Hypothyroidism and thyroid hormone resistance are under-diagnosed
conditions that affect millions of Americans and significantly
contribute to the risk of cardiovascular disease and cancer.
The reason for under-diagnosis is twofold: first patients
believe that their symptoms are a normal part of aging and
second, physicians who take the time to investigate the
thyroid are misled into believing that if the TSH and other
lab values are normal, then function of thyroid hormones
is normal. Physicians are further persuaded by advertising
campaigns that Synthroid is the best treatment of low thyroid
when in fact it is probably the least effective method of
treatment. This paper will discuss the physiology of thyroid
hormones, diagnosis of hypothyroidism and thyroid resistance,
and the drug, nutritional and lifestyle strategies that
may be employed to improve function.
What are the
thyroid hormones and how are they produced?
The thyroid gland is composed of bundles of follicles enclosed
in fibrous capsules. The follicles secrete into the capsules
which store a colloid (suspension) of thyroid hormones and
their constituents such as thyroglobulin. Ribosomes in the
epithelial cells of the follicle walls secrete the carbohydrate-protein
compound called thyroglobulin. This compound is then packaged
in the golgi apparatus of the cells and secreted into the
colloid. The thyroid hormones actually form extracellularly
in the colloid rather than in the cells of the gland, making
thyroid hormone production unique among the endocrine glands.
The microvilli of the follicular cells produces an enzyme
called human thyroid peroxidase. This enzyme oxidises iodide
molecules trapped in the colloid into iodine (the active
form of the iodide molecule). This reaction produces peroxide
radicals which must be neutralized by antioxidants. The
iodine then combines with the amino acid Tyrosine to form
mono-iodotyrosine or T1. Then two of these molecules combine
to form di-iodotyrosine, T2. The peroxidase enzyme then
couples a T1 to T2 to form T3 or combines two molecules
of T2 to from T4. T3 and T4 are the thyroid hormones with
How is the
production of thyroid hormones stimulated?
When serum levels of iodine drop, the hypothalmus secretes
thyroid releasing hormone (TRH) from nerve endings in the
medial eminence of the hypothalmus. Another from of stimulation
that encourages the hypothalmus to produce TRH is prolonged
exposure to cold.
TRH in turn stimulates the anterior pituitary to produce
and release thyroid stimulating hormone or TSH. The anterior
pituitary cells that produce TSH are called thyrotrophs.
Thyrotrophs are the same cell type that produces human growth
hormone (HGH). TRH stimulates the production of TSH by promoting
the activity of phospholipase C. This enzyme catalyzes the
hydrolysis of phosphatidyl-inositol 4,5-bisphosphate to
insositol 1,4,5-bisphosphate and 1,2-diacylglycerol. The
1,2-diacylglycerol activates intracellular protein kinase
C which in turn stimulates the production of TSH. TSH in
turn stimulates the thyroid gland to produce and release
T3 and T4.
Calcium is a cofactor in the activation of TSH. In the thyroid
gland, TSH binds to TSH receptors and activates adenylate
cyclase enzyme. In the presence of magnesium, the activated
enzyme induces conversion of ATP to cyclic AMP. Cyclic AMP
activates the production of T3 and T4. There is a7-34% diurnal
variation in release of T4, with the peak at 12:00 noon
and the low at 2:00 AM.
How is the
production of thyroid hormones regulated?
Over-production of thyroid hormones is prevented by a negative
feedback loop. The greater the amount of circulating T3
and T4, the more inhibition of the hypothalmus and anterior
pituitary. Thyroid hormones directly suppress the production
of TRH in the hypothalmus. Thyroid hormones also increase
hypothalamic production of somatostatin, a hormone that
suppresses the pituitary's production of TSH and human growth
hormone (GH). Thyroid hormones also reduce the number of
TRH receptor sites on the somatotroph cells of the anterior
It should be noted that the major feedback loop for thyroid
hormone control is between the anterior pituitary and the
thyroid, the hypothalmus plays a smaller role in adjusting
the amount of thyroid hormone production and release. It
is also important to note that inactive isoforms of thyroid
hormones and even serum iodine can have a suppressive effect
on thyroid hormone production. Interactions with other hormones
will be discussed later.
How do thyroid
hormones get to the cells?
In order for the thyroid hormones to travel through the
blood to reach the cells, a transport protein is needed.
The three transport proteins are thyroxine-blinding globulin,
albumin and transthyretin (thyroxin-binding prealbumin).
All these transport proteins are produced by the liver,
though transthyretin is also produced in the choroid plexus
and thus is the main thyroxine-binding protein in the brain
and spinal cord. In the rest of the body, transthyretin
carries about 10% of the hormone while albumin binds around
15-20% and thyroxine-binding globulin carries about 70%
of the thyroid hormones. Protein malnutrition, alcoholism
and liver disease can impair the production of these carrier
proteins. T3 binds more weakly (is more easily released
into cells) than T4.
How does thyroid
hormone get into the cells?
Thyroid hormones are thought to easily penetrate cell membranes
however, some researchers believe that uptake may be regulated
by changes in the receptor-transporter interaction. The
interaction, "could be analogous to dimerisation of tyrosine
kinases after ligand binding" .
How does T4
become metabolically active in the cell?
The active form of thyroid hormone is T3 but the thyroid
gland releases 14 times more T4 than T3. Thus in the cell,
the T4 must be converted to T3 by type l 5"-deiodinase,
a selenium-dependent enzyme. (Selenium deficiency in rats
decreased enzyme activity by 90%). This enzyme is completely
inhibited by the drug propylthiourcil. Type ll 5"-deiodinase
is most active in the anterior pituitary, the central nervous
system, placenta and brown (high mitochondrial content)
fat. The drug propylthiourcil does not inhibit the type
T4 can also be converted to reverse T3 (rT3) by the enzyme,
5" deiodinase (especially type l 5' deiodinase in the liver).
Reverse T3 is an inactive form of the molecule. The production
of rT3 is thought to be a way the body prevents the accumulation
of excess T3. Both T3 and rT3 are further reduced to T2
(two iodine molecules), T1 (a single iodine molecule) and
T0 (thyronine without any iodine). The half-life of T3 is
one day while the half-life of T4 is about a week. The released
iodine and thyronine return to the thyroid gland for re-assembly
into T4 and T3.
How do the
thyroid hormones work inside the cell to stimulate metabolism?
Thyroid hormone (T3) increases transcription of beta-adrenergic
receptors and decreases transcriptions of alpha-adrenergic
receptors on the cell membrane. Beta-adrenergic receptors
bind with catacholamines such as norepinephrine which increase
metabolism. When catacholamines bind with alpha-adrenergic
receptors metabolism is reduced. By increasing B-adrenergic
receptors, T3 stimulates increased glycolysis and glycogenolysis,
thus increasing ATP production. In short, T3 encourages
the cell to convert fat and glucose into energy.
Thyroid hormone is an insulin antagonist. It stimulates
lipid turnover, free fatty acid release and cholesterol
synthesis. Thyroid maintains calcium mobilization and is
necessary for the contractility of myosin filaments in the
muscles. It is necessary for CNS, skeletal and sexual maturation.
Thyroid hormone is needed for protein synthesis, including
the apoenzymes. Thus T3 deficiency leads to a wide variety
of symptoms associated with reduced enzyme activity.
What is thyroid
Thyroid resistance, also called peripheral cellular resistance,
is the inability of the cell to accept and utilize circulating
thyroid hormone. This is similar to the plight of the NIDDM
patient. Circulating levels of the hormones are normal and
yet deficiency signs and symptoms abound. The mechanism
of action in most congenital cases of peripheral thyroid
resistance is an alteration in the c-erbAB gene. Mutations
in this gene can lead to as much as a 97% reduction in binding
of T3 to the nuclear receptor sites where transcription
of beta-adrenergic receptors occurs.
Resistance may also occur in the form of elevated cortisol.
High levels of cortisol can inhibit conversion of T4 to
T3 and promote conversion of T4 to r-T3 (the inactive form).
Dioxins and PCB's can also bind to transthyretin and presumably
to nuclear receptor for T3, thus competitively inhibiting
T3 binding. Other toxins that are known in animal models
to produce decreased serum levels of T4 and increased rT3
include chlorinated paraffins, polychlorinated biphenyl,
hexachlorobenzene, 3-methylcholanthrene, 3,3',4,4'-tetrachlorobiphenyl,
2,3,7,8-tetrachloro-p-dioxin and clofibrate. Drugs that
reduce T3 and increase rT3 include; dexamethasone, propylthiourcil,
iopanic acid (radiographic contrast agent), amiodarone,
propranalol. Down-regulation of T3 receptors also occurs
in animals under conditions of prolonged fasting or illness,
presumably to prevent catabolic wasting during periods of
caloric deficit. A similar post-receptor effector mechanism
defect is found in the ob/ob experimental mouse, leading
to ob/ob mouse obesity.
What kinds of complaints characterize an under-active thyroid
system? Low energy and fatigue or tiredness, especially
in the morning. Difficulty losing weight, a sensation of
coldness--especially of the hands and feet, depression,
slowed thinking and reaction times, headaches, swelling
of the face or fluid retention in general, dry coarse skin,
brittle nails, chronic constipation, menstrual problems-such
as PMS and menstrual irregularities including heavy periods,
fertility problems, stiffness of joints, muscular cramps,
shortness of breath on exertion and chest pain are some
of the symptoms that can be seen in people with under-active
Other disorders associated with hypothyroidism include headaches,
migraines, sinus infections, post-nasal drip, visual disturbances,
frequent respiratory infections, difficulty swallowing,
heart palpitations, indigestion, gas, flatulence, constipation,
diarrhea, frequent bladder infections, infertility, reduced
libido and sleep disturbances, including the person requiring
12 or more hours of sleep at times. Other conditions include
intolerance to cold and/or heat, poor circulation, Raynaud's
Syndrome, which involves the hands and feet turning white
in response to cold, allergies, asthma, heart problems,
benign and malignant tumors, cystic breasts and ovaries,
fibroids, dry skin, acne, fluid retention, loss of memory,
depression, mood swings, fears, and joint and muscle pain.
What are the
lab tests for thyroid function?
The standard tests of thyroid function are serum levels
of TSH, total T4, Free T4, T3, T3 uptake, Free T3, the T4
to T3 ratio (also known as "T7"), anti-peroxidase and anti-microsomal
antibodies. Most physicians order a T4 as part of a general
metabolic panel (if they have any interest in the thyroid
at all). Physicians monitoring response to thyroid medication
generally watch the TSH as an indicator to direct the dosage
of Synthroid (T4) or other hormone replacements. Older tests
like protein-bound iodine and basal metabolic rate are rarely
used today. Another rare test, the TSH stimulation test
challenges the pituitary with an injection of TRH. A lack
of response indicates pituitary hypofunction or hypothalamus/pituitary
hypofunction. If this test is positive, imaging such at
CT and MRI are required along with other neurological tests
to look for anatomical lesions of the brain, pituitary and
hypothalmus. Uses for the tests are listed below:
A high TSH and low T4 and T3 indicate thyroid gland disease.
High T4 to T3 ratio (T7) or a high r-T3 (another rare test)
are suggestive of peripheral cellular resistance as these
levels indicate a decreased conversion of T4 to T3. Decreased
conversion may also be due to selenium deficiency or mercury
toxicity. If this ratio is high in conjunction with a high
serum or 24 hour urine cortisol, this may indicate cortisol-induced
decrease of T4 to T3 conversion.
Free (unbound) T4 is perhaps the best early indicator of
High free T3 is the best early indicator of hyperthyroidism.
T3 uptake and total T4 levels rise or fall together with
hyper or hypothyroidism. If the levels diverge, the cause
is more likely to be due to abnormalities in transport binding
High T4 and low T3 uptake indicates excess thyroid binding
Low T4 and high T3 uptake indicates low thyroid binding
R-T3 is abnormal in starvation, cirrhosis, insulin-dependent
diabetes and conditions of elevated cortisol such as Cushing's
FTI is calculated by multiplying T3 uptake by total T4.
This is used as a measure of Free T4.
The anti-peroxidase and anti-microsomal antibodies indicate
auto-immune diseases such as Grave's or Hashimoto's. Since
these conditions are associated with hyperthyroidism, I
will not discuss them here other than to point out that
following a hyperthyroid episode, these enzymes inhibit
the production of thyroxine. They also bind with cells of
the adrenals, pancreas and parietal cells of the stomach.
tests can be used?
The most important single test for thyroid function is basal
temperature. The reason for this is that thyroid hormone
increases the conversion of ATP to ADP to power all the
metabolic functions of the cell. In that conversion, 50%
of the energy is released as heat. That heat is needed to
maintain bodily functions by maintaining the proper temperature
range for enzymatic activities necessary for life. Body
temperature is a good measure of basal metabolic rate and
is cheaper and simpler to perform than measuring the rate
of conversion of oxygen to carbon dioxide, which is the
"gold standard" measure of metabolic activity. Basal temperature
is taken by the patient in his or her own bed upon awakening
and before leaving the bed. A basal thermometer is retained
in the axilla and the results are charted in tenths of degrees
Fahrenheit. Daily measurement also provides many data points
by which to assess the effectiveness of therapy.
According to Broda Barnes, MD , if the average temperature
is below 97.8 Fahrenheit, then the diagnosis of a low functioning
thyroid system is likely. An average temperature between
97.8 and 98.2 is considered normal. An average temperature
above 98.2 is considered high and might reflect an infection
or a hyperthyroid condition. At least three days of measurement
are necessary for an average. The basal temperature in menstruating
women is most accurately measured on the 1st, 2nd, 3rd or
4th day of menses(preferably beginning on the 2nd day).
Males, pre-pubertal girls, and post-menopausal or non-menstruating
women may take basal temperatures any day of the month.
Women taking progesterone should not take the drug the day
before and the days when the basal temperatures are taken.
Other tests include Achilles heel reflex time, pulse rate
and reaction times. Physical signs such as dry skin and
hair, loss of the lateral third of the eyebrow may be observed
and a symptom survey can be used to measure thyroid associated
symptoms. Inability to lose weight, high cholesterol, lethargy,
fibromyalgia and sensitivity to cold are common signs and
symptoms. Myxedema appears in the later stages though mild
sub-dermal fat and water retention may be an early indicator
of thyroid hormone dysfunction (it may also indicate excess
steroid hormones such as progesterone).
hormones interact with thyroid function?
Cortisol suppresses TSH production by reducing the sensitivity
of anterior pituitary thyrotrophs to T3. Cortisol also can
inhibit the conversion of T4 to T3 and promote the conversion
of T4 to reverse-T3, which is biologically inactive. Cortisol
clearance from the blood is decreased in hypothyroid patients.
Exogenous thyroid hormones may exacerbate adrenal insufficiency
by increasing metabolic demand. This can be tested with
the ACTH stimulation test. If ACTH (adrenal corticotropic
hormone) fails to stimulate the adrenals to make more cortisol,
then the adrenals are fatigued and would need support in
order to keep up with he effects of thyroid medication.
Estrogen, corticosteroids and prednisone decrease serum
levels of thyroid binding proteins. Exogenous estrogen (birth
control pills) also lower T3 uptake.
Thyroid hormones regulate dopamine synthesis by controlling
the concentration of it's precursor, DOPA. Thus hypothryoidism
results in low levels of dopamine. Dopamine is the main
neural mediator of pleasure.
strategies for hypothyroidism and thyroid resistance syndromes.
While the primary treatment of these conditions is T3 (Cytomel
or Armour), there are nutrition and lifestyle approaches
that may also be helpful.
Tyrosine – the biggest factors The two most important
nutrient deficiencies associated with hypothyroidism are
iodine and the amino acid Tyrosine. In this country, iodine
deficiency is rare as iodine is routinely added to salt
and the American diet is generally high in salt. In undeveloped
countries where iodine is deficient in the soil and little
fish and sea vegetables are consumed, iodine is a major
cause of goiter and a form of physical and mental retardation
known as Cretinism. Some 800,000,000 people worldwide suffer
from iodine deficiency and goiter. The RDA for iodine is
150 mcg per day for adults age 11 and above, 175 mcg per
day in pregnancy and 200 mcg during lactation. Lab tests
for iodine include plasma iodine (by neutron activation
analysis and urinary iodine. Hair trace mineral analysis
may also be used to screen for iodine deficiency. Excess
iodine may cause inhibition of TRH and TSH however. The
dietary intake of iodine in the United States is estimated
to be over 600 . Levels in excess of that amount are not
Tyrosine is the core of the thyroid hormone molecule. A
molecule of thyroglobulin contains 134 tyrosines, although
only a handful of these are actually used to synthesize
T4 and T3. Deficient intake, digestion or metabolism of
tyrosine may be a cause of hypothyroidism. Tyrosine is a
non-essential amino acid in that it can be made from phenylalanine.
However, some people have an enzyme deficiency and thus
have difficulty in converting phenylalanine to tyrosine.
Supplemental tyrosine may be taken in 500-1000 mg doses
Mercury toxicity can block the conversion of T4 to T3. Similarly
Selenium deficiency will also prevent the conversion of
T4 to T3. Selenium is a chelator of mercury and can be used
with dimercaptosuccinic acid to remove mercury toxicity
from the body.
Zinc supplementation re-established normal thyroid function
in hypothyroid disabled patients treated with anti-convulsants.
In a study, 9 of 13 patients with low free T3 and normal
T4 had mild to moderate zinc deficiency. After oral supplementation
with zinc sulfate (4-6 mg/kg body weight for 12 months),
levels of serum free T3 and T3 normalized, serum rT3 decreased
and TRH induced TSH reaction normalized. Since copper exerts
an antagonistic role, high copper may inhibit thyroid hormone
activity. A study of fourteen pre-adolescent hypothyroid
patients and a similar number of controls for serum zinc
levels revealed zinc levels were significantly lower in
the hypothyroid children before supplementation with thyroxine.
The authors suggest that there is an association with zinc
deficiency and thyroid function. A study of twelve hyperthyroid
and seven hypothyroid patients relative to zinc tolerance
found that high levels of zinc excretion were observed in
hyperthyroid cases and zinc deficiency was observed in hypothyroid
patients leading the authors to conclude that zinc levels
were a marker of thyroid function. Zinc and thyroid hormone
levels both decline with age and may be related. Children's
with Down's syndrome have many symptoms in common with hypothyroidism
and are also commonly deficient in zinc, suggesting an association.
Protein deficiency, starvation, cirrhosis or other liver
disease can reduce the amount of transport proteins available
to carry the T4 to the cell. In the case of liver disease,
overall nutrition and specifically, glutathione may be helpful
in promoting normal liver function.
At the level of cellular utillization, CoEnzyme Q10,
magnesium and B vitamins may be helpful as they play
roles in the Krebs cycle. B vitamins might have more direct
roles as well. In animals, B12 deficiency is associated
with slight reduction of type I 5'-deiodinase activity and
with significant reduction in serum T3. In a study of fifty-two
patients under psychiatric care for B-vitamin deficiencies,
it was observed that in the female patients where there
was depression and a low thyroid index, there was also a
deficiency of vitamin B2.
On the other hand, extreme doses of niacin (mean 2.6 grams
daily for an average duration of 1.3 years) revealed significant
decreases in serum T4, T3 and TBG with no alterations in
free T4 and TSH levels. Similarly, lipoic acid taken with
T4 resulted in a 57% reduction in the expected rise in T3
values in just 9 days, suggesting that lipoic acid should
not be taken with exogenous T4. Vitamins C and E only improved
hepatic 5' –deiodinization in conditions of increased lipid
peroxidation due to heavy metal toxicity.
Foods to avoid
Thiocyanate glucosides, substances found in vegetables from
the cabbage (brassica) family, have an antagonistic effect
on the binding of iodine in the thyroid. Persons with hypothryoidism
would do well to limit consumption of raw brussel sprouts,
cabbage, kale, broccoli and cauliflower. Cooking negates
this effect. Soy isoflavones also appear to exert a negative
effect on thyroid hormone activity. Animals fed soy protein
experienced a decline in T4, free T4 and T3 while experiencing
an increase in r-T3. In one study, 37 healthy adults consumed
30 grams of soybeans for 1-3 months. They experienced significantly
increased TSH levels and hypometabolic symptoms suggestive
of functional thyroid hormone deficiency (malaise, constipation,
sleepiness). Goiters appeared in half the subjects. Symptoms
disappeared after one month cessation of soy ingestion.
Caloric restriction should be avoided as this can reduce
metabolic rate up to 20% within 14 days even while exercising.
Decreases in T3, fT3, and increases in rT3 have been found
in a low carbohydrate, 800 Kcal per day diet. On the other
hand, a vegetarian diet can increase the resting metabolic
rate by 11%
Smoking has harmful effects on the thyroid. A study evaluating
one hundred thirty-five female hypothyroid patients and
a similar number of controls relative to cigarette smoking
observed a statistically significant relationship between
smoking and increased levels of hypothyroidism. The authors
conclude that smoking has both a goitrogenic effect and
other basic thyroid dysfunction influences.
Excessive alcohol consumption may be harmful to hypothyroid
patients. Low T3 and T4 levels are found in alcoholic cirrhosis
patients and animals exposed to ethanol have impaired hepatic
5'-deiodiniation, meaning that their liver's ability to
convert T4 to T3 is impaired.
helpful in the short term
Hypothyroidism causes an increase in three inhibitory molecules,
alpha adrenergic receptors, phosphodiesterase and G1 proteins
(the latter increases cellular sensitivity to adenosine
and adenosine receptor binding). Phosphodiesterase inactivates
cAMP. Adenosine activates an inhibitory GTP-binding protein
(G1) that also decreases cAMP formation. I have always advocated
avoidance of caffeine, especially in the form of coffee
however, caffeine in moderate doses inhibits these potent
enzymes phosphodiesterase and adenosine, which are both
metabolic inhibitors. Caffeine, theophylline and theobromine
are also adenosine receptor antagonists. Caffeine has a
half-life of 5.2 hours. It is a central nervous system stimulant
and thus for most people must be avoided before sleep. It
can also exacerbate osteoporosis and fibrocystic breast
disease. In large doses, tolerance develops and various
other disorder may develop, ranging from arrythmia to a
form of mania known as caffeineism. I recommend taking caffeine
in the form of green tea, and only in a dose that does not
overly stimulate the individual. When thyroid hormone levels
have been normalized, the dose of caffeine can be reduced.
Stress in the form of high cortisol can block the conversion
of T4 to T3, and in fact can promote the conversion of T4
to the inactive r-T3. Efforts must be made to get stress
under control. Many modalities such as Tai Chi, Yoga, meditation,
cognitive therapy, etc. can be employed to reduce the response
to stress. Deep breathing is one of the simplest ways to
change to a "rest and digest" metabolic state.
Sleep-deprivation produces elevations of T4, fT4, T3 and
rT3. The long-term implications of this are not clear but
it appears that the thyroid is responding to sleep-deprivation
as a stressful event.
Exercise creates a metabolic demand and is thus an essential
part of the treatment of hypothyroidism. Numerous studies
link both aerobic and anaerobic exercise with increases
in metabolism ranging from 6 to 11% Aerobic fitness, as
measured by VO2 Max has the strongest association with resting
metabolism. Hypothyroid patients must begin an exercise
program with care as stressful exercise (running as opposed
to walking for instance) can induce the release of catacholamines
such as epinephrine and norepinephrine. Hypothyroid patients
have increased alpha-adrenergic receptors and decreased
beta-adrenergic receptors. These hormones would bind to
the alpha-adrenergic receptors in the cell membranes, causing
a decrease in the cellular metabolism rather than the increase
needed to adapt to vigorous exercise. Moderation in all
We should all be aware of this common, under-diagnosed condition
and utilize basal temperature as a standard part of our
examination. While the primary treatment must be thyroid
hormone (a prescription item), we can provide considerable
support by eliminating adverse influences and normalizing