REVERSE T3 Information
Just came across an interesting article addressing RT3.
This may make a good sticky... welcome additional info/discussion anyone has.
Hypothyroidism (Feb/March 2007) Townsend Letter for Doctors & Patients
Optimizing Medication with Slow-Release Compounded Thyroid Replacement
by Martin Milner, ND
National College of Naturopathic Medicine
Editor's note: This article was originally published in the International Journal of Pharmaceutical Compounding (July/August 2005; 9 ) .
In observing patients taking either levothyroxine (L-thyroxine) USP (e.g., Synthroid, Levoxyl) or dessicated thyroid USP (e.g., Armour Thyroid, Westhroid, Naturethroid), it has become apparent that a significant percentage continue to suffer from thyroid-related symptoms in spite of optimal blood levels of thyroid hormones. This became even more apparent when the American Association of Clinical Endocrinologists (AACE) changed its guidelines for optimal thyroid-stimulating hormone (TSH) values in patients receiving thyroid replacement. The old reference values, while varying somewhat depending on the laboratory test kit used, ranged from 0.5 to 5.0 µIU/mL. The new guidelines for TSH optimization, adopted in 2003, range from 0.3 to 3.0 µIU/mL.
This change required that many patients' doses of thyroid replacement be raised so that their serum levels would fall into the new range. Although this change was intended to optimize treatment outcomes, many hypothyroid patients have continued to suffer from a variety of hypothyroid symptoms, presumably because their dose of thyroid replacement is suboptimal. The most common lingering complaints include fatigue, impaired concentration, and persistent difficulty losing weight in spite of adequate exercise and reasonable caloric restrictions.
In 1996, I began tracking patients who were taking levothyroxine as their thyroid replacement medication, and closely monitoring their symptoms. Although their dosages seemed adequate on the basis of serum testing, it became apparent that more than 75% of the patients continued to suffer from common hypothyroid symptoms. I asked these patients to track their basal body temperature by keeping daily records of either first morning axillary (armpit) temperatures or serial oral temperatures three, six, and nine hours after rising. Both methods revealed temperatures almost always below 98.0°F. Low temperature is commonly reported as a sign of hypometabolism, as described eloquently by Broda Barnes, MD, in the classic text Hypothyroidism: The Unsuspected Illness (see Suggested Reading).
Incidence of Hypothyroidism
It is estimated that approximately two percent of the US population – 5.8 million people – are afflicted with hypothyroidism. Women are more likely to develop hypothyroidism than men, and the incidence increases with age. (See the sidebar, "Signs and Symptoms of Hypothroidism," for a list of the most common signs and symptoms of hypothyroidism.)
Adequacy of Synthetic and Glandular Thyroid Replacement
If a patient is taking thyroid replacement and symptoms persist, the condition is not being optimally managed. The medication most commonly prescribed for hypothyroidism is synthetic thyroid hormone, or levothyroxine (T4). But it is the active form of the hormone, triiodothyronine (T3), that we use in our cells and tissues. The conversion of T4 to T3 happens in the liver and in the cells themselves. T4 is converted into both T3 and reverse T3. Reverse T3 is a stereoisomer of T3 and has no biological activity. T4 can be compared to a key that has not yet been cut by a locksmith to fit in the lock (the thyroid receptor site). When it is cut properly (as T3), it fits in the lock and opens the door. The reverse T3 stereoisomer of T3 is a mirror image of the active T3 molecule – a key that is cut differently enough by the locksmith that it fits in the lock (receptor site) yet doesn't open the door. When there is an excess of reverse T3, no thyroid metabolism is stimulated.
Reverse T3 is biologically essential to slow down metabolism as a natural compensation mechanism during times of starvation or famine. In fact, reverse T3 creates more powerful negative feedback on the production of T3 than vice versa. Under varying stressors such as extreme caloric restrictions, pregnancy, and emotional stress, the conversion of T4 to T3 can become unbalanced as the body produces excessive amounts of reverse T3. Reverse T3 exerts its negative feedback on T3 and ties up thyroid receptors. Reverse T3 must be displaced by the proper biologically active T3 if metabolism is to normalize. This is impossible, however, if a patient is being given synthetic T4 only. In these cases, there is no replacement source of the T3 that is needed to displace the excess accumulations of reverse T3 in the circulation and receptors. In the absence of adequate biologically active T3, symptoms of hypothyroidism remain, despite an adequate level of T4 in the serum and a normal TSH level. Since most of the conversion of T4 into T3 happens in the cells, serum levels of free T3 and reverse T3 may be normal even when T3 and reverse T3 levels are not in balance. It is as though the cells are starving for biologically active T3 in the midst of plenty. Unfortunately, the "plenty" is plenty of T4 and reverse T3 rather than the essential biologically active T3. I see many examples of this in my clinical practice. Many patients continue to suffer with hypothyroid symptoms even though they are taking T4100 µg (0.1 mg) per day. Their blood levels of TSH and T4 are normal, yet symptoms persist.
T3 is available as a manufactured drug in the form of liothyronine sodium (Cytomel). This synthetic T3 is released immediately, without delay, and is manufactured only in 5 µg and 25 µg doses. T3 is three to four times more biologically active than T4 and exerts its effects more rapidly and vigorously than T4. The half-life of T3 is 0.75 days, while that of T4 is 6.7 days (Table 1). Patients are much more likely to experience side effects from Cytomel than from compounded, slowly released T3. These side effects include, yet are not limited to, tachycardia, arrhythmia, anxiety, nervousness, agitation, irritability, sweating, headaches, increased bowel motility, and menstrual irregularities. Angina, congestive heart failure, and atrial fibrillation can be aggravated or induced by excessive doses of T3. Other physiological distinctions between T4 and T3 are worth noting. They are best summarized by Williams and Williams in their Textbook of Endocrinology (see Suggested Reading).
Table 1. Comparison of Triiodothyroxine (T3) and Throxine (T4) in Humans
<<I have snipped out the table for formatting reasons please follow the link to see the table>>
USP dessicated thyroid or Armour Thyroid is made with a ratio of four parts of T4 for every one part of T3. This ratio is comparable to those in the human and porcine thyroid glands, which produce 75% T4 and 25% T3. One grain of Armour Thyroid contains 36 µg of T4and 9 µg of T3. The T3 is released all at once, not slowly.
Another manufactured drug, liotrix (Thyrolar), contains T3 in a similar ratio of 75% T4 to 25% T3. Again, the T3 in Thyrolar is not released slowly. Because T3 is generally considered to be four times more potent than T4, a 25-µg dose of T3 is equivalent to a 100-µg dose of T4.
The amount of slow-release T3 prescribed, whether formulated in combination with T4 or taken separately from T4, should be about 25% more than the mathematical equivalencies would suggest. This is because T4 blunts the utilization of T3 to some extent. The compounded slow-release form seems to allow for less total drug absorption. This can vary considerably from patient to patient. The best approach is to monitor serum levels of free T4, free T3, and TSH in patients taking T4 and slow-release T3 replacement six to eight weeks after every dose adjustment. Further dose adjustments can then be made if necessary. Since T3 has a short half-life and serum levels tend to peak three to four hours after dosing of compounded slow-release T3, we instruct patients to not take their morning slow-release medication until after their blood draw. This allows measurement of their 24-hour lowest levels of circulating serum T4 and T3. (These equivalencies are summarized in the accompanying sidebar, "T4 and T3 Equivalencies.")
T4 and T3 Equivalencies
T4 100 µg = T325 µg
Armour Thyroid 1 grain = T4 36 µg, T39 µg
T3 9 µg x4 = T4 equivalency of 36 µg
Armour Thyroid 1 grain = T4 total equivalency of 72 µg
(36 µg directly from T4 and 36 µg from T3 9 µg x4)
Nutrients as Cofactors in Thyroid Metabolism
Selenium is an essential cofactor in the conversion of T4 into T3. T4 is converted into T3 by the selenium-dependent enzyme 5'-deiodinase. Selenium depletion of soil is common in many areas of the US, and many individuals do not supplement adequately to counteract this deficiency. Iodine is also essential in the conversion of T4 into T3. While iodine depletion is common in US soils, many Americans use iodized salt to counteract this. Commercial farming methods used in the last century, which fertilized soil only with nitrogen, phosphorus, and potassium, have allowed soils formerly rich in selenium and iodine to become fully depleted. Other nutrients essential to optimizing thyroid metabolism are tyrosine, zinc, copper, and essential fatty acids. In a sense, all the essential nutrients play a role in optimizing the health of the thyroid gland (essential amino acids, essential fatty acids, vitamins, minerals, and trace minerals).
Over the years, I have developed several different replacement strategies as alternatives to the use of the standard therapies (levothyroxine and dessicated thyroid). These replacement strategies have in common some blend of T4 with slow-release T3. The example used in the first case is best suited to the patient who has higher demands for energy during the day and/or suffers from some type of sleep disorder at night. The approach used in Case 1 is also best for patients who have a hard time taking more than one pill daily or those who have financial constraints, since this is the least expensive option.
In each of these cases, we start with a patient who is currently taking T4 100 µg as the starting dose. We will be changing each patient's therapy to a blend of T4 and T3, slowly released.
This patient's starting TSH is 2.5 µIU/mL, and we have a target of 1.0 µIU/mL to optimize quality of life and minimize hypothyroid symptoms. The patient's dose of T4 should be increased to 125 µg or 150 µg to drive the TSH level down from 2.5 to 1.0 µIU/ mL. For discussion purposes, this final T4 dose is 150 µg. This dose of T4 must be converted to an appropriate combination of slow-release T4 and T3 at the correct ratio. As already discussed, the thyroid gland maintains a T4:T3 ratio of 4:1, but most patients who are symptomatic are converting an excessive amount of T4 into reverse T3. They need a ratio of T4:T3 of perhaps 3:1 or 2:1 or, rarely, even more T3 relative to T4. This is especially the case at the beginning of therapy. If we decide on a T4:T3 ratio of 2:1, converting 150 µg of T4 to a blend of slowly released T4 and T3 mathematically calculates to 50 µg of T4 and 25 µg of T3. The 25 µg of T3 multiplied by 4 represents a T4 equivalency of 100 µg. Adding the 50 µg of T4 brings the total T4 dose to 150 µg.
Keep in mind, however, that doses of slow-release combinations need to be increased by approximately 25% because of differences in absorption. Mathematical equivalencies are just that, and often a delivery form can increase or reduce absorption from what is mathematically assumed. If we increase this initial dose of 150 µg of T4 by 25% to accommodate this, the correct dose of T4 is 187.5 µg. The equivalency of this dose in a T4:T3 ratio of 2:1 would be about 60 µg of T4 and 30 µg of T3. The 30 µg of T3 multiplied by 4 equals 120 µg of T4 on an equivalency basis; with the 60 µg of T4, this adds up to a finished equivalency of 180 µg, slightly shy of the 187.5 µg target.
A formula can be used to make the calculations easier, as follows:
T4 dose divided by 3 = new T4 dose
T4 dose divided by 6 = new T3 dose
A 300 µg T4 dose would convert to (300/3 = 100 µg T4) plus (300/6 = 50 µg T3)
The same mathematics apply to increasing or decreasing the T4:T3 ratio in subsequent prescriptions. From a practical perspective, however, the levels of T4 and T3 in the patient's serum should guide the prescriber to the proper proportional or disproportional dose adjustments needed to reach targeted serum levels of free T4, free T3, and TSH.
If the degree of thyroid resistance and need for active T3 is not as extreme, we might consider a T4:T3 ratio of 3:1. An equivalency of 187.5 µg would convert to 81 µg of T4 and 27 µg of T3. Multiplication of 27 µg T3 by 4 equals 108 µg; this added to the 81 µg T4 equals approximately 190 µg of T4. The easiest way to calculate this is to realize that the amount of T3 will be slightly less than that needed for the 2:1 ratio (i.e., T4 60 µg/T3 30 µg). Multiply the 27 µg T3 by 3 to preserve the 3:1 ratio and calculate the finished equivalency. These ratios are modified as indicated by remaining symptoms, temperature log results, and balance of free T4, free T3, and TSH in the blood.
In this case, the patient (who is initially taking 100 µg of T4) also requires a dose increase to 150 µg to get her TSH level down to a target of 1.0 µIU/mL. The patient could continue to take T4, yet at a lower dose of 50 µg. These medications come in doses of 25, 50, 75, 88, 100, 112, 125, 137, 150, 175, 200, and 300 µg. Because it has no food dyes or coloring added, I like to use the 50-µg tablet and divide the dose. If the target desired dose is 60 µg as in Case 1, the closest we can get is 50 µg. The 30 µg of T3 needed to make up the correct T4:T3 ratio is compounded as a slow-release tablet, either as 30 µg once daily or 15 µg every 12 hours. I prefer the slow-release capsule to be taken first, upon rising; ideally, the patient would then wait one hour before eating breakfast and take the T4 pill three hours after the T3. The patient would then take the second T3 capsule, if appropriate, 12 hours after the first. Some patients need their T3 slowly released over 24 hours, especially as the doses are increased to avoid side effects or to optimize distribution of energy throughout the day to be more even and to avoid fatigue in the late afternoon or evening.
This dosage regime is more complicated for patients. Remember, these are hypothyroid patients who will take medication daily for the rest of their life. Asking someone to take a morning dose, another dose three hours later, and a third 12 hours after the first can be a compliance nightmare. Some patients feel best on this protocol, however, and are not significantly bothered by the routine. It can be simplified by taking the entire day's dose of T3 in the morning and the T4 three hours later, or even further by taking the T4 and T3 together upon rising. (The T4 does not have to be released slowly, since its half-life is seven days.) Most convenient for the patient is compounding the T4 together with the slow-release T3 in one capsule, so that the patient has to take only one capsule in the morning.
Armour and USP Thyroid
Recall that there is a good chance that a hypothyroid patient with lingering chronic hypothyroid symptoms is converting too much T4 into reverse T3, which is biologically inert. By replacing some of the prescribed T4 with slow-release T3, the reverse T3 gets displaced by the active T3, and metabolism returns to normal.
Glandular Thyroid USP (Armour Thyroid) delivers approximately four parts T4 to one part T3. T3 is about four times more potent than T4 but is metabolized three times faster. The T3 in Armour Thyroid is not released slowly and therefore gets delivered unevenly throughout the day. This is not the way the thyroid gland and tissues work. T3, owing to its high biological activity, should be delivered in even amounts. Compounded slow-release T3 does just that. Furthermore, accurately adjusting the dose of Glandular Thyroid USP is difficult. Amounts of T4 and T3 can vary from batch to batch and from manufacturer to manufacturer. USP thyroid comes in limited strengths, including one-quarter grain, one-half grain, 1 grain, 2 grains, and 3 grains. Optimizing the dose in sensitive and difficult cases may be very challenging.
Please note that I do not advocate treating hypothyroidism with slow-release T3 alone, as the only form of thyroid replacement. T3 works best when combined with T4. Too much T3 without T4 can cause other problems, including osteoporosis and heart arrhythmias. T4 also helps blunt the risk of side effects from T3, which can occur even with slow-release T3. Finally, T4 offers a reservoir of thyroid hormone material with which to make more T3 as needed.
Many patients suffering from years of lingering hypothyroid symptoms while being treated with synthetic T4 or Armour Thyroid will feel much better if their treatment is changed. Appropriate changes include either a lowered dose of the current medication combined with slow-release T3 or a customized compounded blend of slow-release T4 and T3.
I urge patients to consult with their endocrinologist before making any change in thyroid medication. They should be aware, though, that very few physicians are knowledgeable about slow-release T3 and its proper use. Although some available drugs deliver T3 (Cytomel, for example) or combine T4 with T3 (Thyrolar), the T3 in these preparations is not released slowly. As a result, patients continue to suffer from the symptoms that result from uneven T3 distribution.
Compounded Slow-Release T4 and T3
In making the medication, a compounding pharmacist uses properly aliquoted concentrations of T4 and T3. The T4 and/or T3 are combined together with cellulose derivatives that regulate their slow release. This mixture is then either tumbled for at least six hours or blended fully in a V mixer to assure even distribution of the active ingredients. The finished material is then placed into capsules. Once swallowed, the capsule forms a bolus in the stomach and slowly releases T4 and T3. The T4 and T3 used in compounding are synthetic, yet they are biologically identical to the T4 and T3 made by the human thyroid gland (T4= levothyroxine sodium or 3,3',5,5'tetraiodothyronine sodium, and T3= L-triiodothyronine).
Monitoring Medication Adjustments
The T4:T3 ratio initially prescribed is arbitrary and will most likely be adjusted up or down. Adjustments are based on ongoing symptoms, body temperatures, and the balance of serum levels of free T4, free T3, and TSH reported after six to eight weeks on a stable dose. In the most severe cases of thyroid resistance, which require the highest doses of T3, the dose will need to be adjusted until the serum TSH level is 0.2-1 µIU/mL, with the free T4 level at the low end of normal or even below normal, while the free T3 level is at the high end of normal or even above normal.
Since T3 is so biologically active, we like to instruct our patients to take no thyroid medication the morning of the blood draw. We have them come in for this blood draw as the first patient scheduled in the morning (8 to 9 AM). This allows us to capture their lowest level of circulating T3 in the 24-hour period. They are instructed to take their medication immediately after the blood draw.
When changing from T4 to a slow-release blend of T4 and T3, the initial dose is an estimate. The guidelines already described are only guidelines; actual dose varies from patient to patient, depending upon that patient's intestinal health and absorption of thyroid hormone. In our initial change of prescription, we authorize patients to return in three weeks for repeat blood work if they are feeling poorly and in two months if they are doing well. Within three weeks after a dose adjustment, the serum levels of T4 and T3 reach their new steady state. If an individual is feeling poorly from either underdosing or overdosing, we can check at this early juncture their circulating blood levels of free T4 and free T3. TSH level will not stabilize for six to eight weeks after a dose change.
Drug-Drug and Drug-Nutrient Interactions
Thyroid hormone can potentiate the effects of warfarin, requiring a lowering of blood warfarin level to avoid excessive anticoagulation. Digoxin level can be potentiated by thyroid medication, requiring lowering the dose of digoxin. Antidepressant drugs can be mildly potentiated by thyroid hormone. Patients taking thyroid in excessive doses for weight loss can develop life-threatening symptoms of toxicity and/or arrhythmia, especially when the thyroid is given in association with sympathomimetic amines for their anorexic and weight loss effects. No interactions of thyroid with alcohol or tobacco have been documented. Estrogen replacement and estrogen dominance can increase the need for thyroid replacement. As hypothyroid women approach menopause and accumulate more estrogen dominance, their thyroid replacement dose may need to increase. Similarly, estrogen replacement therapy can increase a woman's need for thyroid replacement. Insulin requirements can increase as thyroid replacement dose increases. Thyroid medication can increase the adrenergic effects of epinephrine.
Calcium supplements can reduce utilization of thyroid hormone, especially when taken in high doses. Thyroid hormone replacement is best taken in the morning, and calcium is best absorbed in the evening. Taking calcium with dinner minimizes any impairment of utilization of thyroid taken in the morning. High levels of soy in the diet can impair thyroid hormone utilization. Soy is best eaten in small amounts in the evening meal. Iodine and selenium potentiate the conversion of T4 into T3, acting as cofactors in the conversion. Brassica vegetables (broccoli, cauliflower, Brussels sprouts) can reduce thyroid hormone utilization.
Hypothyroidism is a common condition. A large percentage of patients remain significantly symptomatic in spite of apparently adequate replacement therapy. Symptoms may include intractable chronic fatigue, impaired concentration, and weight gain. These symptoms may have devastating consequences on quality of life. Changing medication to a blend of T4 with slow-release T3 resolves many of these limitations of patients' quality of life. The compounding of exact customized levels of T4 and T3 enables the clinician to achieve optimal targeted serum levels of TSH, free T4, and free T3 with precision. These levels can be carefully customized to optimize symptom resolution while improving metabolic temperature status. Customized compounding allows dose adjustments to achieve whatever balance of T4 and T3 is necessary to achieve optimal health and resolution of symptoms.
Martin Milner, ND
Medical Director, Center for Natural Medicine, Inc.
1330 S.E. 39th Avenue
Portland, Oregon 97214
Martin Milner, ND, received his ND in 1983 from NCNM. He has remained at his alma mater for the past 20 years as Professor of Cardiovascular and Pulmonary Medicine. Dr. Milner is also the CEO and Medical Director of the Center for Holistic Medicine (1983-1991) and Center for Natural Medicine, Inc. (1991-present). He is world renown for his natural treatment protocols for heart disease, menopause and hypothyroidism.
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Originally Posted by mimers
Below is a question asked of Dr. John C. Lowe on a radio show he was on a few weeks ago. This is part of a transcript of questions asked. Don't know if it's any help, but thought I'd pass it along.
4. How useful is a reverse T3 test in diagnosing HYPOTHYROIDISM?
I believe the test is of virtually no value in diagnosing hypothyroidism, if by hypothyroidism we mean a thyroid hormone deficiency. When the thyroid gland produces too little T4 and T3, less of these two hormones are available. The vast bulk of what the thyroid gland produces and releases into the blood is T4. With a lower-than-usual amount of T4 available, it’s likely that more of it will be converted to T3 rather than reverse T3. This presumably results from a need to keep the T3 high enough to maintain effective cell function. Also presumably, reverse T3 production from T4 will decrease to some degree. As a result, in moderate-to-severe hypothyroidism we might find low T4, low-to-mid-range T3, and a low reverse T3. However, as far as I know, no researchers have shown that this lab result pattern is useful for diagnosing hypothyroidism.
This pattern in hypothyroidism is only a conception based on principles. But in actual practice, I’ve rarely seen this pattern in hypothyroid patients. I believe the reason is that when the TSH and thyroid hormone levels are in range, their levels vary (as Japanese researchers say) “dramatically every thirty minutes or so.” There is no correlation from thirty-minute period to thirty-minute period, day-to-day, and week-to-week.
In my opinion, the reverse T3 has served us best in diagnosing a condition that has a variety of names: “euthyroid sick syndrome,” “low T3 syndrome,” and “non-thyroidal illness syndrome.” The word “euthyroid,” of course, means that the person has in-range TSH, T4, and T3 levels. In this condition, the hypothalamus secretes less TRH, the pituitary secretes less TSH, and less thyroid hormone is transported into cells. Also, the enzyme called “5-prime deiodinase,” which converts T4 to T3, becomes far less active. Another enzyme, “5 deiodinase” (no “prime” as a modifier) becomes more active and converts more T4 to reverse T3.
The words “sick syndrome” is somewhat misleading. That term is used presumably because the condition was first identified in sick people, such as anorexics and hospitalized patients in critical condition. Studies showed that the patients had steeply raised cortisol levels. It’s their high cortisol levels that inhibit the enzyme (5-prime deiodinase) that converts T4 to T3.
I’ve found no evidence that this condition becomes chronic, as Dr. Dennis Wilson proposed. Instead, the research literature shows that within a week or two, TSH secretion increases and 5-prime deiodinase escapes the inhibition by cortisol. This happens even though the person’s cortisol levels remain high. For example, if the person undergoes prolonged treatment with prednisone, within a week or two, the TSH level returns to its previous level and 5-prime deiodinase becomes normally active again.
Old studies show that on average, most people convert more than 50% of their T4 to reverse T3; correspondingly, they convert less than 50% of T4 to the metabolically active hormone T3. And the levels of reverse T3 fluctuate up and down through the day. Because of this, I’m never confident of coming to a conclusion that someone has a problem with high reverse T3, not unless the person has had multiple measures of the reverse T3 over a 24-hour period. Like the TSH, free T4, free T3, reverse T3 levels vary dramatically every 30 minutes or so. Depending on when a person’s blood is drawn or saliva taken. Sometimes the levels will vary enough so that a clinician will give the patient a different diagnosis from the one that he or she would have given 30-minutes before or after the blood or saliva sample was taken.
So blood levels vary rapidly. Because of this, I don’t believe the reverse T3 or the other lab tests in general are very useful. However, I do believe the reverse T3 is useful under one circumstance: when we have enough measures to get averages over time, and when the levels are regularly way out of range. So, in my view, the reverse T3 can be useful, but I think its usefulness is limited, which is true of the TSH and other thyroid hormone levels. >>>
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