are named from the Greek word hormon, meaning "to urge
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
a substance common in the sea but rare on land. Iodine is
essential to the structure of TH, and iodine deficiency is the
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
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
(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.
The Role of TH in 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
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
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
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
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
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
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
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
Genetic Disorders Involving TH, TSH, or TRs
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,
(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
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.
Effects of TH Imbalance: Hypothyroidism
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
TH acts as a neurotransmitter.
TH imbalance can mimic psychiatric disease because T3 influences levels of
a neurotransmitter integral to moods and behavior. Low levels of T3 can
cause depression. Some anti-depressants
hypothyroid patients feel even worse because the medications depress T3
levels. Paradoxically, some substances labelled depressants
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
Hypothyroidism is the second leading cause of high cholesterol,
diet. When TH levels drop, the liver no longer functions properly and
produces excess cholesterol, fatty acids, and triglycerides,
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.
Effects of TH Imbalance: 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
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
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.
Causes of Thyroid Disease
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 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
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
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
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
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
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.
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.
- Synthroid, Knoll Pharmaceutical Company
- 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)
- Thyrotropin releasing hormone decreases alcohol intake and preference in rats (Alcohol, 2000 Jan, 20(1):87-91)
- 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)
- Thyroid Foundation of Canada (http://www.thyroid.ca/Guides/HG00.html)
- American Association of Clinical Endocrinologists (http://www.aace.com/pub/spec/tam2001/presstam2001.html)