Hershman’s attestation of the T3 peaks in these medications appears to be a very imprecise estimate, and must be taken with a grain of salt.

• His explanation is misleading, making it seem as if, regardless of the dose strength, T3 will always surpass the top of the reference range in both medications. Of course, in light of Saravanan et al’s 24-hour study shown above, this characterization is worthy of robust ridicule. It’s brazen fearmongering. It also reveals undue obsession regarding the top of the T3 reference range considered in isolation from concurrent T4 levels.

• In addition, there is no reason why LT3’s fall from its T3 peak should be described as “gradual” over 24 hours post dose. It has a steep curve for elimination, as shown below.

Jonklaas et al, 2015

CONTEXT: Jonklaas et al performed a pharmacokinetics study of one 50mcg OVERdose of T3 on 12 healthy people (4 females, 8 males). Most pharmaceutical studies use healthy volunteers.

Reference ranges: TSH: 0.4–4.5 mIU/L | FT3: 2.18–3.98 pg/mL, |TT3: 76–181 ng/dL

Significant results:

“Triiodothyronine concentrations peaked at 2.5 hours following liothyronine administration.” This varied from patient to patient, as seen in the graph above with overlapping curves. Some people are faster absorbers or metabolizers than others.

“Heart rate increased by 5 hours after liothyronine [T3] administration, subsequently reaching a value higher than baseline.”  “No individual participant had a baseline HR of greater than 75 beats/min. Following T3 administration the highest individual HR recorded was 94 beats/min, and no significant ECG abnormalities developed. Mean HR increased by a maximum of 18 beats/min within the first 12 hours after T3 administration.” “The increased heart rate was transient and was followed by a reduction in thyroid stimulating hormone concentration.”

“Oral temperature increased from a mean of 36.2 C to a maximum of 36.6 C, and then dropped back to 35.9 C (see figure 1c). The increase in temperature was not significant.” Body temperature never reached 37.0°C (98.6°F).

Women had a slightly higher peak concentration than men (404 vs. 342 ng/dL Total T3), which may be because of their smaller total blood volume in relation to the 50mcg dose.

There were “no notable changes in blood pressure (SBP, DBP), respiratory rate, oral temperature, ECG recordings or body weight” with a single dose.

Insights: 

• A single OVERDOSE of 50 mcg causes a very high peak above reference. However, the metabolic effects on the patients were very minimal (likely due to higher FT3’s ability to enhance Deiodinase Type 3 conversion of T3 into T2).
• The peak shape is similar to Saravanan et al.
• Peak FT3 arrives earlier, at 2.5 h post-dose.
• Individual variation exists in the peak shape, and the time to peak.
• Both Total T3 and Free T3 have a similar shaped peak.
• There’s a long tail of T3 (FT3) over 72 h.
• It takes a long time for TSH to recover after a single 50 mcg overdose.
• Learn more about T3’s variable half-life in our article “LT3 monotherapy withdrawal: Clearance and effects”

Therefore, a single dosing mistake is extremely unlikely to kill you. The body has ways of breaking down this hormone fast.  In the short term, you’ll be fine. If you’re worried, take some Milk Thistle, which blocks a dominant thyroid hormone transporter, MCT8. The short FT3 peak will pass soon.

Saberi & Utiger, 1974

Context: In Saberi & Utiger’s study, they tried to discover the equivalence of 200 mcg / day of T4 compared to [X] mcg / day of T3 dosing, solving for [X].

They estimated incorrectly. A T3:T4 equivalence ratio of 1:4 was too low.

• 50 mcg 1x/day was not high enough a dose to remove hypothyroidism, in spite of average Total T3 levels at top of reference range and fluctuations far above. “The elevated basal serum TSH levels indicate that, in these 8 patients as a group, 50 mcg T3 was not adequate replacement.”
• 75 mcg/ day, divided into 3 smaller doses throughout the day, was a more reasonable euthyroid dose for adults on T3 monotherapy. Saberi & Utiger referred to Chopra’s study, which proved this.
• The test technology was older: TSH was not as sensitive, especially at the lower end of the range. There was no Free T3 test yet.

Are big T3 fluctuations like this harmful?

T3 Dose-splitting effects on FT3 / T3 levels

In the history of thyroid therapy, desiccated thyroid (NDT) has been routinely dosed at least 2 times a day, and T3 monotherapy about 3 times a day.

A person taking a very small dose, or a person who is a very slow metabolizer, could be fine with a 1x/day dose.

These graphs show why we split the dose in T3-based therapy: to avoid daily hypo / hyper rollercoasters that can cause daily discomfort to us, and to bring down the height of the Peak FT3, at which point T3 is triggering its own inactivation to T2 hormone secretly within our cells as we continue to resupply it by dosing.

Ben-Shachar et al, 2012

This simulation graph shows the potential peak-reducing effect of divided doses.

CONTEXT: Ben-Shachar et al’s simulations (not real dosing) were for the potential use of LT3 therapy in pediatric thyroid cancer patients (children aged 3 to 9 years old). Their aim was to benignly suppress TSH during the replacement period of 3 weeks.

NOTE: Withdrawal period? This is part of thyroid cancer therapy. After thyroidectomy for cancer, thyroid remnants are neutralized with radioactive iodine. First, TSH is suppressed to prevent cancer resurgence during recovery from surgery. Withdrawal of T3 increases TSH and induces iodine uptake into the thyroid tissue. Using T3 alone shortens time to TSH suppression and post-withdrawal time to TSH elevation. It reduces the patient’s time spent suffering in a hypothyroid state. Read more: “LT3 monotherapy withdrawal: Clearance and effects.”

Busnardo et al, 1980

After Ben-Shachar’s simulations, this graph shows REAL people with 3 doses per day, and even a table showing their doses.

CONTEXT: Busnardo’s study was also of patients receiving TSH-suppressive yet non-thyrotoxic LT3 monotherapy.

NOTES: Their goal was achieved: “The results of the present study confirm that T3, when given three times a day, at the minimum dosage necessary to inhibit TSH response to TRH, assures a constant suppression of TSH secretion without causing important side effects.” “TSH suppression is complete within 10-12 days” and withdrawal required the same period to achieve an elevated TSH.

Celi et al, 2010, 2011

CONTEXT: These researchers’ two articles are based on a single experiment that compared T4 monotherapy and T3 monotherapy to achieve a target TSH level in patients.

They discovered that a pharmaceutical substitution of 1mcg T3 for every 3 mcg T4 achieved similar TSH responses. Yes, a 1:3 substitution ratio confirms a lot of earlier science.

However, circulating T3 levels had to be significantly higher to achieve this TSH target. T3 had to fluctuate in some patients above the reference range (note the vertical error bars) and in some patients, it fell to the bottom of reference range before the morning dose.

Unfortunately, Celi’s target TSH of 1-1.5 was NOT truly euthyroid for such patients.

1. Celi and team later published an article that admitted strong doubts (Yavuz et al, 2013): “the data suggest that pituitary euthyroidism, both assessed by basal [TSH] or TRH-stimulated TSH, does not necessarily equate to a state of generalized euthyroidism at the level of the different targets of the hormonal action.”
2. The average T3 dose in Celi’s study was only 40 mcg / day, but most studies have proven that is insufficient to achieve body-wide euthyroid status in adults. The range for T3 monotherapy dosing is 50-100 mcg with 75 mcg being the average dose, as shown above, and as shown in a compilation of studies here.
3. The T3 level during the L-T4 therapy experiment (not shown) was at the low borderline. However, the T3 and FT3 average is mid-range in all healthy people and rarely fluctuates so low, even during circadian rhythm, as shown in Russell, 2008 above.
4. Three recent research studies on thyroidless patients have proven that euthyroidism is only achieved, on average, when TSH is below reference range in such patients treated on LT4 (Larisch et al, 2018; Ito et al, 2019a, 2019b).

In addition, the normalized TSH was extremely difficult to achieve on T3 monotherapy, requiring fine adjustments of compounded medication for each individual. Imagine a dose of 15.5 mcg, followed by a dose of 11.5, then 12.5.

Such a delicate balancing act on the edge of a knife would be necessary if you want to target a very narrow TSH using T3-dominant dosing. The emphasis on T3 hormone will induce an abnormally swift change of TSH from elevated to normal to suppressed as one inches closer to euthyroid status, as researchers have discovered:

• TSH behaves abnormally at T3:T4 dosing ratios equivalent to desiccated thyroid (NDT) At a certain level of FT3, different for each patient, TSH suddenly takes a nosedive, but euthyroid status is achieved at the point of suppression (Snyder & Utiger, 1972).
• TSH suppression is achieved by T3-dominant dosing without causing any thyrotoxicosis (as noted by Busnardo and Ben-Shachar, above).
• Researchers have discovered the swift TSH suppression is a side effect at the hypothalamus, not the pituitary. The pituitary often still responds to TRH stimulation even after basal TSH is suppressed at 60 mcg/day. This means that TSH is often not “truly” suppressed, even when FT3 is elevated (Koutras et al, 1981).

This is why most clinicians in the history of thyroid therapy, before TSH-test obsession took over, calmly accepted the non-thyrotoxic fully suppressed TSH in T3-dominant therapy, rather than the challenging balancing act that would titrate doses down to the microgram to force the TSH to stay normal while the patient suffers.

What do you get from your heroic TSH balancing act if the T3-dosed patient isn’t necessarily euthyroid at a normalized TSH, as research confirms?

Blood test timing

Now you can see why the number of hours post dose matters.

Without consistency from test to test, you can’t compare progress between two lab tests months apart.

Why should we test after the Free T3 peak?

Measuring during peak FT3 is not going to yield consistent results.

Even 20 minutes sitting in the laboratory can make a big difference in FT3 levels during its volatile peak rise and fall. The time it takes for FT3 to rise and fall from that peak is highly individualized and can shift based on D3 conversion activity that will likely be triggered at this time.

As you can see in Saravanan’s graph above, FT3 levels can change 10% from 8 hours post-dose to 10 hours post-dose, and that’s why at least 12 hours is going to yield more consistency from lab test to lab test.

12 hours post T3 / NDT dose is a good rule of thumb

Why? because it is biased neither to the volatile peak, nor to the hypothyroid trough that would deepen after that point, especially by 24h.

Delaying or skipping doses on lab test day

The day of the lab test can be hard on the body if it involves skipping or delaying a dose more than 12 hours. Who wants to cause undue suffering by delaying their next T3-containing dose too long? If most of your therapy is in the form of T3, starving the body of T3 for too long can have side effects afterward for days or a week.

The best idea is to take your final dose in the evening before the lab test. Have a lab appointment already set up for early in the morning the next day so you can time the test appropriately.

After the blood draw, if you delayed your first dose of the day, take it after the lab test and just shift your doses forward in time to avoid taking two doses too close together.

How frequently can you do a test?

• If all you want to check are Free T4 and/or Free T3, you can test at least 3 weeks after a stable T4 dose increase or decrease, and at least 3 days after a stable T3 dose increase or decrease, considering factors like half life and clearance rate.
• If you want an accurate TSH test, then give TSH time to “equilibrate” to a new stable Free T4 level. It can take 6 weeks to 3 months for TSH response accuracy.

Lessons learned from the graphs

Our modern T3-T4 combination therapy trials have too often failed like Saravanan’s because they target TSH as the highest priority even though TSH is no longer in charge.

In addition, too many researchers and doctors like Saravanan also misunderstand T3 dosing dynamics and the complex FT3-FT4 relationship. These are not independent hormones. They interact in a dance in which FT3 dominates in health and must never fall below a baseline, and FT3 can compensate for less FT4, but never vice versa.

Using desiccated thyroid (NDT) or T4 monotherapy with the same classic misunderstandings will also lead to mixed results, and the most vulnerable patients will suffer.

Celi and team would have achieved euthyroid status if they had permitted the TSH to fall and allowed T3 to rise to compensate for no T4 in bloodstream. In all these graphs, the only one that used T3 alone and achieved true euthyroid status was Busnardo, 1980.

If you DO have T4 in bloodstream, the target is still at least a mid range T3 — as it is in health — or higher when needed. You will need to raise T3 to the degree you need to compensate for a reduction in T4 availability. Reducing T4 while adding T3 can be good for poor converters, because a higher FT4 can be an obstacle to achieving sufficient FT3.

Normalcy in TSH and T4 are never the targets of a fully healthy thyroid metabolism, according to the thyroid research leading the way in 2019. These two hormones are a support and a means to an end insofar as your body can still use them well enough as tools. TSH is for stimulating thyroid tissue, because a thyroid has the ability to both secrete variable ratios of T4:T3 and convert T4 to T3 at higher rates when stimulated. T4 is good for people who still convert it well despite thyroid disease. T3? well, supplying the right amount is good for everyone and every situation because it’s not a tool, it’s the end goal.

In other posts on this website, I’ve cited numerous articles to prove these basics:

• T4 is nature’s sustained release T3, but it converts to T3 at a variable rate.
• When T4 is more abundant, it converts poorly and can trigger both T4 and T3 depletion.
• When T3 is more abundant, it inactivates to T2 at a higher rate.
• When neither are sufficient, or T3 alone is insufficient for individual health, you’re hypothyroid.
• When both are overabundant, or T3 alone is in excess of individual health requirements, you’re hyper.

Without a TSH-driven healthy thyroid, your body can’t compensate naturally for thyroid metabolic dysfunction and imbalance to sustain T3 supply to cells.

T3 hormone sufficiency in blood and cells is always the target and the foundation of health:

• with or without a healthy thyroid
• with or without TSH
• and with or without T4.

REFERENCES