New website i found - intersting, RT3, etc

[Guest guest]

This is an interesting site, worth a visit:

http://tiredthyroid.com/rt3.html

Copyright © 2011 by Barbara Lougheed. All rights reserved.If you copy or repost information from this website, you must credit or link to TiredThyroid.com

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" ratio (Free T3/Reverse T3 < 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 T3 split throughout the day, and no T4 whatsoever. Some people can tolerate these high doses of T3, others cannot.

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 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 this 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.

Why should one question the T3-only protocol?

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 less 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. [why TSH is not a valid diagnostic]

Here 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 "if free T3/reverseT3 < 20, then one should only take T3" formula.

Profile I: mid-range to high FreeT3, below mid-range FreeT4

Reverse T3 may be high due to excess T3. This lab profile is often found in those taking desiccated thyroid, because of the high T3/T4 ratio in the pills. Lowering the desiccated thyroid dose and adding T4 has worked for some. 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 do best with a higher proportion of T4 to T3.

Profile II: below mid-range FreeT3, mid-range to high FreeT4

Reverse T3 may be high due to poor conversion and lack of essential cofactors like selenium. This lab profile is often found in those taking T4-only meds. 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.

Profile III: below mid-range FreeT3, below mid-range FreeT4, over range rT3

If reverse T3 is over 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. Serious infections (tonsils and root canals, for example) can cause this. Uterine fibroid or other tumors, as well as damaged heart muscle could also cause an elevated rT3. 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 rT3, 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.

Why the body makes reverse T3

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 elevated levels of reverse T3 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 elevated reverse T3 levels:

<!--[if !supportLists]-->· <!--[endif]-->aging

<!--[if !supportLists]-->· <!--[endif]-->burns/thermal injury

<!--[if !supportLists]-->· <!--[endif]-->chemical exposure

<!--[if !supportLists]-->· <!--[endif]-->cold exposure

<!--[if !supportLists]-->· <!--[endif]-->chronic alcohol intake

<!--[if !supportLists]-->· <!--[endif]-->free radical load

<!--[if !supportLists]-->· <!--[endif]-->hemorrhagic shock (often from severe blood loss)

<!--[if !supportLists]-->· <!--[endif]-->insulin-dependent diabetes mellitus

<!--[if !supportLists]-->· <!--[endif]-->liver disease

<!--[if !supportLists]-->· <!--[endif]-->kidney disease

<!--[if !supportLists]-->· <!--[endif]-->severe or systemic illness

<!--[if !supportLists]-->· <!--[endif]-->severe injury

<!--[if !supportLists]-->· <!--[endif]-->stress

<!--[if !supportLists]-->· <!--[endif]-->surgery

<!--[if !supportLists]-->· <!--[endif]-->toxic metal exposure

<!--[if !supportLists]-->· <!--[endif]-->certain drugs like amiodarone and beta blockers

<!--[if !supportLists]-->· <!--[endif]-->and high cortisol. [10,11,12,13]

It's much healthier to address and correct the conditions just listed, than to take straight T3. 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 that's where the reverse T3 is processed and eliminated. [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

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. It purposely keeps 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 (NTI), 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 NTI, they work together to lower T3 and raise reverse T3, making the patient more hypothyroid. [15]

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 increase 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. 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 levels of reverse T3 , and there are some people on the thyroid internet forums that fit this profile.

High D3 activity has been found in vascular, brain and other tumors, and some malignant cell lines. 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 levels of 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 levels of reverse T3.

Perhaps those with a reverse T3 problem have an underlying condition, like those just listed in the paragraphs above, that keeps reverse T3 high. Quite a few thyroid patients have reported tonsillectomies (infection/inflammation), hysterectomies (fibroid tumors), heart conditions, and problem root canals (infection). 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/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]

Why the body needs T4

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 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 FreeT3 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.

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.

The role of T3 and T4 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 deiodinase enzyme D2. 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 (which is 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 additional 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 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. [39,40] I suffered from this fresh amnesia and 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.

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. The hippocampus and temporal cortex areas of the brain exhibit the highest D3 concentrations, which suggests that these two areas of the brain, which affect memory and cognitive functions, are the most sensitive to excessive T3 levels. [29,30]

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 problems with taking only T3

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 problems:

<!--[if !supportLists]-->· <!--[endif]-->erythrocytosis (thick blood or high RBC, hematocrit, and hemoglobin) [34]

<!--[if !supportLists]-->· <!--[endif]-->osteoporosis [35] – One study where subjects were given 50-75 μg of T3 showed increased bone resorption and fecal calcium loss.

<!--[if !supportLists]-->· <!--[endif]-->muscle weakness [36,39] – ­ (especially the thigh or upper arm muscles--difficult to climb stairs or rise from sitting; or hold arms above head to wash hair) One study found that doses of 60 μg/day or more of T3 enhanced muscle catabolism (breakdown) during fasting. In other words, excessive T3 can cause muscle wasting. The heart is a muscle and is not immune from this effect.

<!--[if !supportLists]-->· <!--[endif]-->insulin resistance [37,38] – One study found that both plasma glucose and insulin increased after T3 ingestion, which is not a desirable effect.

<!--[if !supportLists]-->· <!--[endif]-->fast heart rate or palpitations [39]

<!--[if !supportLists]-->· <!--[endif]-->intolerance to exercise [39]

<!--[if !supportLists]-->· <!--[endif]-->shortness-of-breath [39]

<!--[if !supportLists]-->· <!--[endif]-->insomnia [39]

<!--[if !supportLists]-->· <!--[endif]-->hair loss/thinning [39]

<!--[if !supportLists]-->· <!--[endif]-->brain fog or hyperthyroid dementia- can't remember things that just happened, or trouble solving problems (math, scheduling. etc.) [40,41]

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 (HC), 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 HC helps one tolerate thyroid hormone, there is the potential problem of taking more and more HC to tolerate more and more T3, ultimately resulting in a serious overdose of both hormones.

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 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.

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. While excessive T4 may elevate reverse T3 as the body looks for equilibrium, high levels of T3 will also raise reverse T3, as D3 enzyme activity increases and more T4 is converted to reverse T3 to keep T3 levels normal. Several studies that compared reverse T3 levels of hyperthyroid patients to normal or hypothyroid patients showed elevated 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. 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.

Now, if high reverse T3 really "clogged" receptors, then no one should ever be hyperthyroid. In theory, shouldn't these hyperthyroid patients with the highest reverse T3 levels be severely hypothyroid with such high reverse T3? The enhanced reverse T3 pathway 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. In those with high reverse T3, there is simply not enough T3 available to fill all available receptors, and that is why the person still has hypothyroid symptoms. Remember, the D3 enzyme that converts T4 to rT3 also converts T3 to T2. That leaves very little T3 for the body's functions.

Finding that optimal dose

The T3 distribution curve is skewed, with the majority of the values in the upper half, and the peak 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 one's optimal dose is at the 60% mark, but they are dosing to 100-120% of range, then the elevated reverse T3 could very well be from an overdose of T3 (that is 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 excess T3 that is triggering D3 and reverse T3 production. 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 NDT, 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. Total daily T3 produced by the body averages 30 mcg, but 80% (24 mcg) of this is from conversion, and not directly from the thyroid gland. [49] A 3 grain dose of NDT 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 (and some do not), T4 would need to be added to a reduced dose of NDT to mimic normal thyroid production.

Some people will swear that T3-only therapy gave them their lives back, because anything with T4 (even NDT) 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 rT3 levels; 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 levels of T3 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, 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.

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