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Continuation: Four 2003 Studies of
Thyroid Hormone Replacement Therapies:
Logical Analysis and Ethical Implications
by Dr. John C. Lowe | drlowe@drlowe.com

Introduction | Page1 | Page 2 | Addenda | pdf format
Clarifications | Selected Response Letters

Potential Harm From TSH-Suppressive Dosages of Thyroid Hormone

In arguing that physicians should permit some hypothyroid patients to use TSH-suppressive dosages of thyroid hormone, it is incumbent upon me to justify the argument. To do so, I must explain two contradictory propositions.

The available evidence shows the first proposition to be false and the second true. I’ll show this first by:

A fitting introduction to the evidence for my viewpoint on TSH-suppressive thyroid hormone therapies is a 38-year-old statement by endocrinologist James H. Hutton. (For comments on Dr. Hutton, see Addendum 5) His statement is on alleged harm from the use of thyroid hormone.

Thyroid is a much maligned agent. Certainly it should be administered only under the supervision of a physician, but the danger likely to result from taking it has been portrayed in such lurid fashion that many medical men seem hesitant about giving it. As a matter of fact, overdosage seldom occurs. Signs of such an event are so easily recognized before any damage is done that any medical man should use it wherever he believes it is indicated.[18,p.16]

Dr. Hutton continued,

Hutton wrote that 120-to-180 mg (approximately 2-to-3 grains) daily was optimal for almost all myxedematous patients.

The scores of everything we can measure, when we measure enough instances, fall into a bell curve distribution. This is true of measurable phenomena classified in virtually any way, such as social (ethnic and racial prejudice), psychological (scores on an aptitude test), anatomical (heights of adult males and females), molecular (molecular weight of a chemical), environmental (yearly temperature variations), economic (stock market variations), and physical (mechanical force needed to bend apparently identical steel rods). And we can, on principle, expect that within the population of hypothyroid patients, tissue responsiveness to a particular dosage of thyroid hormone falls into a bell curve distribution. We can expect this even while allowing for variable responsiveness of different tissues within individual patients.

Central Limit Theorem and the Ineffectiveness and
Dangers of Replacement Therapy for Many Patients

In laboratory medicine, current practice for the most part ignores the need of some patients for dosages of thyroid hormone that exceed other patients’ needs. The standard of practice implies that the optimal dosage for all patients is the amount that keeps the TSH within its current reference range. But this implication conflicts with what we can reasonably predict from the central limit theorem of mathematics. The theorem says that for samples that are sufficiently large, the distribution of means is almost always more or less normal. The theorem, I believe, provides an explanation for the ineffectiveness and harm of thyroid hormone replacement for many patients, and for them, the effectiveness and safety of TSH-suppressive dosages.

I don’t mean to imply that laboratory medicine specialists calculate reference ranges without considering the normal variance distributions; indeed, they base the ranges on the 95% confidence intervals of the distributions.[41] I explicitly contend, however, that clinicians, as standard practice, don’t consider the normal distribution of variances in interpreting laboratory thyroid function test results or in making dosage decisions.

The central limit theorem predicts that repeated measurements (reported as the means of multiple samples) of any phenomenon produce readings that vary around a mean, so that they form a normal distribution. Applied to the concept of variable tissue responsiveness, the theorem predicts the following proposition: On the left slope and flange of the bell curve of tissue responsiveness, a progressively decreasing percentage of hypothyroid patients require progressively larger dosages of thyroid hormone to prevent symptoms of hypothyroidism, and ward off pathologies secondary to hypothyroidism. The theorem also predicts that the tissues of this progressively decreasing percentage of patients are progressively more resistant to overstimulation by progressively larger dosages of thyroid hormone.

Thus, the theorem predicts that what to some patients (on the right slope and flange) is an overstimulating dosage of thyroid hormone is to others (on the left slope and flange) innocuous. Our clinical experience and studies of potential adverse effects of TSH suppression bear this out. So do studies in which only a small percentage of patients had adverse effects to TSH-suppressive dosages of thyroid hormone, while most patients had no such effects. Those who had adverse effects represent the right outer slope and flange of the bell curve, where patients’ tissues are more responsive to a particular dosage of thyroid hormone than are most other patients’ tissues.

Unfortunately, many researchers mistakenly conclude that since a subset of patients has adverse effects from TSH-suppressive dosages of thyroid hormone, physicians should protect all patients by denying them such dosages. What these researchers apparently fail to comprehend is a point of crucial importance to the health and safety of the subset of patients on the left end of the curve: for these patients, TSH-suppressive dosages are both harmless and necessary to their health and well-being. Of course, in the vein of patient safety, we must be ever vigilant in clinical practice for potential adverse effects, even in this left-end subset of patients. But it is equally important in the vein of safety that we be cognizant that their health and well-being are assured only when they use the TSH-suppressive dosages that are harmful to patients on the right end of the curve.

The endocrinology specialty overall ignores the predictable phenomenon of a normal distribution of tissue responsiveness among the population of hypothyroid patients. Consistent with ignoring the phenomenon, the specialty implies or explicitly states that unless a patient has thyroid cancer, he/she shouldn’t use a TSH-suppressive dosage of thyroid hormone. The reason the specialty gives is that the dosage is highly likely to harm the patient. For thyroid cancer patients, the specialty argues, the benefits of TSH-suppressive dosages are worth the risks, although they are still not preferable.

Consider, however, a report by nuclear medicine specialists of a man with well-differentiated thyroid cancer.[15] For ten years, he had taken a high dosage of T4 to suppress his TSH level. During that time, his dosage ranged between 0.9-to-3.3 mg (900-to-3300 mcg T4; roughly equivalent to 44.6 grains of desiccated thyroid, which is close to the 60 grains that some patients tolerate well, according to Hutton). The authors wrote, "He was essentially asymptomatic and suffered no apparent ill effects from this prolonged and markedly excessive dosage of L-thyroxine. The literature lists a wide range of ill effects from both chronic and acute thyroid hormone overdosage but also records many examples of tolerance to excessive levels of exogenous thyroid hormone." (Italics mine.)

Treatment of thyroid cancer patients with TSH-suppressive dosages of thyroid hormone has provided a population of patients that enables us to examine the likelihood of harm from such dosages. The general belief within the endocrinology specialty is that for thyroid cancer patients, suppressing the TSH to an undetectable level is acceptable, as long as patients avoid "clinical thyrotoxicosis."[16,p.1150] Researchers have now conducted many studies of these patients to learn whether the TSH-suppressive dosages adversely affect their bones and hearts.

The research literature contains many studies of potential adverse effects of TSH-suppressive dosages on bone. What we’ve learned from these studies provides us with what could evolve into principles for the safe use of such dosages by a subset of hypothyroid patients—those for whom replacement dosages aren’t effective, and therefore not safe (see section below titled "Presumptions of the Endocrinology Specialty: Instability of Desiccated Thyroid, Dangers of T3, and the Safety and Effectiveness of T4-replacement").

That a patient uses a TSH-suppressive dosage of thyroid hormone doesn’t mean that the patient will definitely have reduced bone mineral density. Whether he or she does or doesn’t depends largely on another variable: the number of other risk factors for reduced bone density that impinge on the patient. Susceptibility in an individual patient, then, is the algebraic summation of the presence or absence of multiple risk factors. I’ve listed the most common ones[39][40] in Table 1. It’s worth noting here that the variance within any normal distribution is caused by the influences of many small random effects on the measured variable. Risk factors for reduced bone density are such random effects.

Table 1. Risk factors for decreased bone mineral density* Low calcium Low vitamin D intake or low exposure to sunlight Estrogen deficiency Small body stature Low body weight Advanced age Tobacco smoking High alcohol consumption Use of pharmacologic dosage of corticosteroids Too little back-stretching Too little high-impact and/or weight-bearing exercise *No authors listed: Osteoporosis-prevention, diagnosis and treatment: a systematic literature review: SBU conclusions and summary. Lakartidningen, 100(45):3590-3595, 2003.[39] Yoshimura, N.: Exercise and physical activities for the prevention of osteoporotic fractures: a review of the evidence. Nippon Eiseigaku Zasshi, 58(3):328-337, 2003.[40]

To put the role of risk factors into proper perspective, consider a bell curve of bone responsiveness to TSH-suppressive dosages of thyroid hormone. On the right end of the curve, an increasing number of risk factors for reduced density renders a decreasing percentage of patients progressively more susceptible to reduced bone mineral density from  TSH-suppressive dosages of thyroid hormone. On the left end of the curve, a decreasing number or absence of risk factors for reduced bone density renders a progressively decreasing percentage of patients progressively more resistant to reduced bone mineral density from TSH-suppressive dosages.

Before treating a patient with a thyroid hormone dosage greater than a replacement dosage, we don't know where his or her tissues fall within the bell curve of tissue responsiveness to the hormone. As the four studies at issue here show, presuming that all hypothyroid patients' tissues fall close to the mean of tissue responsiveness to thyroid hormone causes some patients to continue to suffer from hypothyroid symptoms. For some—the diminishing percentage who fall on the right flange of the curve—a particular TSH-suppressive dosage will cause thyrotoxicosis; for others—the diminishing percentage on the left flange—that same dosage is necessary for normal metabolism and freedom from hypothyroid symptoms. The further out these patients' tissue responsiveness falls in the left-side flange of the bell curve, the more resistant to thyrotoxicity they are, and the less effective thyroid hormone replacement is for them.

The 95% confidence interval that lab pathologists use to establish reference ranges is a mathematical calculation that leaves 2.5% of patients on each end of the distribution. Standard practice in medicine is to conclude that lab values within the 95% interval are "normal," and that those in the 2.5% on each end of the distribution are "abnormal." This conclusion is an arbitrary social convention—one that ignores the progressive variance that occurs as lab values proceed outward bilaterally through two standard deviations from the mean. (In general, physicians arbitrarily consider lab values that fall within two standard deviations of the mean "normal.") Patients whose tissue responsiveness falls progressively further out on the left side of the distribution are progressively more susceptible to developing symptoms of hypothyroidism. This is true despite their tissue responsiveness being within two standard deviations of the mean. Much to the patients' misfortune, however, most physicians will conclude that their symptoms can't be caused by hypothyroidism because their TSH and thyroid hormone levels are within the "normal" reference ranges—that is, their respective 95% confidence intervals.

Appreciation of the bell curve distribution of tissue responsiveness to thyroid hormone compels us to acknowledge the existence of a diminishing percentage of patients on the left side of the curve whose tissues are progressively less responsive to a dosage of thyroid hormone that keeps most hypothyroid patients symptom-free. These patients require higher dosages of thyroid hormone—for many, TSH-suppressive dosages—to maintain normal metabolism and health. Correspondingly, these patients’ tissues will predictably be progressively more resistant to dosages of thyroid hormone that for most other patients are thyrotoxic.

In my view, the recent four replacement therapy studies addressed patients on the left-side flange of the bell curve. The studies showed that replacement dosages are insufficient for relieving their hypothyroid symptoms. The studies are ipso facto evidence for a humanitarian imperative: that researchers and physicians now accommodate these patients’ need for dosages of thyroid hormone larger than those dictated by the concept of replacement therapies.

Presumptions of the Endocrinology Specialty: Instability of Desiccated Thyroid, Dangers of T3, and the Safety and Effectiveness of T4-replacement

The endocrinology specialty bases some of its most influential pronouncements on presumption—a basis that hardly justifies the certitude with which it expresses the pronouncements. Three presumptions appear to sustain the practice of T4-replacement. The presumptions are that desiccated thyroid is unstable, that T3 is troublesome and dangerous, and that T4-replacement is invariably safe and effective.

Instability of Desiccated Thyroid

Since the 1960s, the endocrinology specialty has advocated and even enforced only the use of T4-replacement in lieu of desiccated thyroid as a treatment for hypothyroidism. According to endocrinologists, the reason for this advocacy and enforcement is that the potency of desiccated thyroid is difficult to standardize. That is, the endocrinologists claim that too often, desiccated thyroid tablets don’t contain the amount of thyroid hormone reported on the label. They argue that the potency of synthetic T4 is more stable.[42] That synthetic T4 products are more stable, however, is a mere presumption. I can find no studies in which the stability of desiccated thyroid and synthetic T4 were compared. When I searched for studies in Medline, using the keywords "desiccated thyroid," "Armour," "stability," and "potency," I found no studies. But when I searched for "Synthroid" and either "stability" or "potency," I found two abstracts.[67][68] In one, the authors state, "Levothyroxine tablets, 50 microg, have been marketed for many decades but have had numerous recalls due to degradation and failure to meet potency."[67]

The specialty has tenaciously endorsed a T4 product called Synthroid, perpetuating the belief that it is the pinnacle of potency-stable medications. Shomon[46] and I[47] have reported, however, that the FDA has repeatedly recalled batches of Synthroid because tablets from the batches were "subpotent." This term means that tablets didn’t contain the amount of T4 claimed on the label. Despite this public record of serious problems with potency, representatives of the endocrinology specialty have doggedly continued their endorsement of Synthroid—and only Synthroid.

The fact is that all thyroid hormone products, both animal-derived and synthetic, are unstable compared to many other drugs. Thyroid hormones consist of iodine atoms bound to the amino acid tyrosine. The iodine atoms fairly easily separate from the tyrosine. Because of this, it’s prudent for both doctors and patients to be vigilant for subpotent tablets or capsules. The reassurance of the endocrinology specialty that Synthroid is more stable than other products is groundless. Because it misleads doctors and patients, often to the patients’ detriment, the specialty should cease to make this pronouncement.

Dangers of T3

The endocrinology specialty has long opposed the use of products that contain T3. The basis of its opposition, so it claims, is the resulting brief peak blood level of T3. Members of the specialty glibly state that the peak level is in the "thyrotoxic range"[84,p.1225] and that this peak level causes heart palpitations that trouble patients. They further state that the peak level may adversely affect the heart. But, these members resound, by using Synthroid patients can avoid these problems.

The specialty’s claim that T3 causes these problems is a mere presumption; it is contradicted by the reports of researchers with extensive clinical experience with T3. Psychiatric researchers whose patients use T3 point out that it is generally well-tolerated.[35] The experience of my research group agrees with this observation. For some fifteen years, our treatment team has worked directly with hundreds of patients using combined T4/T3 products or T3 alone. Our observations during that time dispute the warning that palpitations are a problem for patients who use T3-containing products. Palpitations in these patients are exceedingly rare. When a patient has experienced palpitations, they have been minor and of little or no concern to the patient. The palpitations have also been of no clinical significance. It’s noteworthy that the researchers of the four studies, as well as those of three other studies comparing the effectiveness of T4 and T4/T3-replacement, didn’t report that their study patients were troubled by palpitations.[1][2][3][4][5][6][7]

I can find no study that members of the specialty have conducted confirming its prediction of adverse effects from T3. Only last year, endocrinologists Kaplan, Sarne, and Schneider wrote: ". . . the possible long-term risks of elevated or fluctuating T3 levels have not been evaluated."[19,p.4541]

Systematic studies have not conclusively ruled out long-term adverse effects. But many patients have used T3 for many years without apparent adverse effects. We have, then, a positive anecdotal record and no long-term safety studies showing that T3 is harmful. Regardless, the specialty has warned of potential harm in a manner that has generated irrational fear of T3 among physicians. It’s common, for example, for patients who’ve asked their doctors to prescribe T3 to hear the reply, "If you take T3, you’re going to have a heart attack and die!"[48,p.10]

It goes without saying, of course, that caution is necessary with patients who have fragile cardiac conditions. This is especially true when such a patient is using a product containing T3, since T3 directly affects the myocardium.[66] But potential harm from T3 is not actual harm, and the endocrinology specialty has so blurred the distinction that most other physicians—and perhaps they themselves—don’t know the difference.

Safety and Effectiveness of T4-replacement Therapy

Just as the endocrinology specialty’s objections to the use of desiccated thyroid and T3 are based on presumption, so is its long-standing dictum that T4-replacement is always safe and effective. Some members of the specialty have been steadfastly convinced of the fail-safe effectiveness of T4-replacement. When patients complain of continuing hypothyroid symptoms despite using "adequate T4-replacement," these members argue that something other than a thyroid hormone deficiency must be causing their symptoms.

Witness, for example, statements by thyroid surgeon Richard Guttler: "We have the most accurate thyroid testing, and if you test normal, and have symptoms, most likely your symptoms aren’t due to abnormal thyroid balance." And further, "[I] rely on accurate thyroid blood testing. The thyroid tests are abnormal way before [patients] have ‘thyroid related symptoms’. Other similar symptoms, such as fatigue, and weight gain are not thyroid related if the testing is stable and normal."[49] (Italics mine, and incorrect punctuation is Guttler’s.)

Similarly, consider a comment of influential endocrinologist M.I. Surks in a chapter on treating hypothyroidism in the widely used thyroidology textbook, Werner’s The Thyroid: "Notwithstanding the physician’s assurance that the T4 dose is optimal, and the demonstration that serum TSH has decreased into the normal range, these patients may ask for a larger dose or take a larger dose on their own initiative. In this setting, the patient should be reassured that the T4 dose prescribed is appropriate, and other causes of the patient’s complaints must be investigated."[43] (Italics mine.)

Surks’ advice to reassure the patient that his or her dosage "is appropriate" presumes that the patient’s T4 dose is adequate for his or her individual needs. His advice that "other causes of the patient’s complaints" be investigated suggests a preconceived notion that replacement dosages of T4 are infallibly effective. In addition, his advice, like that of Guttler, implies that if a patient has hypothyroid-like symptoms despite using T4-replacement, the symptoms are probably caused by some other disorder.

Endocrinologists can maintain this belief only by ignoring published evidence showing it to be false.[8][68] Consider, for example, a finding of Fraser et al.[68] The study result reveals the harm many hypothyroid patients suffer when their physicians make dose decisions based on TSH levels.

The Fraser Study. Three physicians experienced in diagnosing and treating hypothyroidism assessed 148 hypothyroid patients on T4-replacement. The physicians used the Wayne clinical diagnostic index,[69] an objective tool for deciding whether a patient’s thyroid hormone therapy is adequate, excessive, or insufficient. Statistical tests showed that the three physicians’ judgment didn’t differ in classifying patients.

Among the 148 patients, 108 were clinically normal. This means they were taking enough T4 to be free from symptoms of hypothyroidism. Despite this, 53 of them (49%) had TSH levels below the lower limit of the reference range. Conventional physicians, of course, would interpret their TSH test levels as evidence that the patients were "hyperthyroid" or "thyrotoxic." This mistake is understandable when prominent endocrinologists—Dr. Anthony Toft, for example—have incorrectly termed a low TSH as a "thyrotoxic" level.[70,p.91] And probably most physicians would have required these patients to lower their dosages of T4 to raise their TSH levels—even though the patients were clinically normal. As a result of lowering their dosages, however, some of them, and perhaps all, would have begun suffering from hypothyroid symptoms and risked developing diseases from too little thyroid hormone regulation.[37]

Among the 148 patients, 18 were clinically hypothyroid. This means they were taking too little T4 to keep them from suffering from symptoms and signs of thyroid hormone deficiency. Despite being clinically hypothyroid, 3 of the 18 patients (17%) had TSH levels below the lower limit of the reference range. Most physicians would have required these patients to lower their T4 doses to raise their TSH levels. Doing so would surely worsen their symptoms and signs of hypothyroidism,[68,p.809] and would make them more susceptible to potentially fatal diseases associated with hypothyroidism.[37]

The suffering of these patients and their potential for pathology would result from the obstinate demand by the endocrinology specialty that physicians titrate hypothyroid patients’ T4 doses by their TSH levels—and only by those levels. Of course, some endocrinologists also advise other physicians to use the free T4 in making dosage decisions. The Fraser study showed that among the 18 clinically hypothyroid patients, the free T4, like the TSH, led to a false interpretation of the patients’ status. In 4 of the 18 patients (22%), the free T4 was above the upper limit of the reference range. This gave a false signal that the patients were overtreated, when it fact they were undertreated.

Results of the Fraser study should alert all physicians to the potential for harming their patients through following the practice guidelines of the endocrinology specialty. Basing their dosage decisions on TSH and free T4 levels instead of clinical assessment will leave many patients undertreated—a condition that is hazardous to the patients’ health (see following section).

Consequences of the Presumption That
T4-replacement Is Invariably Safe and Effective

As I wrote above, the endocrinology specialty maintains that if patients with hypothyroid-like symptoms have "normal" TSH levels, their symptoms must be caused by something other than a thyroid hormone deficiency. It is precisely this false belief that has led to the "new diseases" of the past 30 years. Prominent among these are so-called "fibromyalgia" and "chronic fatigue syndrome." Considerable evidence indicates that inadequate thyroid hormone regulation is the major underlying causative factor in these supposed new disorders. For example, the only studies in which patients with these diagnoses have fully and lastingly recovered are those in which they underwent thyroid hormone therapy.[10][11][12][13][14][45][71][72][73]

As I have argued with substantial documentary evidence,[44][50][51] the disorder underlying most patients’ fibromyalgia is inadequate thyroid hormone tissue regulation. Our data indicate that the fibromyalgia symptoms and signs of approximately 90% of patients are features of hypothyroidism and/or thyroid hormone resistance. In most cases, patients’ thyroid disease is complicated by low physical fitness levels, nutritional deficiencies, the dysglycemic and proinflammatory effects of poor diet, and the adverse metabolic effects of various medications other than thyroid hormone prescribed to control symptoms of hypothyroidism and/or thyroid hormone resistance. The number of patients with chronic, widespread pain (a classic symptom of hypothyroidism) increased in the mid-1970s to a point that rheumatologists began to take notice. This occurred shortly after endocrinologists, in 1973 and 1974, recommended cutting hypothyroid patients’ thyroid hormone dosages in half. This reduced patients’ dosages from the equivalent of 200-to-400 mcg of T4 to 100-to-200 mcg.[74][75] The purpose was to raise the patients’ TSH levels. (The new TSH test had recently come into widespread use.) The rheumatologists unquestioningly accepted the endocrinologists’ pronouncement that the patients’ reference range TSH levels ruled out thyroid hormone deficiency as the cause of their chronic, widespread pain. Eventually, the rheumatologists gave this classic hypothyroid symptom the name "fibromyalgia."[76]

The numbers of patients with overwhelming chronic fatigue steeply increased in the late 1970s. Eventually, researchers named this classic hypothyroid symptom "chronic fatigue syndrome." As standard practice at this time, physicians had come to adjust patients’ thyroid hormone dosages to keep their TSH levels within the reference range.[77] As Dr. David Derry wrote in the British Medical Journal, "In 1973 thyroidologists officially endorsed the newly designed TSH test for thyroid function . . . . The TSH test caused the appearance six years later of chronic fatigue and fibromyalgia."[78]

The endocrinology specialty has been completely deaf to our reports that inadequate thyroid hormone regulation is the major cause of symptoms diagnosed as fibromyalgia and chronic fatigue syndrome.[44] The reason for the deafness is the belief expressed in the quotes above by Guttler and Surks—that symptoms of patients who have "normal" TSH levels can’t possibly be due to too little thyroid hormone regulation. Our reports that this is false, and that the symptoms of fibromyalgia and chronic fatigue syndrome are those of inadequate thyroid hormone regulation, are supported by a growing body of evidence.

Continued Suffering of Many Patients on T4-replacement 

Three survey studies have shown that many patients on "adequate T4-replacement" continue to suffer from symptoms and signs of hypothyroidism. As one would expect, these patients were dissatisfied with their thyroid hormone therapy.[52][53,p.153][54]

In a study of 37 patients with subclinical hypothyroidism, T4-replacement improved patients’ memories. But the patients had no measurable improvement in other symptoms or their health-related quality of life.[38]

Results of the survey studies and the study of subclinical hypothyroid patients are backed up by three of the four studies at issue.[1][2][3] Patients who still had hypothyroid symptoms despite being treated with T4-replacement were included in the studies. Neither T4- nor T4/T3-replacement relieved their symptoms. In another of the studies, researchers compared the psychomotor development of infants who had congenital hypothyroidism to that of infants who had normal thyroid function. The hypothyroid infants had impaired psychomotor development. Neither T4- nor T4/T3-replacement relieved the infants’ impairment.[4]

Psychiatric researchers reported that patients taking antidepressants often remain depressed when they are on T4-replacement—even TSH-suppressive dosages. Adding T3, further depressing the TSH level, then relieves the patients’ depression.[30]

Researchers recently reported measuring changes in weight of two groups of patients after they had therapeutic destruction of their thyroid glands. The first group, thyroid cancer patients, used TSH-suppressive dosages of thyroid hormone after the destructive therapy. They didn’t gain weight. The second group, Graves’ disease patients, used T4-replacement after destructive therapy. They did gain excessive weight. The researchers concluded, "The excessive weight gain in patients becoming hypothyroid after destructive therapy for Graves' disease suggests that restoration of serum TSH to the reference range by T4 alone may constitute inadequate hormone replacement."[55]

Researchers recently conducted the first large, community-based study in the UK of the health status of hypothyroid patients using T4-replacement therapy.[37] Compared to matched control patients, hypothyroid patients on "adequate" dosages of T4 had a higher reported incidence of four diseases: depression, hypertension, diabetes, and heart disease. Hypothyroid patients on inadequate T4-replacement (their TSH levels were elevated) also had a higher incidence of strokes. In addition, hypothyroid patients chronically used more prescription drugs, especially for diabetes, cardiovascular disease, and gastrointestinal conditions.

We’ve recently been consulted by many hypothyroid patients whose physicians have reduced their T4 dosages to extremely low amounts, in some cases as low as 25 mcg. The patients report to us that their physicians refer to reports by endocrinologists that TSH suppression increases the risk of atrial fibrillation three-fold. As I explain in Addendum 4, this is an unjustified generalization from a study of elderly (60 years of age and older) sedentary people. This misguided practice by physicians is likely to increase the patients’ incidence of coronary artery disease and cardiac fatalities. 

The dosage of T4 that suppresses the TSH level varies considerably, but may be as much as 171 mcg or as little as 50 mcg.[56][57][58][59][60][61][62] Hypothyroid patients should be concerned when their physicians restrict them to lower-end dosages of T4. In one study, researchers used coronary angiography to assess the progression of coronary atherosclerosis in elderly hypothyroid patients. In 5 of 6 patients who kept their T4 dosages at 150 mcg or more, the disease didn’t progress. But in all 6 patients whose dosages were 100 mcg or less, the disease had progressed.[63] This study suggests that elderly patients whose TSH levels are suppressed by fairly low dosages of T4, and whose physicians insist on keeping their TSH levels within the reference range, may, as a result, have increased progression of coronary artery disease, leading to strokes and/or heart attacks. In that the incidence of atherosclerosis is high even among young individuals in modern societies, younger hypothyroid patients should be concerned over the possibility of lower dosages of thyroid hormone inducing or exacerbating atherosclerosis.

Dilemma for the Endocrinology Specialty

The four studies that are the subject of this document clearly show that neither T4- nor T4/T3-replacement is effective for many hypothyroid patients. The ineffectiveness of the two replacement therapies translates into three likely adverse consequences for these patients with inadequate thyroid hormone regulation: continued suffering from symptoms, susceptibility to potentially disabling or lethal diseases, and increased use of drugs to control the symptoms and diseases. The endocrinology specialty sets and maintains practice guidelines for the diagnosis and treatment of hypothyroidism; that it does so imposes upon it an ethical and humanitarian responsibility to expediently act to protect hypothyroid patients from the three adverse consequences. That responsibility is the compelling reason for the endocrinology specialty to promptly reform its incorrect official position that T4-replacement is safe and effective for all hypothyroid patients.

Many researchers, physicians, and patient advocates believe that the endocrinology specialty has been curiously obstinate in its advocacy of T4-replacement. Its obstinacy is evident in its disregard for the protests of thousands of patients and a growing number of doctors that T4-replacement is ineffective and harmful for many patients.

The specialty’s obstinacy may be sustained by financial incentives from corporations that profit from the practice of T4-replacement therapy. This suspicion of financial motivation is reinforced by the specialty’s standard method of enforcing the practice of T4-replacement among doctors: political tyranny rather than scientific argument and debate. The suspicion will only mount if the specialty—despite the recent studies showing replacement therapies to be ineffective[1][2][3][4] and harmful[37][63] for many hypothyroid patients—sidesteps the issue now at hand. How safe and effective is T4-replacement compared to alternate approaches to thyroid hormone therapy now in widespread use? For its own credibility, it is imperative that the specialty immediately address this issue free from prejudicial preconceptions.

References

1. Walsh, J.P., Shiels, L., Mun Lim, E.E., et al.: Combined thyroxine/liothyronine treatment does not improve well-being, quality of life, or cognitive function compared to thyroxine alone: a randomized controlled trial in patients with primary hypothyroidism. J. Clin. Endocrinol. Metab., 88(10):4543-4550, 2003.

2. Sawka, A.M., Gerstein, H.C., Marriott, M.J., et al.: Does a combination regimen of thyroxine (T4) and 3,5,3'-triiodothyronine improve depressive symptoms better than T4 alone in patients with hypothyroidism? Results of a double-blind, randomized, controlled trial. J. Clin. Endocrinol. Metab., 88(10):4551-4555, 2003.

3. Clyde, P.W., Harari, A.E., Getka, E.J., and Shakir, K.M.M.: Combined levothyroxine plus liothyronine compared with levothyroxine alone in primary hypothyroidism: a randomized controlled trial. J.A.M.A., 290:2952-2958, 2003.

4. Cassio, A., Cacciari, E., Cicgnani, A., et al.: Treatment of congenital hypothyroidism: thyroxine alone or thyroxine plus triiodothyronine? Pediatrics, 111(5):1055-1060, 2003.

5. Bunevicius, R., Kazanavicius, G., Zalinkevicius, R., and Prange, A.J. Jr.: Effects of thyroxine as compared with thyroxine plus triiodothyronine in patients with hypothyroidism. N. Engl. J. Med., 11:340(6):424-429, 1999 (Feb).

6. Bunevicius, R. and Prange, A.J.: Mental improvement after replacement therapy with thyroxine plus triiodothyronine: relationship to cause of hypothyroidism. Int. J. Neuropsychopharmacol., 3(2):167-174, 2000 (June).

7. Bunevicius, R., Jakubonien, N., Jurkevicius, R., Cernicat, J., Lasas, L., and Prange, A.J. Jr.: Thyroxine vs thyroxine plus triiodothyronine in treatment of hypothyroidism after thyroidectomy for Graves’ disease. Endocrine, 18(2):129-133, 2002.

8. Johansen, K., Hansen, J.M., and Skovsted, L.: Myxedema and thyrotoxicosis: relations between clinical state and concentrations of thyroxine and triiodothyronine in blood. Acta Med. Scandinav., 204(5):361-364, 1978.

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