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 biological activity.

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 pituitary.
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 ll enzyme.
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 resistance?
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.

Symptoms of low thyroid
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 thyroid systems.
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 hypothyroidism.
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 proteins.
High T4 and low T3 uptake indicates excess thyroid binding protein.
Low T4 and high T3 uptake indicates low thyroid binding protein.
R-T3 is abnormal in starvation, cirrhosis, insulin-dependent diabetes and conditions of elevated cortisol such as Cushing's disease.
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.

What other 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).

What other 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.

Nutritional 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.

Iodine and 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 recommended.
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 tid.

Mercury and Selenium
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 and liver disease
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.

Krebs cycle nutrients
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.

Dietary restriction vs. vegetarianism
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%

Lifestyle factors
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.

Caffeine, 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 things.

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 micronutrient status.


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