Chemistry of Thyroid Hormones

Thyroid hormones are derivatives of the the amino acid tyrosine bound covalently to iodine. The two principal thyroid hormones are:

thyroxine (also known as T4 or L-3,5,3',5'-tetraiodothyronine) triiodothyronine (T3 or L-3,5,3'-triiodothyronine)

As shown in the following diagram, the thyroid hormones are basically two tyrosines linked together with the critical addition of iodine at three or four positions on the aromatic rings. The number and position of the iodines is important. Several other iodinated molecules are generated that have little or no biological activity; so called "reverse T3" (3,3',5'-T3) is such an example.

Thyroid hormones are poorly soluble in water, and more than 99% of the T3 and T4 circulating in blood is bound to carrier proteins. The principle carrier of thyroid hormones is thyroxine-binding globulin, a glycoprotein synthesized in the liver. Two other carriers of import are transthyrein and albumin. Carrier proteins allow maintenance of a stable pool of thyroid hormones from which the active, free hormones are released for uptake by target cells.

Synthesis and Secretion of Thyroid Hormones

Thyroid hormones are synthesized by mechanisms fundamentally different from what is seen in other endocrine systems. Thyroid follicles serve as both factory and warehouse for production of thyroid hormones.

Constructing Thyroid Hormones

The entire synthetic process occurs in three major steps, which are, at least in some ways, analagous to those used in the manufacture of integrated circuits (ICs):

Production and accumulation of the raw materials (in the case of ICs, a large wafer of doped silicon) Fabrication or synthesis of the hormones on a backbone or scaffold of precursor (etching several ICs on the silicon wafer) Release of the free hormones from the scaffold and secretion into blood (cutting individual ICs out of the larger wafer and distributing them)

The recipe for making thyroid hormones calls for two principle raw materials:

Tyrosines are provided from a large glycoprotein scaffold called thyroglobulin, which is synthesized by thyroid epithelial cells and secreted into the lumen of the follicle - colloid is essentially a pool of thyroglobulin. A molecule of thyroglobulin contains 134 tyrosines, although only a handful of these are actually used to synthesize T4 and T3. Iodine, or more accurately iodide (I-), is avidly taken up from blood by thyroid epithelial cells, which have on their outer plasma membrane a sodium-iodide symporter or "iodine trap". Once inside the cell, iodide is transported into the lumen of the follicle along with thyroglobulin.

Fabrication of thyroid hormones is conducted by the enzyme thyroid peroxidase, an integral membrane protein present in the apical (colloid-facing) plasma membrane of thyroid epithelial cells. Thyroid peroxidase catalyzes two sequential reactions: 1. Iodination of tyrosines on thyroglobulin (also known as "organification of iodide"). 2. Synthesis of thyroxine or triiodothyronine from two iodotyrosines.

Through the action of thyroid peroxidase, thyroid hormones accumulate in colloid, on the surface of thyroid epithelial cells. Remember that hormone is still tied up in molecules of thyroglobulin - the task remaining is to liberate it from the scaffold and secrete free hormone into blood. Thyroid hormones are excised from their thyroglobulin scaffold by digestion in lysosomes of thyroid epithelial cells. This final act in thyroid hormone synthesis proceeds in the following steps:

Thyroid epithelial cells ingest colloid by endocytosis from their apical borders - that colloid contains thyroglobulin decorated with thyroid hormone. Colloid-laden endosomes fuse with lysosomes, which contain hydrolytic enzymes that digest thyroglobluin, thereby liberating free thyroid hormones. Finally, free thyroid hormones apparently diffuse out of lysosomes, through the basal plasma membrane of the cell, and into blood where they quickly bind to carrier proteins for transport to target cells.

Control of Thyroid Hormone Synthesis and Secretion

Each of the processes described above appears to be stimulated by thyroid-stimulating hormone from the anterior pituitary gland. Binding of TSH to its receptors on thyroid epithelial cells stimulates synthesis of the iodine transporter, thyroid peroxidase and thyroglobulin. The magnitude of the TSH signal also sets the rate of endocytosis of colloid - high concentrations of TSH lead to faster rates of endocytosis, and hence, thyroid hormone release into the circulation. Conversely, when TSH levels are low, rates of thyroid hormone synthesis and release diminish.

Mechanism of Action and Physiologic Effects of Thyroid Hormones

Thyroid Hormone Receptors and Mechanism of Action

Receptors for thyroid hormones are intracellular DNA-binding proteins that function as hormone-responsive transcription factors, very similar conceptually to the receptors for steroid hormones. Thyroid hormones enter cells through membrane transporter proteins. A number of plasma membrane transporters have been identified, some of which require ATP hydrolysis; the relative importance of different carrier systems is not yet clear and may differ among tissues. Once inside the nucleus, the hormone binds its receptor, and the hormone-receptor complex interacts with specific sequences of DNA in the promoters of responsive genes. The effect of the hormone-receptor complex binding to DNA is to modulate gene expression, either by stimulating or inhibiting transcription of specific genes. For the purpose of illustration, consider one mechanism by which thyroid hormones increase the strength of contraction of the heart. Cardiac contractility depends, in part, on the relative ratio of different types of myosin proteins in cardiac muscle. Transcription of some myosin genes is stimulated by thyroid hormones, while transcription of others in inhibited. The net effect is to alter the ratio toward increased contractility. For additional details on mechanism of action and how these receptors interact with other transcription factors, examine the section Thyroid Hormone Receptors.

Physiologic Effects of Thyroid Hormones

It is likely that all cells in the body are targets for thyroid hormones. While not strictly necessary for life, thyroid hormones have profound effects on many "big time" physiologic processes, such as development, growth and metabolism, and deficiency in thyroid hormones is not compatible with normal health. Additionally, many of the effects of thyroid hormone have been delineated by study of deficiency and excess states, as discussed briefly below. Metabolism: Thyroid hormones stimulate diverse metabolic activities most tissues, leading to an increase in basal metabolic rate. One consequence of this activity is to increase body heat production, which seems to result, at least in part, from increased oxygen consumption and rates of ATP hydrolysis. By way of analogy, the action of thyroid hormones is akin to blowing on a smouldering fire. A few examples of specific metabolic effects of thyroid hormones include:

Lipid metabolism: Increased thyroid hormone levels stimulate fat mobilization, leading to increased concentrations of fatty acids in plasma. They also enhance

oxidation of fatty acids in many tissues. Finally, plasma concentrations of cholesterol and triglycerides are inversely correlated with thyroid hormone levels - one diagnostic indiction of hypothyroidism is increased blood cholesterol concentration. Carbohydrate metabolism: Thyroid hormones stimulate almost all aspects of carbohydrate metabolism, including enhancement of insulin-dependent entry of glucose into cells and increased gluconeogenesis and glycogenolysis to generate free glucose.

Growth: Thyroid hormones are clearly necessary for normal growth in children and young animals, as evidenced by the growth-retardation observed in thyroid deficiency. Not surprisingly, the growth-promoting effect of thyroid hormones is intimately intertwined with that of growth hormone, a clear indiction that complex physiologic processes like growth depend upon multiple endocrine controls. Development: A classical experiment in endocrinology was the demonstration that tadpoles deprived of thyroid hormone failed to undergo metamorphosis into frogs. Of critical importance in mammals is the fact that normal levels of thyroid hormone are essential to the development of the fetal and neonatal brain. Other Effects: As mentioned above, there do not seem to be organs and tissues that are not affected by thyroid hormones. A few additional, well-documented effects of thyroid hormones include:

Cardiovascular system: Thyroid hormones increases heart rate, cardiac contractility and cardiac output. They also promote vasodilation, which leads to enhanced blood flow to many organs. Central nervous system: Both decreased and increased concentrations of thyroid hormones lead to alterations in mental state. Too little thyroid hormone, and the individual tends to feel mentally sluggish, while too much induces anxiety and nervousness. Reproductive system: Normal reproductive behavior and physiology is dependent on having essentially normal levels of thyroid hormone. Hypothyroidism in particular is commonly associated with infertility.

Thyroid Disease States

Disease is associated with both inadequate production and overproduction of thyroid hormones. Both types of disease are relatively common afflictions of man and animals. Hypothyroidism is the result from any condition that results in thyroid hormone deficiency. Two well-known examples include:

Iodine deficiency: Iodide is absolutely necessary for production of thyroid hormones; without adequate iodine intake, thyroid hormones cannot be synthesized. Historically, this problem was seen particularly in areas with iodine-deficient soils, and frank iodine deficiency has been virtually eliminated by iodine supplementation of salt. Primary thyroid disease: Inflammatory diseases of the thyroid that destroy parts of the gland are clearly an important cause of hypothyroidism.

Common symptoms of hypothyroidism arising after early childhood include lethargy, fatigue, cold-intolerance, weakness, hair loss and reproductive failure. If these signs are severe, the clinical condition is called myxedema. In the case of iodide deficiency, the thyroid becomes inordinantly large and is called a goiter. The most severe and devestating form of hypothyroidism is seen in young children with congenital thyroid deficiency. If that condition is not corrected by supplemental therapy soon after birth, the child will suffer from cretinism, a form of irreversible growth and mental retardation. Most cases of hypothyroidism are readily treated by oral administration of synthetic thyroid hormone. In times past, consumption of dessicated animal thyroid gland was used for the same purpose. Hyperthyroidism results from secretion of thyroid hormones. In most species, this condition is less common than hypothyroidism. In humans the most common form of hyperthyroidism is Graves disease, an immune disease in which autoantibodies bind to and activate the thyroid-stimulating hormone receptor, leading to continual stimulation of thyroid hormone synthesis. Another interesting, but rare cause of hyperthyroidism is so-called hamburger thyrotoxicosis. Common signs of hyperthyroidism are basically the opposite of those seen in hypothyroidism, and include nervousness, insomnia, high heart rate, eye disease and anxiety. Graves disease is commonly treated with anti-thyroid drugs (e.g. propylthiourea, methimazole), which suppress synthesis of thyroid hormones primarily by interfering with iodination of thyroglobulin by thyroid peroxidase.

Control of Thyroid Hormone Synthesis and Secretion

The chief stimulator of thyroid hormone synthesis is thyroid-stimulating hormone from the anterior pituitary. Binding of TSH to receptors on thyroid epithelial cells seems to enhance all of the processes necessary for synthesis of thyroid hormones, including synthesis of the iodide transporter, thyroid peroxidase and thyroglobulin. The magnitude of the TSH signal also sets the rate of endocytosis of colloid - high concentrations of TSH lead to faster rates of endocytosis, and hence, thyroid hormone release into the circulation. Conversely, when TSH levels are low, rates of thyroid hormone synthesis and release diminish. The thyroid gland is part of the hypothalamic-pituitary-thyroid axis, and control of thyroid hormone secretion is exerted by classical negative feedback, as depicted in the diagram. Thyroid-releasing hormone (TRH) from the hypothalamus stimulates TSH from the pituitary, which stimulates thyroid hormone release. As blood concentrations of thyroid hormones increase, they inhibit both TSH and TRH, leading to "shutdown" of thyroid epithelial cells. Later, when blood levels of thyroid hormone have decayed, the negative feedback signal fades, and the system wakes up again. A number of other factors have been shown to influence thyroid hormone secretion. In rodents and young children, exposure to a cold environment triggers TRH secretion, leading to enhanced thyroid hormone release. This makes sense considering the known ability of thyroid hormones to spark body heat production.

Calcitonin
Calcitonin is a hormone known to participate in calcium and phosphorus metabolism. In mammals, the major source of calcitonin is from the parafollicular or C cells in the thyroid gland, but it is also synthesized in a wide variety of other tissues, including the lung and intestinal tract. In birds, fish and amphibians, calcitonin is secreted from the ultimobrachial glands. Calcitonin is a 32 amino acid peptide cleaved from a larger prohormone. It contains a single disulfide bond, which causes the amino terminus to assume the shape of a ring. Alternative splicing of the calcitonin pre-mRNA can yield a mRNA encoding calcitonin gene-related peptide; that peptide appears to function in the nervous and vascular systems. The calcitonin receptor has been cloned and shown to be a member of the seven-transmembrane, G protein-coupled receptor family.

Physiologic Effects of Calcitonin

A large and diverse set of effects has been attributed to calcitonin, but in many cases, these were seen in response to pharmacologic doses of the hormone, and their physiologic relevance is suspect. It seems clear however, that calcitonin plays a role in calcium and phosphorus metabolism. In particular, calcitonin has the ability to decrease blood calcium levels at least in part by effects on two well-studied target organs:

Bone: Calcitonin suppresses resorption of bone by inhibiting the activity of osteoclasts, a cell type that "digests" bone matrix, releasing calcium and phosphorus into blood. Kidney: Calcium and phosphorus are prevented from being lost in urine by reabsorption in the kidney tubules. Calcitonin inhibits tubular reabsorption of these two ions, leading to increased rates of their loss in urine.

It seems clear that there are species differences in the importance of calcitonin as a factor affecting calcium homeostasis. In fish, rodents and some domestic animals, calcitonin appears to play a significant role in calcium homeostais. In humans, calcitonin has at best a minor role in regulating blood concentrations of calcium. One interesting piece of evidence to support this statement is that humans with chronically increased (medullary thyroid cancer) or decreased (surgical removal of the thyroid gland) levels of calcitonin in blood usually do not show alterations from normal in serum calcium concentration. Addition information on calcitonin and calcium balance can be found in the section Endocrine Control of Calcium and Phosphate Homeostasis.

Control of Calcitonin Secretion

The most prominent factor controlling calcitonin secretion is the extracellular concentration of ionized calcium. Elevated blood calcium levels strongly stimulate calcitonin secretion, and secretion is suppressed when calcium concentration falls below

normal. A number of other hormones have been shown to stimulate calcitonin release in certain situations, and nervous controls also have been demonstrated.

Disease States
A large number of diseases are associated with abnormally increased or decreased levels of calcitonin, but pathologic effects of abnormal calcitonin secretion per se are not generally recognized. There are several therapeutic uses for calcitonin. It is used to treat hypercalcemia resulting from a number of causes, and has been a valuable therapy for Paget disease, which is a disorder in bone remodeling. Calcitonin also appears to be a valuable aid in the management of certain types of osteoporosis.

Parathyroid Hormone
Parathyroid hormone is the most important endocrine regulator of calcium and phosphorus concentration in extracellular fluid. This hormone is secreted from cells of the parathyroid glands and finds its major target cells in bone and kidney. Another hormone, parathyroid hormone-related protein, binds to the same receptor as parathyroid hormone and has major effects on development. Like most other protein hormones, parathyroid hormone is synthesized as a preprohormone. After intracellular processing, the mature hormone is packaged within the Golgi into secretory vesicles, the secreted into blood by exocytosis. Parathyroid hormone is secreted as a linear protein of 84 amino acids.

Physiologic Effects of Parathyroid Hormone

Writing a job description for parathyroid hormone is straightforward: if calcium ion concentrations in extracellular fluid fall below normal, bring them back within the normal range. In conjunction with increasing calcium concentration, the concentration of phosphate ion in blood is reduced. Parathyroid hormone accomplishes its job by stimulating at least three processes:

Mobilization of calcium from bone: Although the mechanisms remain obscure, a well-documented effect of parathyroid hormone is to stimulate osteoclasts to reabsorb bone mineral, liberating calcium into blood. Enhancing absorption of calcium from the small intestine: Facilitating calcium absorption from the small intestine would clearly serve to elevate blood levels of calcium. Parathyroid hormone stimulates this process, but indirectly by stimulating production of the active form of vitamin D in the kidney. Vitamin D induces synthesis of a calcium-binding protein in intestinal epithelial cells that facilitates efficient absorption of calcium into blood. Suppression of calcium loss in urine: In addition to stimulating fluxes of calcium into blood from bone and intestine, parathyroid hormone puts a brake on excretion of calcium in urine, thus conserving calcium in blood. This effect is mediated by stimulating tubular reabsorption of calcium. Another effect of parathyroid hormone on the kidney is to stimulate loss of phosphate ions in urine.

Control of Parathyroid Hormone Secretion

Parathyroid hormone is released in response to low extracellular concentrations of free calcium. Changes in blood phosphate concentration can be associated with changes in parathyroid hormone secretion, but this appears to be an indirect effect and phosphate per se is not a significant regulator of this hormone. When calcium concentrations fall below the normal range, there is a steep increase in secretion of parathyroid hormone. Low levels of the hormone are secreted even when blood calcium levels are high. The figure to the right depicts parathyroid hormone release from cells cultured in vitro in differing concentrations of calcium. The parathyroid cell monitors extracellular free calcium concentration via an integral membrane protein that functions as a calcium-sensing receptor.

Disease States
Both increased and decreased secretion of parathyroid hormone are recognized as causes of serious disease in man and animals. Excessive secretion of parathyroid hormone is seen in two forms:

Primary hyperparathyroidism is the result of parathyroid gland disease, most commonly due to a parathyroid tumor (adenoma) which secretes the hormone without proper regulation. Common manifestations of this disorder are chronic elevations of blood calcium concentration (hypercalcemia), kidney stones and decalcification of bone. Secondary hyperparathyroidism is the situation where disease outside of the parathyroid gland leads to excessive secretion of parathyroid hormone. A common cause of this disorder is kidney disease - if the kidneys are unable to reabsorb calcium, blood calcium levels will fall, stimulating continual secretion of parathyroid hormone to maintain normal calcium levels in blood. Secondary hyperparathyroidism can also result from inadequate nutrition - for example, diets that are deficient in calcium or vitamin D, or which contain excessive phosphorus (e.g. all meat diets for carnivores). A prominent effect of secondary hyperparathyroidism is decalcification of bone, leading to pathologic fractures or "rubber bones".

There is no doubt that chronic secretion or continuous infusion of parathyroid hormone leads to decalcification of bone and loss of bone mass. However, in certain situations, treatment with parathyroid hormone can actually stimulate an increase in bone mass and bone strength. This seemingly paradoxical effect occurs when the hormone is administered in pulses (e.g. by once daily injection), and such treatment appears to be an effective therapy for diseases such as osteoporosis. Inadequate production of parathyroid hormone - hypoparathyroidism - typically results in decreased concentrations of calcium and increased concentrations of phosphorus in blood. Common causes of this disorder include surgical removal of the parathyroid glands and disease processes that lead to destruction of parathyroid glands. The resulting hypocalcemia often leads to tetany and convulsions, and can be acutely life-threatening. Treatment focuses on restoring normal blood calcium concentrations by calcium infusions, oral calcium

supplements and vitamin D therapy.

Disorders of Thyroid Hormone Receptors

A number of humans with a syndrome of thyroid hormone resistance have been identified, and found to have mutations in the receptor beta gene which abolish ligand binding. Clinicially, such individuals show a type of hypothyroidism characterized by goiter, elevated serum concentrations of T3 and thyroxine and normal or elevated serum concentrations of TSH. More than half of affected children show attention-deficit disorder, which is intriguing considering the role of thyroid hormones in brain development. In most affected families, this disorder is transmitted as a dominant trait, which suggests that the mutant receptors act in a dominant negative manner. Mice with targeted deletions in thyroid receptor genes have provided additional understanding of the possible roles of different forms of thyroid hormone receptors. Knockout mice that are unable to produce the alpha-1 receptor showed subnormal body temperature and mild abnormalities in cardiac function. Other mice which lacked expression of both alpha isoforms were severely hypothyroid and died within the first few weeks of life. Mice with disruptions of the entire beta gene exhibited elevated TSH levels and deafness, while mice with mutations that disrupted only beta-2 expression had elevated TSH, but normal hearing. Such experiments are beginning to allow determination of which functions of the different receptor isoforms are redundant and which are not. Inactivating mutations in thyroid hormone receptors do not produce a syndrome analogous to the lack of thyroid hormones. This is the case even in mice with targeted deletions in both alpha and beta receptor genes. The most likely explanation for the relative mild effects of receptor deficiency is that responsive genes are left in a "neutral" state, rather than being chronically suppressed as happens with hormone deficiency.

Thyroid Hormones: Pregnancy and Fetal Development

Thyroid hormones are critical for development of the fetal and neonatal brain, as well as for many other aspects of fetal growth. Hypothyroidism in either the mother or fetus frequently results in fetal disease; in humans, this includes a high incidence of mental retardation.

Maternal Thyroid Function During Pregnancy

Normal pregnancy entails substantial changes in thyroid function in all animals. These phenomena have been studied most extensively in humans, but probably are similar in all mammals. Major alterations in the thyroid system during pregnancy include:

Increased blood concentrations of T4-binding globulin: TBG is one of several proteins that transport thyroid hormones in blood, and has the highest affinity for T4 (thyroxine) of the group. Estrogens stimulate expression of TBG in liver, and the normal rise in estrogen during pregnancy induces roughly a doubling in serum TBG concentratrations. Increased levels of TBG lead to lowered free T4 concentrations, which results in elevated TSH secretion by the pituitary and, consequently, enhanced production and secretion of thyroid hormones. The net effect of elevated TBG synthesis is to force a new equilibrium between free and bound thyroid hormones and thus a significant increase in total T4 and T3 levels. The increased demand for thyroid hormones is reached by about 20 weeks of gestation and persists until term. Increased demand for iodine: This results from a significant pregnancyassociated increase in iodide clearance by the kidney (due to increased glomerular filtration rate), and siphoning of maternal iodide by the fetus. The World Health Organization recommends increasing iodine intake from the standard 100 to 150 ug/day to at least 200 ug/day during pregnancy. Thyroid stimulation by chorionic gonadotropin: The placentae of humans and other primates secrete huge amounts of a hormone called chorionic gonadotropin (in the case of humans, human chorionic gonadotropin or hCG) which is very closely related to luteinizing hormone. TSH and hCG are similar enough that hCG can bind and transduce signalling from the TSH receptor on thyroid epithelial cells. Toward the end of the first trimester of pregnancy in humans, when hCG levels are highest, a significant fraction of the thyroid-stimulating activity is from hCG. During this time, blood levels of TSH often are suppressed, as depicted in the figure to the right. The thyroid-stimulating activity of hCG actually causes some women to develop transient hyperthyroidism.

The net effect of pregnancy is an increased demand on the thyroid gland. In the normal individuals, this does not appear to represent much of a load to the thyroid gland, but in females with subclinical hypothyroidism, the extra demands of pregnancy can precipitate clinicial disease.

Thyroid Hormones and Fetal Brain Development

In 1888 the Clinical Society of London issued a report underlining the importance of normal thyroid function on development of the brain. Since that time, numerous studies with rats, sheep and humans have reinforced this concept, usually by study of the effects of fetal and/or maternal thyroid deficiency. Thyroid hormones appear to have their most profound effects on the terminal stages of brain differentiation, including synaptogenesis, growth of dendrites and axons, myelination and neuronal migration. Thyroid hormones act by binding to nuclear receptors and modulating transcription of responsive genes. Thyroid hormone receptors are widely distributed in the fetal brain, and present prior to the time the fetus is able to synthesize thyroid hormones. It has proven surprisingly difficult to identify the molecular targets for thyroid hormone action in the developing brain, but some progress has been made. For example, the promoter of the myelin basic protein gene is directly responsive to thyroid hormones and contains the expected hormone response element. This fits with the observation that induced hypothyroidism in rats leads to diminished synthesis of mRNAs for several myelinassociated proteins. It seems clear that there is a great deal more to learn about the molecular mechanisms by which thyroid hormones support normal development of the brain.

Thyroid Deficiency in the Fetus and Neonate

The fetus has two potential sources of thyroid hormones - it's own thyroid and the thyroid of it's mother. Human fetuses acquire the ability to synthesize thyroid hormones at 10 to 12 weeks of gestation, and fetuses from other species at developmentally similar times. Current evidence from several species indicates that there is substantial transfer of maternal thyroid hormones across the placenta. Additionally, the placenta contains deiodinases that can convert T4 to T3. There are three types or combinations of thyroid deficiency states known to impact fetal development: Isolated maternal hypothyroidism: Overt maternal hypothyroidism typically is not a significant cause of fetal disease because it usually is associated with infertility. When pregnancy does occur, there is increased risk of intrauterine fetal death and gestational hypertension. Subclincial hypothyroidism is increasingly being recognized as a cause of developmental disease - this is a rather scary situation. Several investigators have found that mild maternal hypothyroidism, diagnosed only retrospectively from banked serum, may adversely affect the fetus, leading in children to such effects as slightly lower performance on IQ tests and difficulties with schoolwork. The most common cause of subclinical hypothyroidism is autoimmune disease, and it is known that anti-thyroid antibodies cross the human placenta. Thus, the cause of this disorder may be a passive immune attack on the fetal thyroid gland. Isolated fetal hypothyroidism: This condition is also known as sporadic congenital hypothyroidism. It is due to failure of the fetal thyroid gland to produce adequate amounts of thyroid hormone. Most children with this disorder are normal at birth, because maternal thyroid hormones are transported across the placenta during gestation. What is absolutely critical is to identify and treat this condition very shortly after birth.

If treatment is not instituted quickly, the child will become permanently mentally and growth retarded - a disorder called cretinism. This problem has largely disappeared in the US and many other countries due to large scale screening programs to detect hypothyroid infants. Iodine deficiency - Combined maternal and fetal hypothyroidism: Iodine deficiency is, by a large margin, the most common preventable cause of mental retardation in the world. Without adequate maternal iodine intake, both the fetus and mother are hypothyroid, and if supplemental iodine is not provided, the child may well develop cretinism, with mental retardation, deaf-mutism and spasticity. The World Health Organization estimated in 1990 that 20 million people had some degree of brain damage due to iodine deficiency experienced in fetal life. Endemic iodine deficiency remains a substantial public health problem in many parts of the world, including many areas in Europe, Asia, Africa and South America. In areas of severe deficiency, a large fraction of the adult population may show goiters. In such settings, overt cretinism may occur in 5 to 10 percent of offspring, and perhaps five times that many children will have mild mental retardation. This is a serious, tragic and, most importantly, a preventable problem. The fetus of an iodine-deficient mother can be successfully treated if iodine supplementation is given during the first or second trimester. Treatment during the third trimester or after birth will not prevent the mental defects. Iodine deficiency can also be a sigificant problem in animal populations. The most common manifestation in sheep, cattle, pigs and horses is a high incidence of stillbirths and birth of small, weak offspring.

Hyperthyroidism in Pregnancy
Gestational hyperthyroidism is associated with increased risk of several adverse outcomes, including preeclampisa, premature labor, fetal or perinatal death and low birth weight. In humans, hyperthyroidism usually is the result of Grave's disease, which involves development of autoantibodies against the TSH receptor that stimulate the thyroid gland.