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Home: Tired of being Tired, Depressed, Constipated,
Can't Sleep or Think?

Cancer, Depression, Hair Loss, Vertigo, & Infertility Correlate
with Low Thyroid Levels

TSH Levels Fluctuate and often
do not Reflect Thyroid Levels

Osteoporosis, Gum Disease &
Bad Teeth are not from Low TSH

High Blood Sugar & Insulin Resistance Correlate with High T3

Thyroid Blood Tests to Diagnose a
Thyroid or Hormone Imbalance

Thyroid Lab Results are Affected
by the Time of your Last Dose

Thyroid Reference Ranges are too Broad; What is Healthy / Optimal?

Thyroid Hormone Medications:
T4, T3, or Desiccated (T4 + T3)

Thyroid Hormone Requires
Iron, Cortisol, Selenium, Iodine

Hyperthyroid Symptoms (Anxiety, Tachycardia), Hypothyroid Labs

Adrenal Fatigue or Low Cortisol: Hydrocortisone (HC) Side Effects

Reverse T3: Side Effects of T3-only
(or why you need T4 too)

Insomnia, Incontinence, &
Vaginal Dryness Resolve with BHRT

Low Testosterone in Aging Men:
TRT for Andropause

Saw Palmetto, Stinging Nettle, and OTC Men’s Supplements

Asthma, Eczema, Allergies, Hives, and Yellow #5 (Tartrazine)

Graves' Hyperthyroidism:
Antithyroid drugs + Levothyroxine

High Altitude Sickness: Headache, Insomnia, and Hypothyroid?

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Reverse T3: Side Effects of T3-only (or why you need T4 too)

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High reverse T3 (rT3) is a "bad" thing, according to some, because rT3 "blocks" the receptors, keeping T3 out.  Therefore, high doses of T3 should be taken to "clear" rT3, and because rT3 is made from T4,  no T4 should be taken.  I tend to have high reverse T3, did not do well on high doses of T3, and wanted to know if the T3-only protocol had any scientific merit.  In my opinion, it does not.  The T3-only protocol may work for some, but not because it clears "blocked receptors."  There are also side effects from taking such high doses of T3 that are never disclosed.  This reverse T3 page summarizes what I found; it has several sections and was meant to be read in its entirety, ending with the conclusion.  To read or post only one portion of it is taking it out of context.  A link back to this page should be posted instead. There are now over 70 references at the bottom of this page that substantiate everything said, and I highly recommend further reading by anyone considering the protocol.

The T3-only protocol is not for everyone, and some people have had serious side effects.  Inability to think and remember anything (dementia), severe hair loss, muscle wasting, bone loss (osteoporosis), and high blood sugar (diabetes) are just a few of the side effects.  T3-only side effects

Yet other patients claim this protocol gave them their lives back.   How is that possible?   Different biochemistries require different proportions of T3 and T4.  Optimal thyroid dosing

What exactly is the T3-only protocol?  Reverse T3 and the “T3-only” protocol

Estradiol and SHBG rise to unnatural levels on the T3-only protocol.  T3's negative effect on other hormones

Who made this up?  Are they benefiting financially?  The cost of compounded T3 far exceeds the cost of generic T4 or desiccated thyroid.   The reverse T3 ratio is a nonsensical number because it can be low for several different reasons, each requiring a different treatment.

Does reverse T3 have a purpose?  Yes it does!  Reverse T3's role in the body

Reverse T3 is made under certain medical conditions by the D3 deiodinase enzyme.  D3, the deiodinase enzyme that makes reverse T3 (NOT Vitamin D3)

T4 is used by many cells in the body, especially hair; it is more than a prohormone and there are indeed T4 receptors.  T4's role in the body

The brain needs ample T4 to function properly and high levels of T3 cause brain dysfunction.  T3 and T4's role in the brain

Hyperthyroid patients have the highest levels of rT3.  If rT3 really blocked the receptors, no one would ever be hyperthyroid.  Think about it.  Do thyroid receptors really get blocked and take 12 weeks to clear? Is T4 really the problem?

Whom to believe?  Thyroid internet forums

to blog

Reverse T3 and the “T3-only” protocol

Reverse T3 is a thyroid molecule that is similar to regular T3, except one of the iodine atoms is in a different position. This makes it inactive. T3 is the active hormone that the body uses.

High reverse T3 (rT3) levels or a “bad” reverse T3 ratio (Free T3 divided by rT3 is less than 20) are said to be the cause of stubborn hypothyroid symptoms even while one is taking an ample amount of medication. If the ratio is less than 20, then the treatment touted by some is to take 75-125 mcg of T3 only split throughout the day, and no T4 whatsoever. Some people can tolerate these high doses of T3, others cannot.

Why do so many experience side effects on the T3-only protocol? The reasons are explained in detail below, but here is a quick summary of what follows, which basically proves that the reverse T3 ratio theory is based on faulty premises. Recent research in cellular and molecular biology shows that:

  • rT3 does not block the receptor at all; neither rT3 nor T3 is in the receptor, that's the problem
  • T4 is more than a prohormone and is essential for healthy hair, brain, and other functions
  • Excess T3 will cause an imbalance in other hormones (it raises estradiol, which can be problematic, especially for men)
  • Excess T3 (desiccated thyroid has a high amount of T3) can trigger high reverse T3
  • Desiccated thyroid contains rT3, because rT3 is found in a normal thyroid gland [desiccated thyroid contains T4, T3, rT3, but little T2 or T1]
  • The reverse T3 ratio is a nonsensical number because the ratio can be low when Free T3 is high or Free T3 is low. A high FT3 and a low FT3 are different conditions and should not be treated the same way.

T3's negative effect on other hormones

Apparently some people can remain on T3-only indefinitely and actually feel fine, or certainly better than they ever did on T4 medications. Others, however, become worse, because the high T3 levels have side effects and create imbalances in other hormones. In men, high T3 levels will cause sex hormone binding globulin (SHBG) to rise, the production rate of estradiol to rise, and the metabolic clearance rate of estradiol to fall. [1, 52] The net effect is higher estradiol levels, which can have a disastrous effect on men's hormone levels. In men, a hyperthyroid state can elevate estradiol and result in gynecomastia (male breasts). [2] Premature ejaculation seems to be a problem for hyperthyroid men, and delayed ejaculation a problem for hypothyroid men. [53] High SHBG in men also correlates with osteoporosis and a higher fracture risk. [55]

SHBG also rises in women taking additional T3. The metabolic clearance rate of estradiol decreases [52] and anecdotally, women have reported painful breasts on the T3-only protocol. Women’s testosterone levels also decrease on this protocol. This may be desirable if a woman exhibits high androgen symptoms like facial hair, infertility, etc., but undesirable if levels become too low. [54]

In women, estrogen and progesterone can also raise SHBG if taken orally [3], so if a woman is on these other hormones and following the T-3 only protocol, her system can become quite imbalanced. Hormonal imbalance is often the cause of both physical and emotional symptoms.

A reverse T3 ratio greater than 20 does not indicate good health any more than a normal TSH does

Reverse T3, like cholesterol, is a natural substance found in every single body, and has a purpose. To try and rid oneself of it is unnatural, and analogous to taking statins to bring cholesterol levels down. Many have suffered permanent damage from taking statins, and people have suffered serious side effects from taking T3-only. The rule that the reverse T3 ratio should be greater than 20 is analogous to saying one’s TSH should be a certain number. Both are arbitrary numbers that fluctuate and should not dictate treatment. [TSH levels do not reflect thyroid levels]

Below are three different lab profiles where the reverse T3 ratio can be low (in patients already taking thyroid medication). Each has a different cause and requires a different treatment, which is not accounted for with the simplistic reverse T3 ratio formula, which is: if FT3 divided by rT3 is less than 20, then one should only take T3.  This is called nonsense math, where an equation gives an appearance of credibility, even though it makes no sense. [70]   If a low ratio can be from both high or low Free T3, then the ratio is useless, because it can mean two different things; this makes it mathematically invalid.  BMI or Body Mass Index is an example of a valid ratio.  Weight is divided by height.  The higher the BMI ratio, the more overweight the person.   A high BMI ratio does not mean  overweight in some cases, but underweight in others.  But a low rT3 ratio can mean both too much or too little T3, as explained below.

Profile I: mid-range to high Free T3, below mid-range Free T4

Reverse T3 may be slightly high (a few points above the reference range) due to high T3. This lab profile is often found in those taking desiccated thyroid, because of the high T3/T4 ratio in the pills.  The body senses the high T3 levels, and converts some T4 to rT3 to compensate.  Desiccated thyroid also contains rT3, so reverse T3 levels should rise as the desiccated dose is increased.  Lowering the desiccated thyroid dose and adding T4 has lowered rT3 levels in some patients. These people report improved reverse T3 ratios on higher levels of T4 and say they feel more “balanced” with the additional T4. The T3-only protocol does not work well for these patients because it compounds the problem that caused the high reverse T3 in the first place—too much T3. These people feel best with a higher proportion of T4 to T3, and may suffer severe side effects on the T3-only protocol.  The rT3 ratio is too simplistic to differentiate these people from those in Profile III.  

Profile II: below mid-range Free T3, mid-range to high Free T4
Reverse T3 may be high due to poor conversion and lack of essential cofactors like selenium. This lab profile is often found in those who only take T4.  Reverse T3 levels may actually be within the reference range, but the calculated rT3 ratio is low because T3 levels are low.  Changing to desiccated, which has T3, or adding T3 to a lower dose of T4 often helps. Addressing factors that impede conversion, such as high cortisol or low iron, is also recommended. These people do best when their T4/T3 ratio is closest to that found in desiccated thyroid. This ratio can also be attained with synthetic T3 and T4, or customized by adding additional T3 to the desiccated thyroid dose. These people feel better once they add some T3 to their dose.

Profile III: below mid-range Free T3, below mid-range Free T4, over range reverse T3

If reverse T3 is significantly over the reference range (sometimes hundreds of points over the range), and the patient’s Free T3 and Free T4 do not rise with increasing doses of any type of thyroid hormone, this could indicate something more serious that should be investigated.  Iron labs may point to Anemia of Chronic Disease, rather than Iron Deficiency Anemia. Serious infections (root canals, for example) can cause this. Uterine fibroid or other tumors, as well as damaged heart muscle could also cause high reverse T3. The high reverse T3 is a sign of a problem, not the cause of the problem.  Reverse T3 itself does not physically block the receptor.  Surgical removal of the infected part has often brought a relief in symptoms. These are the patients that must take extremely high doses of T3 to overcome an overactive D3 enzyme, which not only converts T4 to reverse T3, but also inactivates any T3 to T2, resulting in minimal T3 for the body’s functions. These people do best with a higher proportion of T3 to T4, but may have a hard time tolerating it due to their iron problems. Some of these patients do not tolerate any T4 because of their underlying condition and only feel functional on T3-only.  However, they are not immune from the side effects of too much T3, and their T4 deficiency may affect other parts of the body that depend on T4, especially the brain.

Reverse T3's role in the body

Normal, healthy people produce reverse T3, it is not poison, and it is a normal pathway for the breakdown of T4. It is actually abnormal to have no reverse T3! [7]

One purpose of reverse T3 is to reduce one’s metabolism, to prevent starvation in cases of famine. Anyone on a severe caloric restriction diet will reach a weight plateau at some point because reverse T3 naturally rises in this condition. [8]

Marathon athletes can also have high reverse T3 levels for the same reason—the body is trying to conserve energy to prevent starvation. So strict dieting and excessive exercise can raise one’s reverse T3 levels. [9]

Studies show that there are many other causes of high reverse T3 levels:

  • aging
  • burns/thermal injury
  • chemical exposure
  • cold exposure
  • chronic alcohol intake
  • free radical load
  • hemorrhagic shock (often from severe blood loss)
  • insulin-dependent diabetes mellitus
  • liver disease
  • kidney disease
  • severe or systemic illness
  • severe injury
  • stress
  • surgery
  • toxic metal exposure
  • certain drugs like amiodarone and beta blockers
  • and high cortisol. [10,11,12,13]

It’s much healthier to address and correct the conditions just listed, than to take T3 only. Diabetics typically have high reverse T3 levels that drop once their glucose is controlled. [14]

Reverse T3 levels can appear high in someone whose liver is not healthy, because reverse T3 is processed and eliminated in the liver. [4,5] There are anecdotal accounts from people who have a suboptimal reverse T3 ratio, with both FT3 and reverse T3 over mid-range, but who feel fine. As long as the FT3 was optimal for them, it didn’t matter what the reverse T3 level was.

D3, the deiodinase enzyme that makes reverse T3 (NOT Vitamin D3)

Because reverse T3 is elevated when a certain deiodinase enzyme known as D3 is high, a closer look at D3 is warranted. D3 is the deiodinase enzyme that converts T4 to reverse T3 and inactivates T3 to T2. Its purpose is to keep T3 levels low. D3 is absent from most adult tissues, though it is found in the skin and certain parts of the brain. It is also found in fetal tissues, the uterine endometrium, and placenta, where it serves to protect the fetus from the mother’s adult levels of thyroid hormones. [16]

There is a condition called Nonthyroidal Illness Syndrome (NTIS), also known as euthyroid sick syndrome or low T3 syndrome, where reverse T3 is high, T3 is low, and T4 and TSH are normal. This condition is the result of a change in the proportion of the three deiodinase enzymes (D1, D2, D3) that convert the various thyroid hormones. In NTIS, they work together to lower T3 and raise reverse T3, making the patient more hypothyroid. The illness itself causes the derangement in thyroid levels. [15] This is an important concept to understand--the thyroid itself has not gone bad (as in autoimmune disease), but a serious illness has taken control of, and downregulated thyroid levels. These are the patients that can take the high doses of T3 recommended in this protocol without any hyperthyroid symptoms, because their extremely high D3 levels inactivate much of their T3.

The brain and spinal cord prefer stable blood serum T3 levels. The deiodinase enzymes work together to ensure that T3 levels are kept at the same, ideal level in all conditions. A rise in T3 will also cause a rise in D3 levels, increasing T3 clearance to T2, while D2 levels are decreased, decreasing T3 production. More T4 would follow the reverse T3 pathway, so less T3 would be made. [17] In effect, too high a dose of T3 can cause high reverse T3, by increasing the D3 enzyme. Desiccated thyroid has a higher proportion of T3 than produced by the human thyroid, so as some raise their desiccated dose, their reverse T3 also increases. Desiccated thyroid also contains reverse T3, so while it raises Free T3, it also raises reverse T3. A large dose of T3 taken all at once (when T4 is also present) could also have the same effect and raise reverse T3 levels.

D3 is reactivated in certain medical conditions in adults. After a heart attack, the heart muscle itself expresses D3. Mice who suffered heart attacks were found to have increased D3 activity in the heart muscle, with a corresponding 50% decrease of T3 in left ventricular tissues. [18] This implies that patients who have had cardiac episodes may always have high reverse T3 levels, and there are some people on the thyroid internet forums that fit this profile.

High D3 activity has been found in vascular (blood vessel), brain, and other tumors, and some malignant cancers. [69]  There is even a condition called consumptive hypothyroidism, where D3 activity from a tumor is so pronounced that it literally consumes any thyroid hormone, resulting in profound hypothyroidism. Blood serum T4 and T3 levels do not increase even with increasing doses of T4 medication, though reverse T3 stays high. [19] In one case, high levels of D3 were found in a woman's liver tumor, and her elevated TSH returned to normal after the mass was surgically removed. [20]

D3 can also be reactivated when cell proliferation is desired, to lower T3, which stimulates cell differentiation and inhibits cell growth. Healing from a burn is an example where cell proliferation is desired, to regenerate new tissue. In one experiment of partial liver removal in rats and mice, D3 activity increased 40-fold in the mice 36 hours after surgery. In the rats, there was a corresponding 2- to 3-fold decrease of blood serum and liver T3 and T4 levels 20 to 24 hours after the surgery. [21] Other studies show high D3 activity in various states of tissue injury: starvation, cryolesion (frostbite or medical procedures that purposely freeze tissue to destroy it), cardiac hypertrophy (thickened heart muscle, usually due to high blood pressure), infarction (heart attack), and chronic inflammation. [22] High reverse T3 should then be expected anytime there is tissue damage that needs repair.

Another experiment showed that during acute bacterial infection, granulocytes (a type of white blood cell) in infected organs expressed D3, and serum thyroid hormones decreased proportionately to the severity of the illness. D3 was also highly expressed in response to chemical inflammation (a turpentine induced abscess). [23] Infections and abscesses would then be expected to cause high reverse T3.

Perhaps those with high reverse T3 have an underlying condition, like those just listed in the paragraphs above. Quite a few thyroid patients have reported tonsillectomies (infection/inflammation), hysterectomies (fibroid tumors), heart conditions, problem root canals (infection), and various cancers. Sinus infections and gut inflammation (celiac) are other possible causes.

Recent research shows individual genetic differences in many aspects of thyroid physiology, and these can all impact T3 and reverse T3 levels. Genetic variations have been found in the TSH receptor, thyroid hormone receptors, thyroid transporters (that take hormone into the cells), and the deiodinase enzymes (a variation in D2 correlates with diabetes, and diabetics have high reverse T3). [24]

T4's role in the body

While T3 appears to be the most metabolically active, all thyroid hormones (T4, T3, T2, T1, T0) have non-genomic effects many are not aware of. All this means is that they can exert an effect on the cell at the plasma membrane (surface) or cytoplasm level, whereas the primary effects of T3 are at the cell's nucleus (after conversion from T4). In other words, T4 exerts these non-genomic effects outside of the nucleus, and before its conversion to T3. So to say it is a prohormone (storage hormone) with no effect is a false statement, because it does have an effect in its unconverted state, as T4. [25]

Hair needs T4, because it lengthens the hair growth phase. [26]  My Free T3 has been below range, mid-range, and over-range, but my hair was still not right at any of those levels. Only since adding T4 to get my Free T4 above mid-range (and lowering my desiccated dose) has both my hair texture and volume improved. It should be noted that hair loss is a symptom of both too much and too little thyroid.

In one experiment on dogs, T4 was administered both topically and orally. In either case, there was an increase in both the rate of hair growth and in the number of hair follicles entering the growth (anagen) phase of the hair cycle. [50]

T4 converts into other essential metabolites besides T3. These cannot be made from T3. Just like T4 is deiodinated (converted) to T3, T4 can also be deaminated (converted) to tetraiodothyroacetic acid (tetrac). Tetrac has been shown to inhibit tumor growth, while T3 and T4 stimulate it. [27] If T4 is eliminated, then there is no source from which to make tetrac, which may be just one of several metabolites that can only be created from T4.

T(1)AM (3-iodothyronamine) is another biologically active T4 metabolite which has nongenomic cardiac effects. This metabolite induces opposite effects from those stimulated by T3 and T4, such as decreased heart muscle contractions and decreased heart rate. Both T3 and T4 have multiple nongenomic cardiac effects, and an equilibrium between T3, T4, and T(1)AM levels is essential for heart health. [63]

T3 and T4's role in the brain

There are two different transporters for T3 and T4 into the brain. One (OATP1c1) transports only T4, the other (MCT8) transports T3 and T4. T4 is then converted locally to T3 by the D2 deiodinase enzyme. The total T3 in the brain comes from what was converted locally (from T4), plus what was transported in as T3. [28]

Deiodinase activity is different in specific regions of the brain. Thyroid hormone levels in the brain are kept in tight ranges because the brain requires that stability. In hyperthyroidism (when T3 levels are too high), D3 expression increases, which increases the T4 to reverse T3 pathway, and D2 expression is suppressed, lowering T4 to T3 conversion.  These two processes together work to lower high T3 levels. Likewise in hypothyroidism (when T3 levels are too low), D2 expression is increased, which raises T4 to T3 conversion, to raise T3 levels in the brain. When someone takes T3-only and no T4, they may lose this important regulatory feature of reverse T3 (to lower high T3 levels), and T3 levels may exceed the brain’s optimal range, since there is no T4 to inactivate. It’s analogous to running too much voltage through a low-voltage appliance. This can result in what is called hyperthyroid dementia or fresh amnesia, where recall of events minutes earlier is impaired. [40,59] I suffered from this fresh amnesia and could not recall things I'd done two minutes earlier. I was also completely unable to perform simple math in my head, which I do routinely. My memory and math skills returned once my T3 dose was reduced. In another case, the person lost their foreign language fluency.

A study of rats treated with T3 supports these observations. After T3 treatment, their brains showed a 50% decrease in specific membranes of the cerebral cortex, which is the part of the brain involved with memory, attention, and language. [62]

Thyroid hormone levels of healthy women (all thyroid labs within normal range) were analyzed for any correlation of their performance in neuropsychological tests to their thyroid levels.  High Free T3 levels were positively associated with slower completion times for certain cognitive tests; in other words, the higher the Free T3, the longer it took the subject to complete three tests.  In Trail Making Test-A, subjects draw a line connecting numbered circles, which are randomly placed on the page.  In other words, after finding circle 1, they draw a line to circle 2, etc. until they reach circle 25.  In Trail Making Test-B, subjects have to connect both numbers and letters in order:  1-A-2-B-3-C etc.  This test can cause extreme confusion and will take longer to complete if the brain isn't working correctly.  The third test that subjects with high Free T3 took longer to complete is the Tower of London test.  In this test, subjects rearrange stacked, colored beads on three posts into a new configuration they're shown.  A bead that was formerly on the bottom or a post in the old configuration may need to be on the top of a different post in the new configuration. Getting the beads in the correct order involves thought and planning.   Because high Free T3 was consistently correlated with slower performance test times, the authors concluded that elevations in thyroid hormones (within the normal range) may negatively affect frontal cortex executive functions in the brain, where memory, attention and language are located.  [65]

Female thyroid cancer patients who had undergone thyroidectomies, had radioactive iodine, and were on suppressive doses of levothyroxine were studied when their levothyroxine doses were to be stopped for an upcoming radioactive iodine whole body scan.  They were tested at three points in time:
  1. before stopping their dose, when they were considered mildly hyperthyroid (suppressed TSH, over range FT4, normal to high FT3)
  2. 4-7 days after stopping their dose, when considered euthyroid (FT3 and FT4 normal, but TSH still suppressed for most), and
  3. about 30 days later, when considered profoundly hypothyroid (TSH high, FT3 and FT4 below range).  Controls of similar ages and backgrounds were also measured for comparison.

A visual scanning test that measures distractibility and visual inattentiveness gave interesting results.  Subjects had to locate a particular symbol in a paper filled with a matrix of symbols, of which 60 were correct.  While nearly all symbols were found by all groups (59/60), the subjects took the longest time to perform the task when they were mildly hyperthyroid, longer even than when they were profoundly hypothyroid! [66]  This suggests that too much thyroid hormone causes some type of brain dysfunction, and may actually be a mild form of hyperthyroid dementia.  In fact, Graves' hyperthyroid patients frequently exhibit deficits in attention, memory, and complex problem solving. [67] 

The hippocampus and temporal cortex areas of the brain, which affect memory and cognitive functions, exhibit the highest D3 concentrations, the enzyme that deactivates T3.  This suggests that these two areas of the brain are the most sensitive to high T3 levels, and the studies just mentioned seem to confirm that statement. In one experiment, D3 could not be detected in hypothyroid brains, and D3 levels were found to correlate with thyroid status in the central nervous system. In other words, D3 would rise as thyroid levels rose, so reverse T3 could be made if T3 levels became too high.  [29,30]

Brain size physically changes when thyroid levels are too high or too low. The hyperthyroid brain is larger than normal, and the hypothyroid brain is smaller than normal. Conversely, ventricular size (which contains the cerebrospinal fluid) is smaller than normal in hyperthyroids, and larger than normal in hypothyroids. The reduction in brain size and increase in ventricular size found in hypothyroids significantly correlated to reduced T4 levels.  In other words, as T4 levels rose, brain size increased and ventricular size decreased towards normal. But the correlation of brain size with T3 levels was not statistically significant. However, ventricular size decrease strongly correlated with rising T3 levels. [60] It is possible that the rapid decrease in ventricular size in the brain might have something to do with the headaches some patients report when increasing their T3 dose on the T3-only protocol.

Another study found that locally deiodinated T3 (from T4 in the brain) accounted for more than 80% of the total T3 specifically bound to nuclear receptors in the cerebral cortex, and approximately 67% of that in the cerebellum. T4 would then be the major source of intracellular T3 in the central nervous system. [31] If 80% of the T3 in the brain came from T4, then a higher than normal dose of T3 would be necessary to compensate for this loss of T4 in a T3-only protocol. But a dose that high may have adverse effects on other systems that are more sensitive to T3, like the cardiovascular system, and may cause problems like tachycardia (rapid heart rate) and high blood pressure.

EEGs (brain electrical activity) of hypothyroid patients (thyroidectomy followed by radioactive iodine) were compared while they were still hypothyroid, after supplementation with T3, and after supplementation with T3 + T4. The EEGs only normalized when T4 was added to the T3, and correlated significantly with the rise in serum T4 levels. So it appears that T4 is essential for normal brain function. [32,33]

The psychological well-being of patients on thyroid hormone replacement was compared to their Free T3, Free T4, and reverse T3 levels.  There was a strong positive correlation of higher FT4 levels with well-being; in other words, patients with higher FT4 levels (even above the reference range) just felt better mood-wise.  But there was no correlation of psychological well-being to Free T3, rT3, rT3/FT4, or FT3/rT3.  The authors noted that all measures are serum measures and do not reflect intracellular levels, and that many tissues obtain their T3 by conversion from T4. [68]  As stated earlier, with ample T4, the brain can create the optimal amount of T3 it needs with the appropriate deiodinase enzymes.  If T4 levels are too high, more will be shunted to rT3.  If T4 levels are low, nearly all T4 will be converted to T3.  But if T4 is extremely low, then T3 in the brain will be insufficient.  

T3-only side effects

The problem with T3-only treatment is that one must usually go over-range on T3 levels to compensate for the lack of T4 in the body. People on thyroid internet forums that have been on T3-only protocols have reported the following side effects:

  • erythrocytosis (thick blood or high RBC, hematocrit, and hemoglobin) [34]
  • osteoporosis [35] – A study where subjects were given 50-75 μg of T3 showed increased bone resorption and fecal calcium loss.
  • muscle weakness [36,39] – ­ (especially the thigh or upper arm muscles--difficult to climb stairs or rise from sitting; or to hold arms above head to wash hair) A study found that doses of 60 μg/day or more of T3 enhanced muscle catabolism (breakdown) during fasting. In other words, high T3 can cause muscle wasting. The heart is a muscle and is not immune from this effect.
  • insulin resistance [37,38] – A study found that both plasma glucose and insulin increased after T3 ingestion, which is not a desirable effect. A correlation was found between higher Free T3 and Free T4 levels and insulin resistance in the early stages of Type 2 diabetes. [58]
  • fast heart rate or palpitations [39]
  • intolerance to exercise [39]
  • shortness-of-breath [39]
  • insomnia [39]
  • hair loss/thinning [39]
  • elevated liver enzymes (AST and/or ALT) [57]
  • brain fog or hyperthyroid dementia- can't remember things that just happened, or trouble solving problems (math, scheduling. etc.) [40,41,59]

These are symptoms that anyone on T3-only therapy should be aware of, and are actually classic symptoms of hyperthyroidism. Hypothyroidism presents with some of these same symptoms, so it can be difficult for patients to tell whether they are over or undermedicated. Like hydrocortisone, there are side effects to this therapy that one should know about before undertaking this protocol. Many have ended up feeling worse than before they started. Because hydrocortisone helps one tolerate thyroid hormone, there is the potential problem of taking more and more hydrocortisone to tolerate more and more T3, ultimately resulting in a serious overdose of both hormones. In fact, high T3 levels have been observed to lower cortisol levels to the point of adrenal insufficiency in hyperthyroid Graves’ patients. Cortisol levels returned to normal when thyroid levels were brought back into the normal range with antithyroid medications. [61]

One of the dangers of T3-only therapy is the potential to “run out” of thyroid hormone in the event of an emergency. The half-life of T3 is approximately one day, whereas the half-life of T4 is 5-7 days. [42] Without any T4 reserves, constant T3 dosing is essential. An incident where one was rendered unconscious or could not access their medication (natural disasters) would result in rapidly declining thyroid levels in the body after only 24 hours. This severe hypothyroid state would hinder any recovery.

Do thyroid receptors really get blocked and take 12 weeks to clear? Is T4 really the problem?

Proponents of T3-only therapy believe that reverse T3 "clogs" the T3 receptors, therefore only T3 should be taken for 12 weeks until the reverse T3 is "cleared." Yet others who have not changed their dose to T3-only (and continued to take some T4) have reported reduced reverse T3 levels in subsequent labs, by addressing problems like low iron, or increasing their caloric intake and eating more frequently. A study in Calcutta, India illustrates that reverse T3 is indeed dynamic. Patients who suffered from malnutrition had reverse T3 values that were above the values of normal subjects, but their reverse T3 fell once they were fed, so the condition is dynamic, not static. [43] In another experiment on fasting obese subjects, reverse T3 levels rose significantly by day 7, but returned to normal after 4 days of refeeding. [44] In both studies, the subjects' reverse T3 levels returned to normal without being put on a T3-only regimen, so this seems to refute the "clogged" receptor theory.

Reverse T3 inhibits the D2 enzyme that converts T4 to T3 in the rat brain cortex and pituitary. Rats were infused daily with four increasing levels of reverse T3, and D2 enzyme activity decreased (so T4 to T3 conversion decreased) as the reverse T3 levels increased. Tracers on the reverse T3 showed the reverse T3 was not detectable in the cell nuclei, and only 1% was found elsewhere in a homogenized mixture of the rat brain and pituitary tissue. The infused reverse T3 was no longer present, which means reverse T3 did not "clog" these receptors, nor would it be present 12 weeks later. [64] This corroborates the fact that reverse T3 has a much higher clearance rate than FT3. [6]

A study was performed to observe the effects of reverse T3 vs. T3 on cellular metabolism in vitro (in a lab). As expected, cells incubated with reverse T3 showed a decrease in metabolism, and those incubated with T3 showed an increase. But the later addition of T3 to the cells that had been incubated with reverse T3 completely reversed the metabolic reduction. There was no 12-week delay for "clearing." This suggests that the lack of T3, not the blocking by reverse T3, is the cause of reduced cellular metabolism. [51]

T4 is not always to blame for high reverse T3. High levels of T4 will lower D2 enzyme activity, which lowers T4 conversion to T3. But high levels of T3 will raise D3 enzyme activity, so more T4 is converted to reverse T3 to keep T3 levels normal. So neither T4 nor T3 can be too high, or the appropriate enzymes are invoked to keep the levels where the body deems appropriate. Several studies that compared reverse T3 levels of hyperthyroid patients to normal or hypothyroid patients showed high reverse T3 levels in the hyperthyroid patients. The reverse T3 was high whether measured in urine [45], blood serum [46], or production rate [47]. Urinary excretion of reverse T3 was 6.4 times higher in hyperthyroids than hypothyroids, up to 43 times higher in blood serum in hyperthyroids vs. hypothyroids, and the production rate was 63 times higher in hyperthyroids vs. hypothyroids.  The T3/rT3 ratio was lower in hyperthyroid patients compared to normal controls. [71]  In addition, reverse T3 has a metabolic clearance rate that is almost three times faster than FT3 [6], so as long as there is adequate FT3, there should be sufficient thyroid energy reaching the cells.

If the hyperthyroid state causes high reverse T3 levels, and reverse T3 really "clogged" receptors, then no one could ever be hyperthyroid. The enhanced reverse T3 pathway in hyperthyroids lowers Free T3 levels, but apparently enough T3 is still getting to the cells to create hyperthyroid symptoms. This is the strongest argument against the “clogged receptors” theory. The receptors are not clogged at all; there is no reverse T3 or T3 in the receptors if someone is still hypothyroid. In those with high reverse T3, there is simply not enough T3 available to fill the receptors, and that is why the person still has hypothyroid symptoms. Here is a graphic that illustrates the D3 deiodinase enzyme at work. In Image A, both T3 and T4 enter the cell, but the D3 enzyme converts T4 to reverse T3 and T3 to T2, leaving little T3 for the nuclear thyroid receptor to perform its function. The T3 is inactivated at the cell membrane, shortly after it enters the cell, and never has a chance to reach the nucleus. Image B shows normal T4 to T3 conversion with the D2 enzyme, and as a result, a nucleus with ample T3, ready to perform. [56] The T3-only protocol is actually modeled after the hyperthyroid condition, where T3 levels are so high, that they exhaust the capacity of the D3 enzyme to inactivate any T3 to T2. What is left gets through to the open receptor. There is no reverse T3 to "unclog." However, as described in the sections above, too much T3 and lack of T4 can cause other problems, so the protocol is not without risk.

Optimal thyroid dosing

The reference range for T3 is not based on a normal (bell-shaped) distribution curve. The values are actually negatively skewed, meaning the majority of the values fall in the upper half of the reference range, and the peak (where the most values lie) is somewhere to the right of the midpoint [48], and not at the top of the range. This curve suggests that most people's T3 “sweet spot” may be anywhere from 60-100% of the range. If someone’s optimal dose is at the 60% mark, but they are dosing to 100-120% of range, then the high reverse T3 could very well be from high T3 levels (that are encouraging any T4 to convert to reverse T3 because of increased D3 activity). If someone is taking Natural Desiccated Thyroid (NDT), a decrease in dose may actually reduce reverse T3 by lowering high T3 levels that are triggering the D3 enzyme and reverse T3 production. Since desiccated thyroid contains reverse T3, lowering the dose also eliminates another source of reverse T3. Splitting the dose up so smaller amounts are taken in multiple doses throughout the day may also reduce the reverse T3. Additional T4 could be added to make up for any drop in Free T4 levels if one is taking desiccated thyroid, as long as conditions that favor reverse T3 production (such as diabetes, alcoholism, or others mentioned earlier) are not present. Here is a fact that many will find shocking: A normal thyroid gland produces about 100 mcg T4 and 6 mcg T3 daily, although it secretes closer to 10 mcg T3 daily, because some T4 to T3 conversion occurs in the thyroid gland before release. Total daily T3 produced by the body averages 30 mcg, but 80% (24 mcg) of this is from conversion in other tissues. [49] A 3 grain dose of desiccated thyroid will provide 114 mcg T4 and 27 mcg T3, which closely matches daily thyroid production, but assumes nearly zero conversion. If one has any T4 to T3 conversion (some do and some do not), T4 would need to be added to a reduced dose of desiccated thyroid to mimic normal thyroid production. Gut absorption problems may also affect one's optimal dose, with some needing higher doses to reach optimal thyroid levels.

Are some people really recovering with T3? Some swear that T3-only therapy gave them their lives back, because anything with T4 (even desiccated thyroid) simply did not work. And then you have people like me, who went "brain dead" on only slightly elevated doses of T3, and many men who ended up with sexual problems because the high T3 levels affected their testosterone and estradiol levels. Perhaps the people who can tolerate high doses of T3 have either: 1) nonthyroidal illness, where the illness itself causes a rise in the D3 enzyme, resulting in high reverse T3 levels and the inactivation of any T3; or 2) genetic differences in the deiodinase enzymes, which would produce drastically different T4 to T3 conversion rates in different people. This is not that far-fetched, with the genetic variations that were referenced above. [24] An analogy most are familiar with is lactose-intolerance, caused by a deficiency of the lactase enzyme. If you have the lactase enzyme, you can drink a gallon of milk with no problem, but if you're deficient, well that amount of milk would cause some serious gastrointestinal distress! Perhaps the people who can take extremely high doses of T3 have D1 or D2 deficiencies; those are the deiodinase enzymes that convert T4 to T3, both in the plasma, and at the cellular/peripheral level. If one does not have an enzyme deficiency, then they can quickly become overdosed with the high T3 levels recommended by those who believe in this protocol.

To accommodate these deiodinase enzyme genetic differences, thyroid dosing should be thought of as a continuum with 100% T4 on one end, 100% T3 on the other end, and combinations of T4/T3 in the middle. If this were a normal distribution curve, most people would need a combination of T3 and T4, with the individual T4/T3 concentrations customized for each patient's biochemistry. Unfortunately, patience is essential in finding this optimal dose, because this is a trial and error process, and changes should only be made every six weeks.

Still questioning the reverse T3 theory and T3-only protocol?

More food for thought about thyroid internet forums.

copy and paste url at the end of each reference into your browser if you want to see it

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2. A. Wayne Meikle. The Interrelationships Between Thyroid Dysfunction and Hypogonadism in Men and Boys. Thyroid. April 2004, 14(supplement 1): 17-25.

3Shifren, Jan L., Desindes, Sophie, McIlwain, Marilyn, Doros, Gheorghe, Mazer, Norman A. A randomized, open-label, crossover study comparing the effects of oral versus transdermal estrogen therapy on serum androgens, thyroid hormones, and adrenal hormones in naturally menopausal women. Menopause: November/December 2007 - Volume 14 - Issue 6 - pp 985-994. abstract

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