Hormones are named from the Greek word hormon, meaning "to urge or excite", because they were first discovered to play a role in hunger, sex, flight-or-fight response, and many other basic drives. Hormones serve within the body as invaluable messengers, governors of development, and regulators of metabolism. This Hot Topic will focus on the effects of thyroid hormone (TH) and the disorders that are associated with TH imbalance.

TH, found in all chordate animals, is the only major biochemical molecule known to incorporate iodine, a substance common in the sea but rare on land. Iodine is essential to the structure of TH, and iodine deficiency is the leading cause of hypothyroidism in undeveloped countries. TH is produced by the thyroid, a butterfly-shaped gland behind the larynx, in response to thyroid stimulating hormone (TSH), which is released by the pituitary gland.

TH exists in two major forms. Levothyroxine (T4), with four iodine atoms per molecule, is an inactive form that can be converted into T3, and is produced exclusively by the thyroid gland. Triiodothyronine (T3), with three iodine atoms per molecule, is eight times more effective than T4. It is converted from T4 in the thyroid, brain, liver, and bloodstream, and in various tissues of the body.

One important function of TH is helping the body convert food into energy and heat. T3 directly boosts energy metabolism in mitochondria, the powerhouses of cells. T3 triggers rapid protein synthesis and influences mitochondrial gene transcription, the reading of genes and synthesis of proteins from genetic information. These activities cause breakdown of proteins and an increase in free fatty acids, as well as increased oxygen use. TH elevates the heart rate to meet the increased oxygen needs.

TH also regulates body temperature. TSH, which stimulates the thyroid to produce TH, also stimulates brown adipose tissue, a mitochondria-rich tissue, to boost heat production in mammals without muscle activity. TH fluctuates in response to caloric intake and external temperature. During starvation, the body naturally lowers TH, not only to reduce caloric needs, but also to prevent ketone bodies from building up in the blood and kidneys. Ketone build-up, which can also happen in diabetes, can cause damage to the kidneys and other part of the body. Injury and illness lower TH levels, which rebound once the patient is healed.

TH is sensitive to the levels of other hormones besides TSH. Estrogen partially blocks the efficiency of TH, so women compensate by producing more TH than men. This may be why women have larger thyroids than men and are more prone to thyroid disease of all types. Women who take TH replacement pills must increase their TH dosage if they start taking birth control pills, to compensate for the higher levels of estrogen from birth control pills. Growth hormone also partially blocks TH, but it also complements TH in its effects on growth, development, and metabolism.

TH plays a major role in metamorphosis and development in all vertebrates. It affects development by binding to thyroid hormone receptors (TRs), molecules that then change their shape to an activated form. Once activated by TH, TRs can bind to responsive elements in the DNA, triggering gene transcription. The position of the TR attaching to the responsive elements facilitates the copying of some genes, and blocks others from being copied. Two major forms of thyroid hormone receptors exist: TRa and TRb.

TRs are nuclear receptors like retinoid A receptors, Vitamin D receptors, and steroid hormone receptors. TRs change configuration when attached to T3, and this changed configuration allows them to attach to responsive elements in the genome. Nuclear receptors are often dimerized (attached to another nuclear receptor of the same or different type), but they remain inactive until bonded by the usual trigger. For example, thyroid hormone receptors dimerized with retinoid X receptors will not activate until they are bonded with T3 or retinoids (derivatives of Vitamin A).

We still do not know all the genes that are regulated by TH. Some TR-responsive elements in the DNA are Alu elements, which are able to move around in the genome on occasion, creating even more Alu elements in the genome. This allows many different genes to come under the control of TH without the genes themselves mutating. Different species may have different genes under control of TH, especially these concerned with development. For instance, while most mammals show similar symptoms of hypothyroidism (fatigue, apathy, etc.), dogs show the additional symptom of seizures. Most chemicals that cause hypothyroidism do not block thyroid receptors in the genes; they only block the efficiency or synthesis of TH. Hence most of our information about which genes are regulated by TH comes from studying genetic disorders in which the TRs are non-functional.

Resistance to TH is a genetic disorder caused by mutations in the TRb gene. Patients with this disorder have high TH levels and TSH levels, goiter (enlarged thyroid gland), and mild hypothyroid metabolisms. Clinical effects are less severe than with congenital hypothyroidism and can include short stature, delayed bone maturation, hyperactivity, learning disabilities, and hearing defects, as well as mixed features of hyper- and hypothyroidism. This condition is usually inherited dominantly.

Pendred's Syndrome is caused by a genetic defect that limits the incorporation of iodine into thyroid hormone, which wrecks the structure of the hormone. Pendred's Syndrome can cause hypothyroidism with goiter. The body compensates by producing more TSH and working harder to make enough thyroid hormone that works. The syndrome can also cause more serious problems, such as profound deafness, or non-syndromal deafness alone. These symptoms are present from birth. People who develop hypothyroidism later in life may have ringing in their ears and dulled hearing, but these symptoms are usually correctable by TH therapy, while deafness caused by Pendred's Syndrome is not.

TSH receptor (thyrotropin receptor) gene mutations often cause hyperthyroidism, or TSH insensitivity, which leads to normal TH levels in the blood with elevated TSH levels. TSH has unknown effects on lymphocytes and brain cells; therefore imbalances affecting TSH levels may cause additional, unknown effects on the brain and immune system. One mutation was found in association with Graves' disease. Graves' disease is an autoimmune form of hyperthyroidism, and the genes that seem to increase risk of Graves' disease are associated with immunity.

In humans, thyroid hormone plays a notable role in brain development from the middle of pregnancy to the second year of life. Maternal or fetal hypothyroidism, whether caused by lack of iodine during the pregnancy, or by other problems, can cause a non-genetic condition called cretinism. Babies affected by cretinism can develop normal intelligence if the condition is remedied within a few months, but otherwise they suffer severe, irreversible mental retardation. One severe type of cretinism can also be caused by mutations in the TRa gene, and may be untreatable.

Some of the most profound effects of TH imbalance are in the mental arena. Hypothyroid people sleep easily and do not get full refreshment from their sleep. During waking hours, they experience fatigue, apathy, and "brain fog" (short-term memory problems and attention deficits). These problems may affect their daily functioning and cause increased stress and depression.

TH acts as a neurotransmitter. TH imbalance can mimic psychiatric disease because T3 influences levels of serotonin, a neurotransmitter integral to moods and behavior. Low levels of T3 can cause depression. Some anti-depressants make hypothyroid patients feel even worse because the medications depress T3 levels. Paradoxically, some substances labelled depressants such as alcohol or opiates can increase T3 levels by impairing the breakdown of T3 in the brain, thus lifting mood. This may be one reason why these substances are so addictive.

Severe hypothyroidism can cause symptoms similar to Alzheimer's disease: memory loss, confusion, slowness, paranoid depression, and in extreme stages, hallucinations. Thyroid disease is one of the many treatable diseases that must be ruled out before arriving at the diagnosis of Alzheimer's, which is incurable and cannot be definitely diagnosed until after death. Risk of hypothyroidism increases with age; by age 60, 17% of women and 9% of men have symptoms of thyroid disease¹ .

Low TH levels also produce fatigue, slight hypoglycemia (low blood sugar), slowed digestion of food, and constipation. Infertility is common. These symptoms can indicate that other diseases are present, particularly because TH levels tend to go down during prolonged illness in an effort to conserve energy. Chronic disease, such as Lyme disease, can mimic (or cause) hypothyroidism. Hypothyroidism is not difficult to diagnose by symptoms, if the patient reports enough symptoms to the doctor and if the doctor thinks of it. Diagnosis can be confirmed by blood tests, but the cause is less easy to discern.

TH imbalance has a profound effect on cardiovascular fitness because TH helps control heart rate and blood pressure. Under hypothyroid conditions, the heart can slow to 30 heart beats a minute and develop arrhythmia. Blood pressure may fall from normal levels of 120/90 to 70/50. Hypothyroidism also weakens muscles, including the diaphragm. As a result, breathing can become less efficient. A goiter impairs breathing even more. Snoring may start or become worse. Fatigue sets in easily; in fact it never quite leaves a person with symptomatic hypothyroidism. Muscles and joints often ache. With respiration impaired and oxygen in short supply, exercise takes a heavy toll on the body, and muscles do not strengthen in response to exercise; nor does stamina improve.

Low thyroid levels actually trigger muscle fibers to change their type, from fast-twitch fibers to slow-twitch fibers. This may be an adaptive strategy for coping with starvation, since blood sugar is low under hypothyroid conditions and fast-twitch muscle fibers require high levels of glucose to operate. Fatty acid levels in the blood are elevated to provide fuel for the fat-burning slow-twitch muscles. However, low oxygen in the blood due to slow heart rate and respiratory problems limits the slow-twitch muscles' effectiveness.

Even after receiving treatment for hypothyroidism, many people find that their caloric needs and ability to handle exercise have changed permanently. Strength training can help restore their fitness, but only after thyroid hormone levels have normalized. Therefore, hypothyroidism affects the ability of people to undergo both aerobic and anaerobic exercise.

Hypothyroidism is the second leading cause of high cholesterol, after diet. When TH levels drop, the liver no longer functions properly and produces excess cholesterol, fatty acids, and triglycerides, which increase the risk of heart disease. High cholesterol may also contribute to the risk of Alzheimer's disease. Hypothyroid patients may develop yellowed skin due to carotenoid (Vitamin A precursors) deposits in the skin when the liver no longer can store enough. Vitamin A usage and synthesis drops as thyroid hormone levels drop.

Hyperthyroidism is associated with a different set of symptoms. People with this disorder sleep with difficulty and sleep much less than normal. Unlike hypothyroid patients, they exhibit manic-depressive behavior as the TH levels drive their energy levels beyond their physical limits. In fact, thyroid hormone testing is routine at psychiatric admission for suspected manic-depressive patients. Lithium, a common treatment for manic-depression, is known to depress T3 in the brain back to normal levels.

Hyperthyroidism causes accelerated heart rate and fatigue, even when patients are at rest. It produces lower exercise tolerance because protein and fat catabolism are accelerated, resulting in build-up of ketones. Hyperthyroid people often show a fine tremor in their hands. They have higher resting heart rates, but not higher maximum heart rates for exercise, in comparison to normal subjects. Some experience thyroid storms--high overloads of thyroid hormones that accelerate their heart rate to as high as 300 beats a minute. This is a very life-endangering condition and can result in arrhythmia or heart attack.

Some drugs cause a temporary TH imbalance. Caffeine and other stimulants interfere with T3 and adrenal hormone metabolism while in the body. Smoking depresses TH levels and produces an chronic underlying hypothyroidism as well as low adrenal hormone levels. The hormonal imbalances due to smoking may contribute to the severity of withdrawal symptoms in smokers trying to quit. Research shows that nicotine increases the synthesis of T3 from T4 in the brain, while alcohol and opiates block the breakdown of T3 in the brain². Research into thyroid hormone's role in addiction might lead to better treatment and prevention of drug addiction³.

The most common causes of acquired thyroid disorders are iodine deficiency and autoimmune thyroid disease. Iodine deficiency is the major cause of hypothyroidism for much of the world, due to absence of iodine in the diet and/or high consumption of soy, corn, and brassica plants (cabbage, broccoli, brussel sprouts, etc.). These plants produce natural goitrogens. Goitrogens can be largely abolished through proper cooking. In the U.S., salt is iodized to ensure people get enough iodine. Iodine overdose rarely is a problem, as the thyroid gland stores iodine until it is necessary, and releases TH in the less active T4 form, and TH is also bound up by transport proteins in the blood until it is needed. Some experts believe that continual iodine overdoses leads to autoimmune thyroid disease, because it seems to be the major cause of thyroid disorder in developed countries.

Two autoimmune thyroid diseases, Graves' disease and Hashimoto's thyroiditis, are thought to be inherited, but have not been linked positively to any genes. Autoimmune thyroid disease is identified by detecting antibodies in the blood. In the case of Graves' disease, antibodies latch onto an enzyme essential for making T4, and keep it active and continually turned on. Graves' disease is treated by suppressing or killing (removing) the thyroid and then stabilizing the patient on thyroid hormone replacements. In Hashimoto's thyroiditis, antibodies latch onto the same enzyme, but block its function, and help trigger destruction of the thyroid. In the early stages of Hashimoto's thyroiditis, the thyroid may produce too much TH, but as the thyroid is slowly destroyed, the patients TH levels drop. Hashimoto's thyroiditis is treated with thyroid hormone replacements.

Some experts have suggested that autoimmune thyroid disease develops as a result of iodine overconsumption. Both the U.S. and Japan have high levels of iodine consumption and of autoimmune thyroid disease. Japanese people consume iodine because seafood makes up a large proportion of the diet, and Americans do because salt is iodinated and the food industry uses iodine as a machine wash. Other experts believe that pollutants are a more important factor. Pollutant chemicals like polychlorinated biphenyls (PCBs) and dioxins have been shown to interfere with thyroid function and are more prevalent in industrialized countries where thyroid disease levels are high. Autoimmune thyroid disease, either hyperthyroidism or hypothyroidism, is also linked to post-traumatic stress disorder and is often first observed clinically after periods of prolonged stress.

Research on the treatment of thyroid disease is proceeding in promising directions. Autoimmune thyroid disease is being intensively studied, and synthetic antibodies have been produced that neutralize Graves' antibodies in mice. Other studies are uncovering the role of TH in the brain, and finding new genetic causes of thyroid hormone metabolism disorders. TH function is being studied in various vertebrates, and environmental chemicals are undergoing examination as possible TH disruptors. Such research provides hope that autoimmune thyroid disease can one day be attacked at its source.

However, adequate information has not spread into the medical field. Labs performing blood work use overly broad normal ranges of TSH levels. Published research indicates 1-3 µg/ml in the blood (micrograms per milliliter of blood) is the best range of normal⁴, but most doctors work under the assumption that values as high as 5.5 are normal, which results in underdiagnosis and undertreatment of many cases of hypothyroidism.

A worse problem is the lack of testing. Though an estimated 200 million people worldwide have thyroid disorders⁵, thyroid function tests are rarely given unless the doctor suspects a thyroid disorder, and most doctors do not suspect hypothyroidism in their patients because the symptoms are subtle. Of the estimated 13 million Americans affected by thyroid disease, more than half are unaware of their condition⁶. Thyroid disease affects 8 times as many women as men, possibly because women need higher levels of TH than men do, but it has no age, gender, or ethnic barriers. Patients may have some or all the obvious symptoms: fatigue, lack of focus, depression, constipation, anxiety attacks, dry hair, dry skin, edema (swelling), lack of exercise tolerance, weight gain (especially in the stomach), muscle and joint pains, problems swallowing (due to enlarged thyroid), goiter, facial puffiness, unusual new headaches, loss of eyebrows, lack of sex drive, lowered body temperature, low or high blood pressure, and slowed heart rate. Yet patients may not be diagnosed for years.

The link between high cholesterol and underlying hypothyroidism is vastly overlooked, even though cholesterol's role in heart disease is heavily publicized. People have their cholesterol tested more regularly than their thyroid hormone levels. The result is prescriptions for expensive cholesterol-lowering drugs that don't address the real problem. People diagnosed with high cholesterol, especially those with low body temperature, should have their thyroid function tested before they begin taking such drugs. Also, smokers and other substance abusers should be watched for hypothyroidism (and urged to quit), as stimulants and depressants both can affect TH metabolism.

The under-diagnosis of thyroid disease handicaps research as well as the lives of affected patients. Researchers need to understand the proper function of thyroid hormone and the pathology of thyroid disease to fully understand how our bodies, brains, and immune systems develop and work, in health and in illness. It is impossible to know the prevalence of thyroid disease and figure out all the causes if patients take years on average to be diagnosed. We still do not know what causes the high prevalence of autoimmune thyroid disease in developed countries. Until researchers turn up strong and clear evidence on the cause, more cases of autoimmune thyroid disease will occur every year.

1. Synthroid, Knoll Pharmaceutical Company (http://www.synthroid.com/consumer/1310.htm)
2. Examination of antithyroid effects of smoking products in cultured thyroid follicles: only thiocyanate is a potent antithyroid agent (Acta Endocrinol (Copenh), 1992 Dec, 127(6):520-5)
3. Thyrotropin releasing hormone decreases alcohol intake and preference in rats (Alcohol, 2000 Jan, 20(1):87-91)
4. Weetman AP. Fortnightly review: Hypothyroidism: screening and subclinical disease. BMJ 1997;314:1175 (19 April) (http://www.bmj.com/cgi/content/full/314/7088/1175)
5. Thyroid Foundation of Canada (http://www.thyroid.ca/Guides/HG00.html)
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6. American Association of Clinical Endocrinologists (http://www.aace.com/pub/spec/tam2001/presstam2001.html)