Thyroid Resistance
Not only is it possible that conversion thyroid hormone problem might occur, but there is evidence that thyroid resistance might well be a secondary response to the initial trigger causing CFS. Although the concept of euthyroid fatigue was recognized in conventional medicine in the 1950, it is not until recently that it is gaining acceptance again in the medical literature. Current medical literature is identifying euthyroid patients who exhibit hypothyroid symptoms as thyroid resistance. Thyroid resistance shares many of the same symptoms as CFS, including headaches, anxiety, fatigue, and recurring sore throats.
One postulated mechanism for thyroid hormone resistance found in WTS/CFS might be due to a dysregulation in the type I interferons (IFN-alpha/beta) pathway. This results in a sustained upregulation of 2(‘), 5(‘)-oligoadenylate synthetases (2-5OAS). Patients treated with IFN-alpha/beta therapy usually complain of severe fatigue as a limiting side effect, perhaps due to the same effect. The 2-5OAS, IFN-alpha/beta instigates the expression of three closely related proteins. The amino acid sequences of the 2-5OASL proteins display 96% identity with the partial sequence of the thyroid receptor interacting protein (TRIP). It is hypothesized that the 2-5OASL proteins are TRIPs mechanism of suppressing the TR transactivation and/or possibly destroying the thyroid receptor by the proteasome. This is perhaps how CFS /WTS patients might have normal TSH values yet have a clinical hypothyroid state in CFS/WTS.52
One other mechanism of thyroid resistance found in CFS might be due to a chronic consumptive coagulopathy, which itself might be associated with chronic infections, such as mycoplasmids, and other microbes. It is suggested that supraphysiological doses of thyroid hormone or anti-coagulants and anti-infective agents might be effective treatments options. Current research has not found any clear association between an infectious agent and CFS.53 However, based on a multi-causal model, it is possible that some infectious agent might be a contributory cause for a certain subset of patients, or that it might be a trigger for CFS even after the infection is gone.54
Immune system defect might be involved in certain amount of CFS patients. There is evidence of inappropriate cytokine response.55 The etiological cause is still not known. However, it is hypothesized that it might be due to decreased thyroid function. Thyroid resistance has been associated with increased infections, such as chronic sore throats.56
Stress stimulates the hypothalamic-pituitary-adrenal axis, or HPA axis, which leads to increased levels of cortisol. Increased levels of cortisol inhibit thyroid function.57 Some CFS studies have found cortisol levels to be lower than healthy controls.58 However since studies have not found conclusively that cortisol replacement is an effective treatment, cortisol deficiency as the main causative factor for CFS seems not promising. Low thyroid function has shown to affect cortisol levels.59 Some researchers have found that hypothyroidism increases cortisol levels and others have found that it decreases cortisol levels.60
In conclusion CFS/WTS might have a variety of causative factors that compromise immune system by stress or other insults that come from viruses, bacteria, toxins, or other triggering agents that upset the body’s normal functioning. After the initial insult to the body, CFS/WTS symptoms remain, perhaps due to thyroid hormone resistance or peripheral thyroid hormone conversion problems.
Regardless of the mechanism, WT3 therapy seems to restore metabolism to the vast majority of patients.
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Monograph
SR-T3 Protocol
(Reproduced from WTSmed.com, with adaptations, by permission.)
In the clinical setting, T3 therapy is not used to correct a measurable thyroid hormone deficiency, but rather to recalibrate metabolism and body temperature patterns.
Dr Denis Wilson developed the SR-T3 treatment protocol over a 2-year period via empirical observations of treating patients with intractable fatigue. He subsequently treated more than 5,000 people over a period of 4 years. The Wilson’s Temperature Syndrome (WTS) web site (www.WTSmed.com), established in 1997, provides information to the general public regarding Wilson’s Temperature Syndrome. The web site designates at least 250 doctors in the United States (as well as others in Australia, Canada, Finland, New Zealand, Russia, and the United Kingdom) on its list of “Wilson’s Temperature Syndrome Treating Physicians.” Currently, there is an estimated 1,000 American doctors who use the therapy for fatigue and other WTS symptoms.
Unique Features
The unique features of the Wilson protocol that distinguish it from conventional T3 therapy are that it uses a sustained release form of T3, as opposed to Cytomel, and it is cyclic in its administration, with the dose and cycle-length adjusted according to patient symptomatic response. The subjects are treated with Liothyronine compounded in a hydrophilic matrix system, employing hydroxypropyl-methylcellulose (HPMC) designed to be taken every 12 hours. The liothyronine is synthetically made and does not differ from any standard pharmaceutical preparation of T3, except that it is compounded with the sustained release agent methylcellulose. Clinical observation using SR-T3 shows that prolonged exposure to T3 changes patient susceptibility to the drug, necessitating alterations in dose. For example, the first cycle SR-T3 may require 90 mcg of T3 b.i.d. to obtain a normal temperature, while the second cycle may require only 45 mcg of T3 to achieve the same temperature. Body temperature is used in determining dosage and cycle length.
The original protocol used liothyronine sodium (Cytomel), but undesirable side effects (e.g., irregular heartbeat and occasional atrial fibrillation) prompted exclusive use of SR-T3. The SR-T3 produced fewer and milder side effects. There are no known cases of patients suffering from atrial fibrillation with the use of SR-T3 since its development in 1990.
However, a significant amount of patients still suffer from some symptoms, including increased awareness of heartbeats, heart palpitations, increased heart rate, irritability, shakiness, fatigue, and headaches. These effects are usually successfully treated with a “test dose” of T4. A test dose of T4 is a small dosage (.0125-.025 mg) of Levothyroxine taken to dampen the effects of T3 therapy through competitive inhibition of T3 by T4. T4 has 25% the potency of T3, and administration of T4 usually decreases or eliminates the side effects of T3 therapy within 45 minutes.
The clinical experience of numerous physicians suggests that T3 compounded in a hydrophilic matrix system (sustained release system) in capsules taken every 12 hours provides a predictable, well-tolerated means to influence body temperature patterns and alleviate the debilitating symptoms experienced by WTS patients. Once symptoms improve or resolve, patients are able to wean off SR-T3 therapy. Patients often report no return of symptoms after the treatment has been discontinued. Some patients do relapse, but a very short cycle of SR-T3 will bring them back to normal.
Long-term Success
The use of T3 outside of the WT3 protocol has not been shown to normalize body temperature. Dr Wilson’s clinical experience indicates that long-term success in resetting metabolism and alleviating symptoms using the cyclic SR-T3 therapy proposed for this study seems to be related to holding body temperatures close to 98.6°F for a specified set of time. Patients whose body temperatures have been successfully raised to or near 98.6°F show sustained positive responses after the treatment is discontinued. Patients whose oral temperatures are not successfully raised to that level seem to retain less benefit from the treatment.
It is known that exogenous T3 suppresses T4 levels due to negative feedback inhibition of TSH. It is speculated that T4 suppression is an important effect of the Wilson protocol that is essential to its effectiveness. Often more than one cycle of SR-T3 therapy may be needed to increase body temperature to near-normal values. In many cases, one or more cycles reaching a maximum dose of SR-T3 (90 mcg b.i.d.) fails to raise the patient’s temperature to normal. The temperature may reach normal on a subsequent cycle at a lower dose. In such cases, we speculate that greater T4 suppression is achieved with each successive cycle until the body temperature reaches normal. Serial measurements of serum free T4 may help to elucidate this proposed mechanism.
It is speculated that T4 suppression from repeated cycles of SR-T3 therapy results in lower serum levels of T4 and RT3, and therefore less competitive inhibition of T3. This suppression may increase from cycle to cycle, increasing T3 expression with each cycle. Increased expression of T3 may result in greater T4 suppression until body temperature is finally normalized and the metabolism is “re-calibrated.” Once temperature is normalized, decreased SR-T3 is needed on subsequent cycles to maintain normal body temperature. Clinical evidence thus far indicates that patients can safely discontinue the sustained-release T3 therapy and maintain benefits once oral body temperature are held at 98.6°F for a specified set of time. More information can be found at this free site www.wtsmed.com/eManual.
After the treatment is discontinued, normally 3-6 months after initiation of treatment, the majority of WTS patients report significant and continued improvement in their symptoms. Many patients experience complete resolution of their WTS symptoms persisting years after treatment has been discontinued. Based on clinical observations, many patients are completely freed of fatigue, depression, muscle aches and other complaints related to WTS.
Clinical Studies
Most studies on thyroid hormone supplementation have been done using levothyroxine. There is current controversy over the effects of thyroid hormone supplementation on osteopenia. Most studies indicated no effect,61-62 while one study of long term suppressive dose of T4 did show a increase in bone loss.63
Clinical studies using supraphysiological doses of T3 ranging from 93.75 to 105 mcg daily in euthyroid fibromyalgia, over an 8-month period indicated no change in serum calcium and phosphorous, nor in bone densitometry vs. placebo. However there were higher levels of urinary N telopeptides. Liver function tests were no different vs placebo at 4- month follow-up, \serum creatinine and calcium were also normal, indicating no change in muscle mass. Mean heart rate significantly increased from 68.5 bpm in placebo vs 83.94 bpm in T3 patients during the study. No patients developed tachycardia. There was no significant difference in diastolic or systolic blood pressure in T3 or placebo group. Serial EKG indicated no significance except that the placebo QT intervals shortened within the normal range during T phases.64
Adverse reactions to liothyronine sodium are generally due to therapeutic over-dosage, and thus are characterized by the typical symptoms of hyperthyroidism (e.g., tachycardia, irritability, nervousness, and increased bowel motility). In rare instances, allergic skin reactions have been observed in patients taking liothyronine sodium.
Most patients on sustained-release T3 do not experience any cardiac manifestations; however, a small percentage report increased awareness of heartbeat/palpitations and/or increased pulse rate. Dr Wilson noted that the patients most likely to experience these phenomena were individuals who had previously experienced heart flutters or PVC’s prior to starting treatment with sustained-release T3.65
Physicians who use the WT3 protocol have noticed that cardiac support with CardiaCare Plus, containing the botanicals night blooming cactus (Cereues grandiflorus), lilly of the valley (Convallaria officinalis), motherwort (Leounurus cardiaca), and lemon balm (Melissa officinalis), aids in patient comfort by decreasing the amount of palpitations and preventing tachycardia.
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Case Study
SR-T3 Protocol
A 43-year-old businessman came to the office complaining of severe fatigue, difficulty in sleeping, and headaches. All tests were normal, but his temperature averaged a degree lower than normal during the day. He was started on a cycle of T3 therapy consisting of 7.5 mcg p.o. b.i.d and was instructed to increase the dose by 7.5 mcg/dose/day if he was without complaints until his average temperature got to 98.6º F by mouth.
He was also instructed to call the office if he developed any complaints and to return to the office after 2 weeks. At the 2-week visit, the patient related that he was taking 90 mcg B.I.D and his temperature was still not up. Since his temperature did not change at all during the first cycle and he had noticed no difference at all in the way he felt since starting the treatment, he was instructed to try weaning off the T3 therapy by 7.5 mcg/dose/day if he remained without complaints. This was done so that the next part of the treatment would not be unnecessarily delayed. He was able to decrease the dose every day without complaints.
The patient was then started on a second cycle, with the same instructions as the first cycle. This time his temperature went up to 98.6º F on 75 mcg b.i.d. His symptoms began to improve, but after about 3 days, his temperature dropped again. The dose was increased to 82.5 and his temperature returned to normal. After about a week on that dosage, his temperature started to go down again and some of the recent clinical improvements were lost. The dose was increased to 90 mcg/dose, and his temperature went up again, restoring some of his clinical improvement. His temperature went down again after an undetermined time (he wasn’t recording his temperature three times a day as instructed). Since he had been showing a definite response to each recent increase and was without complaints, he was increased above the usual maximum dose of 90 mcg b.i.d. to see if the temperature of 98.6° F could be captured with one or two more increases. The temperature responded and dropped again on the 97.5 mcg dose. Then his temperature went up and stayed normal on 105 mcg b.i.d. and did not drop again.
He was maintained at 105 mcg b.i.d. for at least 3 weeks to help make sure that his temperature was indeed stable. During that 3-week period of time, he did not take his medicine at the correct time for a few days, and he began to experience headaches and felt tired and edgy. His temperature log revealed that his temperature had become slightly unsteady. His temperature was ranging more widely across his 3 daily temperatures. He was then given a T4 test dose of half a .025 mg tablet (.0125mg) of levothyroxine, and within 45 minutes his complaints resolved completely. Anxious to see if he might be able to capture his temperature with a smaller dose of T3 on the third cycle, he was weaned off the second cycle.
The patient demonstrated unsteady T3 levels in the second cycle with the T4 test dose. He wondered how successful the T3 therapy was going to be for him (even though he had gotten a fairly good response to treatment so far). He tried weaning down with a 7.5 mcg decrease dose of the T3 every 2 days, but with the third decrease his temperature started to decrease. At this point it became clear that he would require one or two more cycles of the treatment to resolve his symptoms. We decided to decelerate the weaning process to every 4 days. He then was able to decrease his dose without a drop in temperature. He was instructed to remain off the medicine for 10 days after cycle 2 in order to let his T3 levels steady down as much as possible.
On the next cycle, he was able to capture 98.6º F on 60 mcg b.i.d. His symptoms were nearly resolved. After a few weeks, he was instructed to decrease his dose of T3 to see if he could capture his temperature with less medicine on a subsequent cycle for complete resolution of his symptoms. He decreased the dose by one decrement every 4 days without any drop in his temperature. On the fourth cycle, his temperature was captured with 15 mcg b.i.d., and his symptoms resolved completely. He was later able to wean off the T3 and remain improved even after the T3 had been discontinued. His temperature remained normal as well.
