The Clinical Diagnosis and Treatment

of Hypothyroidism

Summary:

The current TSH-based approach to thyroidology is illogical and ineffective,

distorting the research, the interpretation of the research, and the free T4 and free

T3 reference ranges.

Thyroidology must be based upon the assessment of T3 effects in all tissues as

indicated by the patient’s clinical criteria (signs and symptoms).

Combination T4/T3 therapy is required to produce optimal T3 effects in all tissues

while minimizing negative effects. Thyroid hormone effects cannot be understood in isolation from the rest of the

endocrine system; in particular the patient’s cortisol status.

The ultimate test of whether a patient is experiencing the effects of too much or too little

thyroid hormone is not the measurement of hormone concentration in the blood but the effect of

thyroid hormones on the peripheral tissues.1

1 The Tyranny of False Assumptions

Hypothyroidism is the state of inadequate T3 effect in some or all tissues of the body. T3

is arguably the most powerful molecule in biology; it increases mitochondrial energy

production2,3 and thus improves the function of every cell, tissue and organ in the body. It

has many other direct and indirect effects that we are only beginning to understand. T4 is

the inactive thyroid prohormone, but is much more abundant in the blood and is the source

of most of the T3 in the body. Any degree of T3 deficiency degrades our physical and mental

functioning and our long-term health. The symptoms and signs of hypothyroidism are so

many and varied (See Table 1.) that hypothyroid patients often receive many other

diagnoses.4 The ability to diagnose and effectively treat every form and degree of

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hypothyroidism is central to medical practice, and, I will argue, the key to understanding the

endocrine system as a whole. In particular, one must be able to diagnose and effectively

treat hypothyroidism in order to understand cortisol deficiency (adrenal insufficiency). T3

and cortisol have very powerful interactions and deficiencies of one or both of these

hormones cause most of the unexplained fatigue, depression, and pain that affect so many

people. What guidance do physicians now receive regarding the diagnosis and treatment of

hypothyroidism?

Clinical medicine is defined as “the study and practice of medicine in relation to the

actual patient; the art of medicine as distinguished from laboratory science”.5 The American

Association of Clinical Endocrinology (AACE)

and American Thyroid Association (ATA) claim

to provide “evidence-based clinical guidelines

for the clinical management of

hypothyroidism”,6 but instead provide a TSH-T4

laboratory reference-range scheme that

ignores evidence and dismisses clinical criteria

(the patient’s signs and symptoms) as

irrelevant to diagnosis and treatment.

The guideline’s authors define

“euthyroidism” not as a physiological state of

optimal T3 effect, but as having a thyroid

stimulating hormone (TSH) level and/or free T4

(FT4) level anywhere within the laboratory’s

reference ranges. Now TSH is not a thyroid

hormone, and its level is an indirect and fallible

indicator of a person’s thyroid hormone status.

So they do state that the diagnosis of

hypothyroidism must always be “biochemically confirmed” by a low FT4. (I use “normal”

and “low” throughout to refer to reference ranges only, with no clinical implication.) The

authors say nothing about how FT4 reference ranges are determined; so they have

delegated the diagnosis of hypothyroidism to some laboratory scientists. They assert that

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Table 1: Signs and Symptoms of HypothyroidismFatigue, excessive need for sleepCold intoleranceWeight gain, cannot lose weightConstipation, poor digestionDry skin, itchingEsophageal refluxMuscle aches, cramps, stiffnessMyxedema of the face, lower legsPoor concentration, memoryDepression or anxietyVoice changes, hoarsenessHeadache, often upon awakeningElevated total and LDL cholesterolAtherosclerosisHypertensionCarotenemia, yellowing of skinDry hair and/or hair lossSlow heart rate, palpitationsInsomnia, daytime restlessnessHeavy menses or amenorrheaInfertilityCarpal tunnel syndromeSleep apnea

the free T3 (FT3) level, the level of the active thyroid hormone in the blood, is of no

consequence, even if low during treatment, and should not be tested.

The authors assume that almost all hypothyroidism is primary, due to failure of the end-

hormone producing gland. This requires the

unstated assumption that any degree of

central hypothyroidism, due to hypothalamic-

pituitary dysfunction and inadequate TSH

production, is rare. They are thus assuming

that, absent any obvious hypothalamic-

pituitary (HP) disease or damage, TSH

production is perfectly vigorous and will always assure optimal thyroid levels/effects for

every individual. So they believe that dysfunctional central hypothyroidism does not exist; a

belief for which no evidence can possibly be cited as support. It is a belief that, however,

underlies their thyroidology.

When it comes to treatment of primary hypothyroidism, which the TSH is usually

elevated, they add yet another assumption: that the individual’s perfectly vigorous TSH

secretion also reacts to once-daily oral T4 therapy exactly as it does to endogenous thyroidal

production. Thus they believe that all they must do is prescribe enough of the inactive T4

hormone, levothyroxine, to lower the elevated TSH back to within its population range. They

unthinkingly equate “euthyroidism” with a normal TSH, treated or untreated. The resultant

thyroidology scheme is utterly simplistic: a normal TSH is euthyroidism; a high TSH is

hypothyroidism and is treated with enough levothyroxine (T4) to normalize the TSH. Both

the clinical effect of the treatment on the patient and the patients’ actual thyroid hormone

levels (FT4 and FT3) are ignored as irrelevant because both lack “sufficient specificity to

serve as therapeutic endpoints”.

The AACE/ATA TSH-T4 reference range scheme is a closed system of assumptions and

conclusions that is completely insulated from clinical reality. When it doesn’t work, the

patient is presumed to have some other medical or psychological problem. The scheme

cannot be “disproved” by any research because it is used to both produce the research and

interpret it. It thus continues to persist in spite of its abject failure in scientific studies and in

physicians’ and patients’ daily experiences. It is no coincidence that since it began to be

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Abbreviations:HP hypothalamic-pituitaryTSH thyroid stimulating hormoneFT3 free triiodothyronine levelFT4 free thyroxine levelTFTs thyroid function testsTRT thyroid replacement therapyTSHT4Rx TSH-normalizing T4 therapy

adopted in the 1970s, there has been an explosion in the number of people diagnosed with

chronic fatigue syndrome, fibromyalgia, depression and other disorders that can be caused

by hypothyroidism. T4-treated patients are increasingly vocal about their dissatisfaction

with their treatment. in many websites and forums laypersons are helping each other to

obtain diagnosis and effective treatment according to an alternative thyroidology.7 Some

patients have taken this issue to their legislature.8 To deal comprehensively with this

problem I must thoroughly expose the false assumptions underlying TSH-T4 thyroidology. I

will contrast them with the available evidence and then describe an approach to clinical

thyroidology based upon the available research and my own experience.

2 TSH-based thyroidology

Let us state the assumptions of the ATA/AACE diagnosis-and-treatment scheme explicitly:

1. Thyroid stimulating hormone (TSH) secretion is always perfect, assuring thyroid

sufficiency for each person, unless there is obvious HP damage/disease. Almost all

hypothyroidism is primary and detectable by an elevated TSH. (Immaculate TSH)

2. Primary hypothyroidism is sufficiently treated by normalizing the TSH with replacement

therapy.

I will discuss the use of the TSH to guide T4 therapy below. First I will address the

Immaculate TSH assumption. It is not just improbable; it is known to be false. HP function is

highly complex and variable. The most direct and reliable laboratory tests of thyroid status

are the thyroid hormone levels, FT4 and FT3. This is acknowledged by the AACE/ATA as they

describe the “pitfalls” of interpreting the TSH and are careful to define hypothyroidism as a

low FT4. However the authors believe that they can consider HP dysfunction to be rare,

limited to cases with obvious intracranial pathology. They believe that they can avoid the

“pitfalls” so well that they can substitute the TSH test for the FT4 and FT3 levels. This is

illogical; it is analogous to insisting that one’s home-heating thermostat always works

perfectly even as the house gets colder and colder. HP function is not immaculate; it is

fallible. The stimulatory pituitary hormone level is always an indirect test. It is not a reliable

inverse indicator of end-hormone levels or effects throughout the body. In no other

endocrine system do we assume HP perfection. We do not use luteinizing hormone (LH),

follicle-stimulating hormone, or adrenocorticotropin levels as guides for diagnosis or 4

treatment. Dysfunctional LH hyposecretion, without any gross pathology, is nearly universal

in aging males and contributes to the age-related decline in testosterone levels. 9 TSH

production also declines with age. Children and young adults have more vigorous TSH

secretion and higher thyroid hormone levels. Between the ages of 20 and 80 FT3 declines by

30% 10 and the TSH response to low FT4 levels declines by 75%.11 In thyroidology as in the

rest of endocrinology, logic requires us to first determine that a hormone deficiency exists

based upon symptoms and hormone levels, and then check the pituitary hormone to see if

the deficiency is primary or central.

It is easy to draw false inferences from population correlations. The level of the

stimulatory pituitary hormone will be usually be elevated when the primary gland is failing

and suppressed if the gland is overactive. Due to the presence of primary hyper- and

hypothyroidism in the population there is an inverse population correlation between TSH

and FT4/FT3 levels. However, there is no correlation within the normal TSH range of 0.5 to

3.0mIU/L. The slope in this region is flat;12 meaning that a TSH anywhere in this range

coexists with the same broad range of FT4 values, from low to high. This fact attests to the

variability of HP function. HP dysfunction exists; a normal TSH does not imply thyroid

hormone sufficiency. Even outside this range the TSH is not diagnostic: an elevated TSH can

be due to thyroid hormone resistance, adrenal insufficiency,13 or a TSH-secreting adenoma

producing hyperthyroidism.14 Even an elevated TSH cause by thyroid gland pathology does

not imply hypothyroidism; if TSH secretion is vigorous it may be compensatory, maintaining

thyroid sufficiency. A low TSH can be associated with either low or high thyroid levels (i.e.,

central hypothyroidism or primary hyperthyroidism).

Some attempt to defend the AACE/ATA’s reliance on the TSH test because it is a

“sensitive” test. The latest generation TSH test is indeed more sensitive to lower TSH levels.

The TSH level is sensitive too in that it responds in a logarithmically-amplified way to

changes in the serum FT4 level in any given person. These facts do not imply that HP

function is perfect or that the TSH is the right test for diagnosis or treatment.

In my experience, dysfunctional central hypothyroidism (CH) is more common than

primary hypothyroidism. This should be expected as the HP system is part of the brain and

thus far more complex than the thyroid gland. It is much more likely to be dysfunctional.

The hypothalamus is affected by inputs from many regions of the brain and by many

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neurotransmitters, environmental chemicals, drugs, illnesses15 and other factors.

Dysfunctional central hypothyroidism has been associated with a number of mutations and

other molecular disorders, including the secretion of an inactive form of TSH. 16,17,18 There are

reports of central hypothyroidism with normal imaging studies;19,20,21 these are the tip of an

iceberg.

Even if we had some independent way of knowing that HP function and TSH secretion

were perfectly vigorous in a given patient, the TSH level still reflects only the HP system’s

response to circulating T4 and T3, not T3-effect in other tissues. The HP system is more

sensitive than other tissues to circulating T4; the brain and pituitary gland have higher levels

of the deiodinase D2 causing them to convert T4 to T3 more avidly. 22,23 The central nervous

system has no D1, but in other tissues D1 is a major determinant of T3 production. The

production and activity of D1, D2, and D3 are variously affected by many factors. 24 There are

also 4 different thyroid hormone receptors25,26 and at least 10 different active transport

systems with variable tissue distribution.27,28,29 All of these proteins are subject to single

nucleotide polymorphisms.30,31 Peripheral thyroid hormone resistance may be more

common than previously realized.32 Even the serum FT4 and FT3 levels are indirect

indicators of intracellular T3 levels-effects. To reduce all of thyroidology to TSH or even T4

management is to ignore its complexities—known and unknown.

3 The misuse of the TSH distorts the FT4 reference ranges

Diagnostic assays produced by different manufacturers can vary significantly in the

results they produce; this is particularly true of FT4 immunoassays.33 Each assay

manufacturer provides a FT4 range based upon “apparently healthy” non-patients as

described above. They may be screened with TSH and thyroid antibody tests to exclude PH,

but are not screened for hypothyroid symptoms; so severely hypothyroid persons can be

included.34 Each laboratory must “validate” a reference range for their use of the assay with

their population.35 They do so by combining the values from the manufacturer’s range, the

published literature and tests that they perform.36 Here again the immaculate TSH doctrine

leads to error. Assuming that a normal TSH means euthyroidism, laboratories save time and

money by including FT4 and FT3 values from physician-ordered thyroid panels they’ve

performed in which the TSH was normal.37

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The laboratories’ inclusion of both symptomatic undiagnosed and T4-treated hypothyroid

clinic patients in their FT4 and FT3 ranges and this is evident in the breadth of the FT4

ranges that they report. Published studies of non-patient populations, without symptom

screening, consistently yield relatively narrow 2 S.D. FT4 ranges of around 1.0 to 1.65ng/dL

(12.9–21.3pmol/L).38,39,40,41,42 (The actual values vary with the immunoassay.) However, most

laboratories using similar assays report considerably broader FT4 ranges with lower limits of

only 0.6-0.8ng/dL and upper limits of 1.7-2.2ng/dL (7.7-10.3pmol/L to 23.2-28.4pmol/L). I

submit that the lower limit is reduced by the inclusion of symptomatic clinic patients with

TSH-normal central hypothyroidism, and the upper limit raised by the inclusion of T4-

treated primary hypothyroidism patients. The lower FT4 limit attests to the prevalence of

dysfunctional central hypothyroidism in the patient population, and explains why many

cases of central hypothyroidism due to HP damage-disease have low-normal FT4 levels.43,44,45

Indeed, in my experience, dysfunctional central hypothyroidism is far more prevalent than

primary hypothyroidism. A study of patients with depression found normal TSH levels but

low or low-normal FT4 and FT3 values. The mean FT4 was only 11.43 (range: 10.6–19.40

pmol/l). The mean FT3 was only 4.45 (±0.81) pmol/l (range: 4.00–8.3 pmol/l). While the TSH

levels were normal, 16% of the FT4 and 30% of the FT3 values were below the reference

ranges.46

If laboratories were to report FT4 results with the unscreened, non-patient range of 1.0

to 1.65ng/dL (12.9–21.3pmol/L), the impact on medical practice would be immense. Many

symptomatic patients have normal TSHs and FT4s below 1.0ng/dL. They would all be

diagnosed with central hypothyroidism. Yet 1.0ng/dL is still not a diagnostic lower limit.

With careful screening for signs and symptoms of hypothyroidism the lower limit would be

higher, probably around 1.2ng/dL (15.5pmol/L); yet this is still just a 2 S.D. population

statistic. Persons differ in their need for thyroid hormone,47,48 their conversion of T4 to T3,

their sensitivity to T3, their cortisol levels, and in other physiological parameters that affect

thyroid hormone action. The validity of FT4 assays also falls far short of ideal.49 Therefore, a

FT4 at the 50th percentile of a meaningful reference range may not be sufficient for some

persons, while a low FT4 may be adequate for others. There is simply no laboratory

substitute for clinical thyroidology.

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4 FT4 and FT3 Levels Matter

The excessive breadth of the FT4 and FT3 ranges is also evidenced by many studies that

show detrimental effects with lower levels and beneficial effects with higher levels within

the ranges, and that show benefits with treatment for patients with low-normal levels.

Lower FT4 levels, even within the range, in the first trimester of pregnancy are associated

with lower neonatal neurobehavioral scales,50 impaired psychomotor development51 and

autism.52 In middle-aged adults, higher FT4 levels are associated with lower all-cause

mortality, and higher FT3 levels with lower cancer mortality.53

Hypothyroidism is known to cause hypercholesterolemia and to increase atherosclerosis.

Carotid artery intimal thickness is inversely associated with FT4 levels within the range.54,55

Persons with FT3s in the upper third of the range have half the incidence of severe

atherosclerosis as those with FT3s in the lower third.56 Higher T4 doses prevent the

progression of coronary artery atherosclerosis, whereas lower doses allow progression [57].

A lower FT4 within the range is associated with hypercoagulability.58 Subclinical

hypothyroidism (SH), where FT4 levels are generally lower within the range, is associated

with cardiovascular disease and mortality; the risk rises with higher TSH levels.59 SH is

associated with higher blood pressure.60 Patients with SH have elevated lipid levels

compared to controls and to eliminate the difference requires TSH-suppressing T4 doses. 61

Lowering the TSH to under 2.0 mIU/L with T4 therapy, rather than just normalizing it,

produces lower cholesterol, homocysteine, and CRP levels.62

The negative health and quality-of-life consequences of obesity are well-documented. In

untreated persons, lower FT4 values within the range are associated with greater body mass

index, weight gain,63 subcutaneous fat,64 and with four of the five components of the

metabolic syndrome.65 Lower FT3 levels within the range are also associated with lower

metabolic rate and weight gain.66 PCOS can be caused by hypothyroidism and can resolve

with thyroid replacement therapy.67

Optimal, not just normal thyroid levels are also beneficial for cognitive function, mood,

and well-being. Higher T4 levels within the range are associated with better cognitive

function68,69 and lower risk of cognitive decline.70 Lower thyroid hormone levels and/or

higher TSH levels within the ranges have been associated with depression or a worse

prognosis for remission of depression.71,72,73,74,75,76 T3 therapy alleviates depression in persons

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with normal thyroid function tests (TFTs).77,78,79,80,81,82,83 Those who respond are more likely to

have T4 levels in the lower third of the range.84 In T4-treated primary hypothyroidism

patients, higher FT4 and lower TSH levels within the ranges are associated with

psychological well-being.85 Persons with SH and lower FT4 levels complain more of myalgias

and weakness and have lower muscle strength on testing.86 80% of persons with symptoms

but normal TFTs experienced better mood and energy on 125mcg T4 daily.87

In spite of such evidence, physicians claim that those with normal TFTs who experience

subjective improvement on thyroid replacement therapy must have “thyrotoxic euphoria”.

This ad hoc diagnosis illustrates the closed nature of the TSH-T4 reference range scheme; all

clinical evidence that contradicts it is rejected. In fact, people usually feel worse, not better

when they have excessive thyroid hormone levels-effects. Patients with endogenous

subclinical hyperthyroidism have the same negative, undesirable symptoms as hyperthyroid

patients.88 Women on TSH-suppressive therapy with excessive T4 doses have lower quality-

of-life and psychometric functionality scores.89 Asymptomatic controls given 100mcg of T4

daily can suffer thyrotoxic symptoms initially.90 Excessive T3-for-T4 substitution therapy also

reduces quality of life. (Appendix) T4 and T3 are not drugs. Thyroid supplementation that

makes an individual feel and function better and produces no signs or symptoms of excess

must be considered necessary and beneficial until proven otherwise.

5 T3 and the ineffectiveness of TSH-T4-normalizing T4 therapy

These assumptions are also contradicted by the evidence. Oral T4 monotherapy is an

unphysiological intervention into a highly complex system. Studies of TSH-normalizing T4

therapy (TSHT4Rx) in primary hypothyroidism consistently show that it does not restore

clinical euthyroidism in most persons, at any TSH or FT4 level within the range. Patients

receiving TSHT4Rx display significant impairment in psychological well being, health status,

and cognitive function compared to controls.91,92,93 They have more depression and anxiety

and their symptoms are worse with higher TSH levels within the range.94 They are twice as

likely to be taking anti-depressant medications.95 They have higher hypothyroid index

scores and body-mass indices,96 and 21% greater fat mass than controls.97 They have

persistent endothelial dysfunction [98] and an increased risk of cardiovascular morbidity.99

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After thyroid ablation, patients on TSHT4Rx gain weight (avg. 4kg) whereas those on TSH-

suppressive therapy do not.100

The use of the TSH to guide to T4 therapy was definitively tested when four experienced

clinicians adjusted the T4 doses of 148 hypothyroid patients based on clinical criteria, using

signs and symptoms as quantified by the Wayne index.101 After dose adjustment, for

patients they judged to be clinically euthyroid, the treated TSH 2 S.D. range was <0.1-

13.7mIU/L (conventional range: 0.35-5.0mIU/L). The treated FT4 range was 50% higher than

the conventional range (12-36pmol/L vs. 9-25pmol/L). Only the treated FT3 range was

similar to the conventional range (3.0-8.6 vs. 2.9-8.9pmol/L). With T4 therapy, the TSH was

the least accurate measure of euthyroidism and the FT3 the most accurate.

As this study suggests, the explanation for the inadequacy of TSHT4Rx is found in the T3

levels. Serum T3 reflects the amount of T4-to-T3 conversion throughout the body and thus

the T3 levels and action in the tissues. Patients with untreated primary hypothyroidism

are much less symptomatic if their FT3 is normal rather than low.102 TSHT4Rx produces

higher FT4 levels, but lower T3 levels than in controls.103,104,105,106,107,108,109,110 T4-treated

patients can have the same 24-hour urine T3 levels as untreated hypothyroid patients.111

After thyroidectomy the restoration of pre-operative T3 levels requires T4 doses that either

suppress the TSH112 or produce T4 levels 40% higher than before surgery.113 On TSH-

suppressive T4 therapy, a FT4 that is 66% higher than controls produces the same T3 level

and no symptoms of hyperthyroidism.114 Patients on T4 therapy feel better when their TSH is

suppressed below its range and their FT4 and FT3 are in the upper half of their ranges.115 In

SH the TSH can be normalized with T4 doses of only 25 to 50mcg, whereas the average

replacement dose is 145mcg/day.116 These low T4 doses do not improve symptoms or raise

T3 levels;117 they often lower the patient’s T3 level.118 T4 therapy given to “euthyroid”

women to lower their TSH to the bottom of the range had no effect at all on parameters of

thyroid status.119 Raising or lowering patient’s TSH-normalizing T4 dose by 25mcg also had

no effect on symptoms. 120 The ineffectiveness of TSHT4Rx has led some investigators to

recommend adjusting T4 therapy according to the T3 level.121,122 In a trial comparing T3-only

and T4-only therapy titrated to the same normal TSH value, The TSH-normalizing T3-only

therapy produced no negative effects but did produce an average weight loss of 2.1kg with a

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5% decrease in total fat mass. T3 therapy and lowered total and LDL cholesterol levels by

more than 10% and apoliprotein B by 18%.123

Why are T3 levels and effects so low in TSHT4Rx? There are many reasons. First, there is

no guarantee that the treated patient has perfectly vigorous TSH production to start with. If

there is any degree of central hypothyroidism, any lack of vigor in the TSH response, TSH

normalization will produce undertreatment. The aging process reduces HP function, and

middle-aged adults most often receive thyroid treatment and are most often included in

studies. Even if TSH secretion is perfectly vigorous in a given patient, the HP feedback

control system evolved to interact with the thyroid gland’s continuous production of T4 and

T3 and with the various deiodinases. It did not evolve to tell physicians how much T4 a

person should swallow every morning. T4 monotherapy must often produce

supraphysiological serum T4 levels in order to normalize T3 levels within the HP system, and

thus normalize the TSH level. This is true even though the HP system is more sensitive than

other tissues to circulating T4. The thyrotrophs can increase D2 expression to maintain intra-

pituitary T3 production at higher T4 concentrations,124,125 whereas outside the HP system D2

is suppressed by higher FT4 levels.126 D2 in skeletal muscle is the major source of circulating

T3.127 Therefore, the supraphysiological T4 levels that can normalize or suppress the TSH do

not produce proportionate increases in serum FT3,128 which represents T3 production

throughout the body.

The higher FT4 levels on T4 therapy also induce D3 action, promoting the conversion of

T4 to reverse T3 (RT3). RT3 is not only inactive, but also inhibits T4-to-T3 conversion.129 On

TSHT4Rx, RT3 levels are often high;130 they are 50% higher than on T4/T3 therapy that

produces the same TSH.131 In sum, normalizing the TSH produces “euthyroidism” in the HP

system, but not in the rest of the body.

Whereas endogenous T4 and T3 production are essentially constant over 24hrs, oral

dosing releases the entire day’s hormone into the circulation within a few hours. The peak

FT4 levels at 3hrs. after a T4 dose are 13% to 36% higher, and FT3 levels 8% higher than at

the 24hr trough.132,133,134 Even so, little variation is seen in TSH levels on once-daily T4

therapy,135 indicating that the T4 peaks may have a stronger and longer-lasting effect on the

HP system than the rest of the body. When hypothyroid patients are given a single dose of

50mcg T4, their TSH drops by 30% at 6 hrs. but their T4 and T3 levels do not change. 136 In

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rats, rapid T4 infusions suppress the TSH for over 22 hours;137 only a continuous T4/T3

infusion produces tissue thyroid sufficiency without suppressing the TSH.138

Furthermore, the reduction in TSH with T4 therapy reduces thyroidal production of both

T4 and T3; the amount of T4 supplied may not compensate for these reductions, especially

when low T4 doses are given to normalize a mildly elevated TSH. Lowering the TSH with T4

therapy also reduces T3 production throughout the body. TSH stimulates D1 and D2 activity

in the periphery,139 where approximately 75% of T3 in the serum is produced.140 In

thyroidectomized dogs on T4 therapy, TSH-injections raise serum T3 levels by 40% while

lowering T4 levels.141 The T3:T4 ratio in primary hypothyroidism with its high TSH is double

that in CH.142

Some patients may be sufficiently treated TSHT4Rx, but in my experience careful

questioning reveals persisting hypothyroid symptoms; and some are markedly hypothyroid.

Their FT4s may be only mid-range or low-normal and FT3s low-normal or low. Those with

high-normal or high FT4s usually have high-normal or high RT3s, reducing the effectiveness

of the therapy. Consider that in CH, where the TSH cannot be used to guide treatment,

merely normalizing the FT4 with oral T4 is known to be insufficient,143 leaving the FT3 low in

one-half of patients.144 In central hypothyroidism most guidelines recommend keeping the

FT4 above the middle of range. However, with no TSH to promote T4-to-T3 conversion, this

too is inadequate. The nearly universal weight gain with central hypothyroidism

(“hypothalamic obesity”) is iatrogenic; the addition of T3 to T4 therapy produces weight loss

and eliminates hypothyroid symptoms.145 Some experts recommend keeping the FT4 near

the upper limit and FT3 in the upper half of the range,146 while others recommend

monitoring clinical indices of thyroid action.147 Persons with central hypothyroidism are

sometimes grossly undertreated by physicians who try to keep their TSH within the ref.

range, to escape the grip of TSH-based thyroidology.

6 TSH-suppression on thyroid replacement therapy does not imply

thyrotoxicosis

Because of the AACE/ATA’s endorsement of the TSH as the “best test”, physicians and

even thyroid researchers assume that a low TSH level on thyroid replacement has the same

implications as endogenous hyperthyroidism,148 and will cause bone loss, muscle wasting,

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cardiac dysfunction and atrial fibrillation. However, some experts disagree. The Royal

College of Physicians states that sufficient T4 therapy may produce a below normal serum

thyroid stimulating hormone,149 and senior thyroidologists have asserted that “Some

patients achieve a sense of wellbeing only if free T4 is slightly elevated and TSH low or

undetectable. The evidence that this exogenous form of subclinical hyperthyroidism is

harmful is lacking… and it is not unreasonable to allow these patients to take a higher dose if

T3 is unequivocally normal”.150

The TSH test is simply the wrong test, both for any patient and for scientific studies. It is

not a measure of thyroid hormone levels or effects in the untreated state, and is even less

relevant in the unphysiological treated state. Since TSHT4Rx is usually inadequate, sufficient

treatment must produce a low or suppressed TSH in most persons. True, a suppressed TSH

will be seen with overtreatment too. It is also true that persons with certain underlying

conditions will have negative effects with otherwise optimal thyroid replacement therapy.

What matters in every patient, whether untreated or treated, are the clinical status as

indicated by signs and symptoms first, and the FT4 and FT3 levels second.

There is plenty of evidence, for those who need it, showing that TSH-suppressive therapy

(TSHSupRx) does not equal hyperthyroidism. Calorimetry studies in thyroidectomy patients

on TSHSupRx show no increase in metabolism compared with the pre-surgical state.151 A

large study of T4-treated patients grouped by TSH levels found that those with low but not

suppressed TSH levels (0.04-0.4mIU/L) had no increase in cardiovascular disease,

dysrhythmias, fractures, or mortality compared to those with normal TSH values. Only those

with completely suppressed TSH levels had some increase in morbidity,152 as expected since

some patients with suppressed TSH levels may be overtreated. Another study found no

increase in morbidity with suppressed TSH levels; and the average T4 level was only mid-

range.153 It’s the wrong test.

The benign nature of a low or suppressed TSH with T4 therapy contrasts sharply with the

thyrotoxicosis seen in persons with similarly low TSH values caused by endogenous

overproduction, again revealing the disconnect between endogenous and supplemented

TSH levels. Patients with endogenous subclinical hyperthyroidism have signs and symptoms

of thyroid excess even though their TSH is only slightly low (avg. 0.15mIU/L). Their FT4 and

FT3 are both in the upper thirds of their ranges,154 a pattern not seen with a similar TSH on

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T4 therapy. In endogenous hyperthyroidism, FT3 levels are uniformly high, a result that is

hard to achieve with T4 therapy.

TSHSupRx has been associated with increased bone loss in some studies—and most

physicians believe that a low TSH on TRT heralds bone loss. However, thyroid hormone does

not cause bone loss. Any increase in thyroid levels-effects increases metabolic activity

throughout the body, including the rate of bone turnover. If a person is in a bone-catabolic

state—is losing bone—higher thyroid levels will speed the bone loss and lower levels will

slow the loss. Men and women begin losing bone at around age 30, and women suffer a 10-

year period of accelerated bone loss around menopause.155 This bone loss with age is

primarily due to reduced estradiol and testosterone levels. Menopausal women are thus

most at risk for excess bone loss with TSHSupRx;156 which is preventable with estrogen

replacement.157 Conversely, adolescent females, in a hormone-sufficient bone-anabolic

state, have increased bone mineral density on TSHSupRx.158 Bone loss is not seen in men on

TSHSupRx,159 as they retain significant testosterone and estradiol levels. The solution to

bone loss is not to keep all patients hypothyroid, but to assure sufficient levels of bone-

anabolic hormones and Vitamin D3.

Muscle wasting is seen only in endogenous hyperthyroidism where FT3 and FT4 levels are

2 or more times the upper limit of their ranges. Due to the fast metabolism, more calories

are needed. Muscle is broken down for gluconeogenesis if the diet does not supply

sufficient calories. Anti-thyroid therapy that lowers the FT3 and FT4 to high-normal levels

eliminates muscle breakdown, even though the TSH remains low.160 Again, this problem is

due to high FT3 and FT4 levels, not a low TSH level.

Thyroid hormone effects exist on a continuum in the cardiovascular system too.

Hypothyroidism with its inadequate T3-effect produces high blood pressure, atherosclerosis,

bradycardia, cardiac dysfunction and congestive heart failure. Hyperthyroidism, on the

other hand, overstimulates the heart producing hyperkinesis, increased heart rate,

excessive contractility, impaired diastolic relaxation, and thickening of the walls of the

heart.161 These changes increase cardiac work and reduce exercise tolerance. Patients on

TSHSupRx with an excessive T4 dose have echocardiographic and ergometabolic signs of

thyroid hormone excess;162 especially when there is clinical evidence of thyrotoxicosis.163

Lowering the T4 dose eliminates the symptoms and cardiac abnormalities, even though the

14

TSH remains low.164 A study of athyreotic patients on TSHSupRx found no cardiac symptoms

and cardiovascular studies were similar to controls. The FT4 was high but the FT3 was

identical to that of the controls.165 The authors concluded that in the absence of symptoms

of thyrotoxicosis, patients treated with TSHSupRx may be followed clinically without

specific cardiac laboratory studies. Again, the TSH level during TRT is irrelevant.

Perhaps the main reason that physicians fear a low TSH during TRT is the risk of atrial

fibrillation (AF). This is a valid concern, but must be understood in context. AF is common,

affecting 1 in 25 of persons over 60 and 1 in 10 of persons over 80.166 By the age of 80, a

person has a 22% lifetime risk of AF.167 Risk factors for AF are prevalent in the population. In

addition to age they include family history, obesity, sleep apnea, diabetes, alcohol use and

many medical disorders. It is true that any increase in thyroid hormone levels or effects

increases automaticity and trigger activity in the pulmonary vein myocytes which initiate

AF,168 and thereby increases the risk of AF in susceptible persons. The prevalence of AF rises

with higher endogenous FT4 levels within the reference range: from only 3% near the

bottom to 7% near the top of the range.169 Therefore any attempt to increase thyroid

levels/effects with TRT entails a risk of triggering AF in susceptible patients; it does not

require overtreatment but would be more likely with overtreatment. Logically, then,

clinically-effective T4 or T4/T3 treatment that suppresses the TSH entails a higher risk of AF

than less effective therapy that leaves the TSH within the normal range. The AACE/ATA TSH-

based guidelines do minimize the risk of AF, but at the cost of universal underdiagnosis and

undertreatment. This is neither medically nor ethically justifiable. The patient has the right

to choose effective therapy. The physician and patient must weigh the risk of AF against the

health and quality-of-life benefits of optimal thyroid levels and effects. The physician can

resolve the ethical dilemma by obtaining informed consent for thyroid optimization therapy,

with specific mention of the risk of AF. Fortunately, AF induced by TRT usually resolves with

reducing the dose, except in older patients with significant underlying heart disease.170

7 The greater efficacy of T4/T3 combination therapy

The elevation of the TSH in the face of thyroid gland dysfunction is a compensatory

mechanism, stimulating more thyroidal production and greater T4-to-T3 conversion

throughout the body. Lowering the TSH with TRT interferes with these mechanisms,

15

reducing both thyroidal and peripheral T3 production. T3 production is reduced in central

hypothyroidism due to inadequate TSH production. It is thus only logical that TRT should

include T3 in addition to T4; especially when the TSH is low or suppressed. In addition, some

16% of persons have a genetic polymorphism of their D2 gene that impairs T4-to-T3

conversion. They have lower quality of life scores on T4 therapy and significant

improvement with the addition of T3.171 TSH and TRH also directly induce mitochondrial

biogenesis and activity;172,173 higher T3 levels help to compensate for their absence.

The effects of T4, T3 and T4/T3 combination therapy in various tissues and organs were

revealed in a series of experiments with thyroidectomized rats. The investigators

determined both serum and post mortem tissue levels of T4 and T3 in rats receiving

continuous thyroid hormone infusions. A T3-only infusion failed to restore T3 levels in all

tissues—illustrating the importance of T4-to-T3 conversion.174 A continuous T4-only infusion

failed to restore T3 levels in the serum and some tissues until T4 levels were

supraphysiological and the TSH suppressed,175 identical to our experience with oral T4

therapy in humans. A continuous infusion of T4 and T3 in the same ratio produced by the

rat’s thyroid gland (6:1) allowed a normalization of both serum and tissue levels of both

hormones without suppressing TSH.176 This implies that if we could give patients

continuous infusions of T4 and T3 in the human thyroid’s 14:1 ratio 177 we might need to

only normalize the TSH in pure PH, where TSH production is vigorous (no partial CH).

However, due to the peak levels with once-daily oral T4/T3 therapy, TSH production is

over-suppressed, reducing thyroidal output and peripheral T3 production. To

compensate and achieve optimal T3 effects in all tissues we need to include T3 in TRT.

Many studies have compared various T4/T3 combinations with T4-only therapy. They

provide abundant detailed clinical data on the effects of substituting various amounts of T3

for T4. In most studies, the doses were adjusted to keep the TSH normal; so they compared

two forms of undertreatment. Still, in 4 of 14 studies, the authors concluded that T4/T3

therapy was superior. In the other 10 studies the differences generally favored T4/T3, for

many if not most of the patients. Typically, authors dismissed non-significant trends favoring

T4/T3 and the patients’ usual blinded preference for combination therapy.

Statistical conclusions can be misleading; if one-half of the patients improve and one-half

deteriorate, the result is no change. One must separate the two groups and determine why

16

they reacted as they did. While oral T3 is generally 3 times more potent than T4178 there can

be a 3-fold range in their relative potency in various persons with treatment.179 Arbitrary

substitutions will produce over-replacement in some persons and under-replacement in

others. Doses that produce negative symptoms do not have to be excessive doses. The

patient may have underlying hormonal or other medical conditions that make them

intolerant of youthful/optimal thyroid hormone effects. We know that thyroid replacement

worsens cortisol deficiency, so if the patient has any degree of hypocortisolism, more

effective TRT that includes T3 will produce negative symptoms. Autoimmune diseases

including autoimmune thyroid diseases are associated with lower cortisol levels.180,181,182

Many persons included in T4/T3 studies have Hashimoto’s or Grave’s disease, and in my

experience these patients often cannot tolerate effective TRT due to a relative cortisol

deficiency.

From my review of the existing T4/T3 studies (see Appendix), I draw the following

conclusions:

1. Patients on TSH-normalizing doses of either T4 or T4/T3 have higher symptom scores

than euthyroid controls, as noted in other studies. They are undertreated.

2. At any given TSH level, T4/T3 combination therapy is more effective than T4

monotherapy, in objective scales and especially in subjective effect.

3. Higher thyroid doses that produce low or suppressed TSH levels usually produce better

clinical effects; both with T4 and T4/T3 therapy; but some patients do not tolerate such

doses.

4. Arbitrary substitutions of some amount of T3 for T4 can produce under- or over-

replacement in a significant number of patients.

5. Persons with low-normal or low TSH levels on T4 treatment experience the greatest

improvement with adding T3 to their regimen; consistent with the fact that they have

less thyroidal and extra-thyroidal T3 production.

6. T3/T4 therapy is safe and causes no problems due to fluctuations in T3 levels, even with

once-daily T3 doses.

In sum, the T4/T3 combination studies support the hypothesis that the addition of T3 to

T4 therapy is beneficial for most if not all patients, and also support the need for clinical

17

thyroidology—for the adjustment of T4 or T4/T3 combination therapy to produce optimal

clinical effects for each patient, without regard for the TSH level.

What is the ideal proportion of T4/T3 for oral thyroid replacement? I do not know; it

probably varies from patient-to-patient. Once-daily oral replacement certainly requires a

lower T4/T3 ratio (more T3) than thyroidal production due to the factors mentioned above.

This explains the popularity (with patients) and efficacy (in my and other clinicians’

experience) of natural desiccated thyroid (NDT) products. NDT has a T4:T3 ratio of around

4:1, similar to the optimal ratio found in the T4/T3 study by Taylor. 183 This ratio provides

much more T3 than thyroidal production; whether a different ratio would be best for most

persons is a project for future research. NDT is the only T4/T3 combination product

available in the USA at this time. In Europe, synthetic combination products are available

with T4:T3 ratios varying from 4:1 to 10:1. NDT was the only form of TRT prescribed in the

United States until the 1970s when synthetic T4 became available—it worked perfectly well

for millions of patients for many decades. Pharmaceutical NDT brands in the US (Armour,

Nature-Throid, NP Thyroid) are USP-certified, meeting the same standards for consistency as

synthetic T4 and T3 products. They provide and convenient and inexpensive form of T4/T3

combination therapy. NDT may have advantages over synthetic T4/T3 combination therapy.

NDT is composed of whole thyroid gland; it also contains T2 which has metabolic

activity.184,185,186 60mg (1 grain) of Armour Thyroid® contains 38mcg of T4 and 9mcg of T3. In

spite of its decades of successful use, physicians often claim that it has not been studied. In

fact, Armour Thyroid was recently compared to T4 therapy in a randomized, double-blind,

crossover study. With doses adjusted to achieve the same normal TSH level, the clinical

differences favored Armour and there were no adverse effects. Judged by its efficacy in

lowering the TSH, 1mg of Armour Thyroid was found to be equivalent to 1.5mcg T4. 187 So

60mg of NDT is similar in its effect on the TSH to 90mg of levothyroxine.

8 The clinical diagnosis of hypothyroidism

Clinical thyroidology requires all the skills of clinical medicine: taking a history, gathering

the symptoms, querying the patient for diagnostic clues, and performing a focused physical

exam. The diagnosis of hypothyroidism requires clinical suspicion; the physician must be

aware of the many symptoms that can be caused by hypothyroidism, (Table 1.) and must

18

consider the diagnosis whenever there are no other medical explanations for the patients

symptoms. While there are classical signs and symptoms of hypothyroidism, many persons

have atypical presentations. The diagnosis of hypothyroidism, as of other diseases and

disorders, is the clinician’s theory; the best theory that he/she can produce to explain the

patient’s history, signs, symptoms and laboratory tests. The ultimate test of any diagnostic

theory is a therapeutic trial.

An often-overlooked problem that mimics hypothyroidism is iron deficiency. It is

common in females due to menstruation. Iron deficiency even seems to reduce thyroid

levels and effects.188 Non-anemic women with fatigue and ferritin levels under 50ng/ml

experience improved energy with iron replacement therapy.189,190 Young women with ferritin

levels under 20ng/ml experience improved energy and mental function with replacement. 191

Anemia does not occur until ferritin levels are <5ng/ml or so. Thus a normal hemoglobin and

hematocrit does not rule out symptomatic iron deficiency. So if a female’s ferritin is very

low, I will usually try to see how much benefit will be obtained with optimizing her iron

levels first; even when FT3 and FT3 levels are rather low.

Initial thyroid testing should include a FT4, FT3 and TSH level. The TSH is, logically,

unnecessary for assessing thyroid hormone status. However it is inexpensive, readily

available, and provides immediate evidence regarding thyroidal and HP function. Elevated

total and LDL cholesterol levels suggest hypothyroidism. A serum prolactin may be mildly

elevated in hypothyroidism. Thyroid antibody testing is not relevant to either diagnosis or

treatment of hypothyroidism, but does help determine the cause of PH. Persons with

Hashimoto’s thyroiditis need not be treated, even if the TSH is elevated, as long as they feel

and function well. As stated above, many of them have rather low cortisol levels/effects and

may not tolerate T4/T3 optimization therapy. Small doses of levothyroxine that satisfy the

physician’s desire to see a normal TSH on laboratory testing may make the patient

hypothyroid or may reduce cortisol levels/effects so as to cause negative symptoms (heart

racing, fatigue, anxiety, insomnia, etc.). I have many Hashimoto’s patients who did not

require TRT and did not progress to overt hypothyroidism.

When the patient has symptoms and/or signs that can be explained by hypothyroidism

and has relatively low FT4 and/or FT3 levels, the physician should offer him/her a trial of

thyroid optimization therapy. The greater the number of hypothyroid symptoms and signs

19

and the lower the FT4 and FT3 levels, the more certain is the diagnosis and the response to

therapy. Certainly, any person with unexplained chronic fatigue, myalgias, depression,

and/or cognitive dysfunction and relatively low thyroid hormone levels should be offered a

therapeutic trial. If the patient experiences few benefits or worsens, then either they do not

have hypothyroidism or they have hypothyroidism plus cortisol deficiency or some other

disorder(s).

The TSH is irrelevant to diagnosis. In fact the TSH level is normal in the majority of

patients who consult me with symptoms of hypothyroidism and low-normal FT4/FT3 levels,

and who respond well to T4/T3 optimization therapy. They thus have a form of

dysfunctional CH, mixed CH-PH, or some form of thyroid resistance. In untreated persons,

the FT4 is the more sensitive test of thyroid status192 as the FT3 is usually maintained by

enhanced T4-to-T3 conversion. Symptomatic patients usually have a FT4 level between 0.7

and 1.2ng/dL (with assays that have an upper limit of 1.6 to 1.8nd/dL) and a mid-range or

low-normal FT3 level. A mid-range FT4 with a low-normal FT3 also suggests hypothyroidism;

and if both FT4 and FT3 are low-normal, the patient can be markedly hypothyroid.

Myxedema coma has been reported with such levels.193 A relatively high FT3 can

compensate for a relatively low FT4, maintaining clinical euthyroidism. Again, the primary

criterion must always be the clinical state of the patient.

TSH-normal patients with hypothyroid symptoms and low-normal thyroid hormone levels

usually respond very well to effective treatment; others have reported the same.194 The

treatment of patients with normal TFTs is often dismissed by quoting a single study in which

symptomatic persons were given a fixed dose of 100mcg T4. It decreased the TSH to a lower

point within range, increased the free T4 slightly, and did not increase the FT3. 195 Such

subreplacement doses of inactive T4 cannot improve most patients’ thyroid status long term

and can even make patients more hypothyroid, as discussed above. This was clearly not an

inadequate trial. What does constitute an adequate trial of TRT?

9 Clinical T4/T3 thyroid optimization therapy

At this point, I can only discuss what I have learned from my own experience in

attempting to optimize thyroid hormone levels and effects with T4/T3 combination therapy

in more than a thousand patients with hypothyroidism of various kinds and degrees. The

20

therapeutic goal is simple: The elimination, as much as is possible, of all symptoms and signs

of hypothyroidism (Table 1.) without producing any signs or symptoms of thyrotoxicosis

(Table 2.). The optimal dose is ultimately a decision reached by the physician and patient

together—in light of the FT4 and FT3 levels. This is clinical thyroidology; it cannot be

reduced to a number, scheme, scale, or a rule.

I prescribe NDT preferentially, and adjust the dose by clinical criteria first and by the free

hormone levels second, without regard to the TSH. As the TSH is usually normal initially, it is

usually suppressed with therapy, often with initial doses that are clearly insufficient. Even in

pure PH, clinically-optimized T4/T3 therapy usually suppresses the TSH, but there are some

patients who seem well-replaced whose TSH is normal.

Thyroid optimization therapy is one of the most powerful medical interventions a

physician can make; it has powerful effects in every tissue. The physician who attempts to

provide optimal T4/T3 replacement therapy must understand the actions of T3 in the

various tissues/organs of the body, the interactions of oral T4/T3 with the patient’s own

thyroid production system, the first-pass effects of oral T4/T3 therapy on the liver, and the

effect of higher thyroid levels on other endocrine and somatic systems. Every patient is

different; one cannot apply a simple algorithm.

With the initiation of oral T4/T3 therapy, the exogenous hormone initially adds to the

patient’s endogenous levels until his/her TSH and endogenous production decline,

necessitating a dose increase. Thus it’s best to start T4/T3 therapy at a low dose and

increase it at weekly or bi-weekly intervals to a moderate replacement dose, then test after

6 to 8 weeks. In the first months, one tries to obtain some symptom resolution and good

T4/T3 levels. Patience is required because clinical improvements can continue to occur after

many months on a sufficient dose. I have found it most efficient to begin healthy patients on

30mg of NDT (19mcg T4 + 4.5mcg T3) daily upon awakening. Once-daily AM dosing with

NDT generally works well, but some patients feel better with splitting the dose. In healthy

patients who appear to be cortisol-sufficient, I increase the dose by 30mg each week up to

120mg or more depending on body weight. In ill or elderly patients or those with suspected

cortisol deficiency I will use 15mg NDT tablets and the dose every two weeks up to only

90mg daily. I then adjust the dose by clinical criteria and the 24hr. trough FT4 and FT3

levels. I do not tell patients to abstain from eating breakfast or drinking beverages for 1 to 2

21

hrs after their morning dose. Such recommendations are impractical for most people. I tell

them to take their dose immediately upon awakening and then go about their usual

morning routine. If with that routine, with their usual timing of eating and drinking, they

tend to absorb less thyroid hormone, I will increase the dose as needed. NDT is inexpensive

and there is no need to suffer every morning in order to maximize its absorption. I do advise

them to continue to follow the same routine.

Blood should be drawn in the morning, prior to taking the thyroid dose. The timing of the

test is important as after a daily dose of NDT the FT3 levels are supraphysiologic for several

hours. This is necessary because NDT contains more T3 and less T4 compared to thyroidal

production. T3 has a relatively short half-life of 17 to 24hrs, and its levels peak at 3 hrs. after

a dose. T4 have a half-life in the serum of one week and much lower peaks after an oral

dose. Most healthy persons who are well replaced on once-daily NDT therapy will have a 24

hr. trough FT4 that is low-normal, around 1.0 to 1.3ng/dL, and a FT3 that is in the upper half

of range or even slightly high. The high FT3 levels through much of the day on NDT are of no

concern and do not represent overdosing. FT4 circulates in amounts 4 times greater than

FT3, and every molecule of T4 can be converted to T3. So a proportionately higher FT3 is

needed to compensate for a lower FT4 on NDT. The high-normal or high 24 hr. avg. FT3 level

compensates for the rather low level of FT4. As the TSH is usually suppressed, more T3 is

needed to compensate for the reduced T4-to-T3 conversion. NDT thus is well-suited to the

non-physiological process of TRT. Excessive NDT dosing should be suspected when the FT4 is

high-normal and the FT3 high-normal or high at trough. RT3 levels are generally normal on

NDT. A high RT3 may indicate overtreatment as the body protects itself by converting more

T4 into RT3 instead of T3. A normal RT3 on NDT therapy provides some assurance that the

dose is not excessive. However, FT4, FT3, and RT3 levels are only indirect indicators of end-

organ effect. The primary determinant of optimal dosing must always be clinical criteria. A

small number of my patients require FT4 and FT3 levels that are both high in order to feel

well, and have no signs or symptoms of overdosing. We must treat the patient, not the

numbers.

22

Perhaps the best way for physicians to begin prescribing T4/T3 therapy is to add 5mcg T3

tablets to the existing T4 regimen for their patients who remain symptomatic on TSHT4Rx.

The T3 dose can be gradually increased by 5mcg

every 6 weeks according to clinical criteria and

FT4-FT3 testing. The TSH will become low or

suppressed. The physician can be confident that

the patient is not overtreated if there are no signs

or symptoms of thyrotoxicosis and the trough FT4

and FT3 are normal with ratios of 5:1 to 10:1. In

my experience, the 4:1 ratio of NDT works well for

most persons, but a higher ratio may be better in

general or for particular patients. The

combination of a 25mcg tablet of T4 with a 5mcg

of T3 is slightly higher dose than 30mg NDT. To

use this 5:1 ratio, the healthy patient can start with one tablet each, and add one more of

each every week or two up to 3 tablets each (75mcg T4 + 15mcgT3). A higher ratio may

work well, and a few patients require a lower ratio or even T3-only therapy to eliminate

their hypothyroid symptoms.196,197,198 On T3 monotherapy the FT3 must be high at all times,

even at the 24hr. trough, in order to compensate for the complete absence of the more

abundant T4.

Any persistent signs or symptoms of thyrotoxicosis and any intolerance of the therapy

require a reduction in the dose, at least temporarily. (Table 2.) It often happens that

patients later need—and benefit from—a dose they were unable to tolerate earlier. As I

have optimized thyroid hormone levels-effects with T4/T3 therapy that suppresses the TSH,

I have seen a phenomenon not described in the medical literature. FT4 and FT3 levels on a

given T4/T3 dose tend to fall in the first year or two and the dose needs to be raised several

times. What I surmise is happening is that even with the suppression of TSH, the thyroid

gland continues to produce significant amounts of T4 and T3. This endogenous production

only gradually declines over a year or two. With TSH-suppressive therapy that is gradual

atrophy of the thyroid gland. With TSH suppression there is also a gradual down-regulation

of D2 and D1,199 reducing T4-to-T3 conversion. This process can even result in

23

Table 2: Signs and Symptoms of Excessive Thyroid Dosing

Increase in malaise or fatigueHeat intoleranceExcessive sweatingIrritability, inability to relax Hand tremorLower exercise toleranceShortness of breathPressured speechPupillary dilatationInsomniaHigh systolic blood pressurePalpitations or rapid heart rateFrequent premature atrial or ventricular contractions

hypothyroidism with a suppressed TSH on T4/T3 combination therapy. So it is very

important to monitor FT4/FT3 levels every 3 months or so for the first 18 months. After 2

years one can generally reduce the frequency of testing to once yearly. However, patients

will sometimes change their morning routine and start eating or drinking sooner after their

thyroid dose, causing a decline in their levels and a return of symptoms.

After obtaining good serum levels and clinical effect, testing should be done every 3 to 6

months in the first 2 years. After that time the FT4 and FT3 levels generally remain stable on

a given dose. The physician can then see the patient once per year to reassess the clinical

criteria and FT4/FT3 levels. The physician and patient decide together whether to keep the

dose the same, or try a higher or lower dose to see if a better clinical result can be obtained.

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24

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