Principles and Practice of Endocrinology and Metabolism



Thyroid-Stimulating Hormone Structure, Biosynthesis, and Function

Glycoprotein Hormone Structure

Biosynthesis of Thyroid-Stimulating Hormone

Thyroid-Stimulating Hormone Receptor

Biologic Actions of Thyroid-Stimulating Hormone
Control of Thyroid-Stimulating Hormone Secretion: Neural and Humoral Modulators

Neural Control of Thyroid-Stimulating Hormone Secretion

Thyrotropin-Releasing Hormone

Thyroid Hormones

Dopamine and Somatostatin

Steroid Hormones

Integrated Control of Thyroid-Stimulating Hormone Secretion
Control of Thyroid-Stimulating Hormone Secretion: Physiologic Modulation

Effects of Age and Sex

Daily Rhythm

Effects of Stress

Effects of Fasting and Severe Illness
Clinical Applications of Thyroid-Stimulating Hormone Measurement

Thyroid-Stimulating Hormone Assay

Thyroid-Stimulating Hormone in Primary Hypothyroidism

Thyroid-Stimulating Hormone in Hyperthyroidism

Evaluation of Therapy for Thyroid Diseases
Disorders of Thyroid-Stimulating Hormone Control

Disorders Causing Hypothyroidism

Disorders Causing Hyperthyroidism

Defects in Thyroid-Stimulating Hormone Receptor Function
Clinical Use of Recombinant Human Thyroid-Stimulating Hormone
Chapter References

Thyroid-stimulating hormone (TSH, thyrotropin) is one of a family of glycoprotein hormones that also includes follicle-stimulating hormone (FSH), luteinizing hormone (LH), and human chorionic gonadotropin (hCG, Table 15-1). These hormones each consist of two dissimilar subunits, a and b, held together by strong noncovalent bonds.1 Each subunit consists of a polypeptide core that is stabilized by internal disulfide bonds and glycosylated at specific residues. The a subunits of all the glycoprotein hormones are identical and are highly conserved among different species. The b subunits of different hormones have extensive sequence homologies.

TABLE 15-1. Characteristics of Human Glycoprotein Hormones

The glycoprotein hormones bind to membrane receptors in their target tissues. Hormonal specificities are determined by the respective b subunits. However, hCG and LH have weak intrinsic TSH bioactivity. The isolated a and b subunits are not bioactive. However, both a -TSH and b-TSH subunits contain receptor-binding domains. Modifications of amino-acid residues or of the carbohydrate side chains can result in TSH analogs with enhanced bioactivity or altered metabolic clearance.2
TSH has a molecular mass of ~28 kDa. It is glycosylated at two sites on the a subunit and at one site on the b subunit. Glycosylation is required for subunit association, intracellular processing of the precursors to the secretory form of the hormone, and metabolic clearance of secreted hormone. Chemically deglycosylated TSH binds to its receptor but does not elicit a biologic response, suggesting that the glycosyl residues may have a role in receptor activation.3
The x-ray crystallographic structure of hCG is known,4 and a homologous structure for TSH has been proposed.5 The aand b subunits of the glycoprotein hormones share a common structural motif consisting of a central “cystine knot” formed by disulfide bonds, with two hairpin loops on one side of the knot and a single loop on the other. This cystine knot structure is found in growth factors and hormones, including platelet-derived growth factor, nerve growth factor, inhibins, and others.5 Another structural element presumed common to hCG, TSH, and the other glycoprotein hormones is a “seat-belt” region near the carboxyl terminus of the b subunit that wraps around the a subunit to maintain the heterodimeric structure.
Separate genes encode the a-TSH and b-TSH subunits.6 The human a gene is present in a single copy on chromosome 6 and is transcribed in all pituitary and placental cells synthesizing glycoprotein hormones. The human b-TSH gene is on chromosome 1. Hence, regulation of TSH gene transcription requires control of separate DNA regulatory elements for each subunit gene. Although all of the b subunits probably evolved from a common ancestor, b subunit genes are on separate chromosomes and do not form a single linkage group (see Table 15-1).
The a-TSH and b-TSH apoprotein cores are transcribed as prehormones, starting with leader sequences of hydrophobic amino acids that direct the nascent chains through the rough endoplasmic reticulum membrane (see Chap. 3). Pituitary glands contain excess a subunit relative to their b subunit content, and free subunits as well as intact hormone are secreted by the thyrotrope. Free a subunit generally can be detected in serum from euthyroid persons. It is increased in persons with primary hypothyroidism; free b-TSH also can be detected. Free a subunit (secreted by gonadotropes) also is increased in postmenopausal women. Free a subunit contains an additional oligosaccharide group that prevents it from combining with b-TSH.5
Thyrotropin-releasing hormone (TRH) stimulates a-TSH and b-TSH subunit gene transcription by inducing or activating specific transcriptional regulatory factors.7,8 Triiodothyronine (T3) causes a rapid fall in transcription of the a-TSH and b-TSH genes.9 The synthesis of b-TSH appears to be the rate-limiting step and a major regulatory point in the control of TSH. Regulatory regions involved in T3 suppression of subunit gene transcription (negative T3 response elements, TREs) have been identified for both the a-TSH and b-TSH genes.6 These negative TREs contain nucleotide sequences for interaction with the b receptor.10
Glycosylation of the subunits begins cotranslationally, with the transfer of preassembled oligosaccharides to specific asparagine residues.3 Initial core glycosylation is required for the polypeptide chains to assume their tertiary structures and associate into heterodimers of a-TSH and b-TSH. Glycosylation of TSH also is under hormonal control by TRH and thyroid hormone.3 TSH from patients with severe primary hypothyroidism and TSH released acutely by TRH stimulation differ in glycosylation compared to basal TSH.11 TSH extracted from sera of patients with nonthyroid illnesses also has alterations in glycosylation. Because alterations in glycosylation affect its biologic properties, control of TSH glycosylation may be of physiologic significance.
The TSH receptor is a member of the superfamily of guanine nucleotide regulatory protein (G protein)–coupled receptors.12,13 Binding of TSH stimulates receptor interaction with the a subunit of the Gs protein. This leads to the release of guanosine diphosphate (GDP) from the a subunit and its replacement with guanosine triphosphate (GTP) as well as dissociation of the G protein into a and bg subunits that stimulate adenylate cyclase, increasing intracellular cyclic adenosine monophosphate (cAMP) and activating protein kinase A. At higher TSH concentrations, the receptor may interact with other G proteins, leading to modulation of other intracellular signaling pathways such as the Ca2+, phosphatidylinositol phosphate, protein kinase C cascade.14
The TSH receptor gene was cloned by probing thyroid complementary DNA (cDNA) libraries with oligonucleotide probes complementary to cDNA sequences coding for segments of the LH/hCG and FSH hormone receptors thought likely to be conserved in the TSH receptor.15 The TSH receptor gene, located on chromosome 14, contains 10 exons coding for a 764-amino-acid polypeptide (including a 21-amino-acid leader sequence). The apoprotein core of the TSH receptor has a molecular mass of 84.5 kDa.16 Functional recombinant receptor has been expressed in stably trans-fected Chinese hamster ovary cells and has been used for bioassay of TSH and of thyroid-stimulating immunoglobulin (TSI) activity.
The TSH receptor and other G protein–coupled receptors contain three major structural and functional domains (Fig. 15-1) The extracellular region is the site of receptor-ligand interaction and also is involved in signal transduction. The membrane-spanning region contains seven hydrophobic transmembrane segments joined by short extracellular and cytoplasmic connecting loops. The transmembrane segments and connecting loops interact with the G-protein a subunit. The cytoplasmic tail contains phosphorylation sites that may be targets for protein kinases to regulate receptor activity. Binding of TSH to the extracellular domain results in a conformational change that alters the interaction of the membrane-spanning domain with the Gsasubunit, leading to activation of the GDP/GTP cycle.

FIGURE 15-1. Schematic illustration of the human thyrotropin receptor with the sites of mutations resulting in constitutive activation or loss of function.82,83,84,85,86,87,88,89,90,91,92,93,94,95,96,97,98,99 and 100 The initial 21 amino acids form the leader sequence and are cleaved during intracellular processing of the receptor. Germline activating mutations have been found in families with hereditary thyrotoxicosis and in neonates with nonautoimmune thyrotoxicosis. Somatic activating mutations have been found in solitary toxic nodules and toxic multinodular glands. (A database of thyroid-stimulating hormone receptor mutations is accessible through the internet at http://www.uni-leipzig.de/innere.)

The extracellular region of the TSH receptor contains 398 amino acids, including six potential glycosylation sites. A major structural feature of the extracellular domain of the glycoprotein receptors is the presence of “leucine-rich repeats” (LRRs). Proteins containing LRRs generally have functions involving interaction with polypeptide ligands.17 Based on the crystallo-graphic structure of ribonuclease inhibitor, an LRR-containing protein, a model of the extracellular domain of the TSH receptor has been proposed.18 The LRRs form a concave surface in the extracellular domain that can provide an extensive area for interaction with the hormone. This model is compatible with studies that have identified multiple regions in the TSH a and b subunits involved in hormone binding.
Within the thyroid, TSH stimulates virtually all metabolic and cellular processes involved in the synthesis and secretion of thyroid hormones, including iodine uptake and organification, thyroglobulin synthesis, iodotyrosine coupling, colloid droplet formation, and iodothyronine secretion.19 TSH also stimulates intermediary metabolism as well as protein and nucleic acid synthesis and thyroid growth. Clinically observable effects of TSH on the normal thyroid gland include thyroid gland enlargement, increased radioactive iodine uptake, and increased secretion of thyroxine (T4) and T3.
The thyrotrope secretes TSH in response to humoral signals (Fig. 15-2). The hypothalamic neurohormones TRH, somatostatin, and dopamine are released under control of the central nervous system. Thyroid hormones feed back to suppress TSH release. Other hormones, including corticosteroids and cytokines, also can modulate TSH secretion.

FIGURE 15-2. Interactions of the major humoral mediators of thyroid-stimulating hormone (TSH) secretion. Solid arrows denote stimulatory effect; shaded arrows denote inhibitory effect. (DA, dopamine; TRH, thyrotropin-releasing hormone; T4, thyroxine; T3, triiodothyronine.)

Physiologic alterations in TSH secretion in response to factors such as circadian rhythm, cold exposure (in neonates and lower animals), and stress are controlled by the central nervous system through pathways that project to hypothalamic nuclei to modulate hypothalamic releasing hormone secretion. Numerous neurotransmitters, including biogenic amines, amino acids, endogenous opioids, and neuropeptides, have been found to modulate TSH secretion in animals.20,21 For example, in rats, the TSH response to cold exposure appears to be mediated by a-adrenergic pathways.
TRH, a tripeptide (pyroglutamyl-histidyl-proline amide), was one of the first hypothalamic releasing hormones to be isolated and characterized (Fig. 15-3). The mammalian TRH prohormone contains multiple copies of the sequence Gln-His-Pro-Gly, suggesting that several TRH molecules could be derived from each precursor.22 The highest density of TRH-containing cells in the central nervous system is found in the hypothalamic paraventricular nucleus.23 TRH also is distributed extensively in the extrahypothalamic brain and in nonneuronal tissue, including the heart and testis.24 High-affinity TRH receptors are widely distributed; many behavioral, pharmacologic, and neurophysiologic effects have been reported after TRH administration. Hence, TRH may function as a neurotransmitter.21 However, probably only TRH released into the hypothalamic-pituitary portal circulation is involved in control of TSH secretion. Transcription of TRH is also under negative feedback regulation by T3. TREs have been identified in the regulatory region of the TRH gene.24

FIGURE 15-3. Chemical structure of thyrotropin-releasing hormone (TRH). TRH is the smallest identified hypophysiotropic hormone. Cyclization of the glutamate and amidation of the proline are required for full bioactivity.

The binding of TRH to its G-protein–coupled receptor on the thyrotrope stimulates hydrolysis of the membrane lipid phosphatidylinositol 4,5-bisphosphate to yield inositol 1,4,5-triphosphate and diacylglycerol25; each of these may function as an intracellular second messenger (see Chap. 4). Inositol triphosphate stimulates the mobilization of calcium from intracellular stores. Free calcium is bound rapidly by the calcium-binding protein calmodulin. The resulting complex activates kinases that phosphorylate proteins involved in the exocytosis of secretory granules. Diacylglycerol activates protein kinase C, leading to phosphorylation of other proteins that also may be needed for TSH secretion. TRH also stimulates adenylate cyclase in the pituitary.
Experimental evidence for the role of TRH in the control of TSH includes the observation that hypothalamic lesions that reduce TRH content cause a decrease in TSH secretion and hypothyroidism. In addition, the administration of anti-TRH antiserum to neutralize endogenous TRH causes a decrease in basal and cold-stimulated TSH levels in normal and hypothyroid rats.21
TRH administration also stimulates prolactin release. The physiologic role of TRH in the normal control of prolactin secretion is unclear, however (see Chap. 13). Prolactin, but not TSH, is elevated in nursing women. The administration of anti-TRH antibody does not block the physiologic prolactin rise during pregnancy or suckling. Hyperprolactinemia and galactorrhea have been observed in primary hypothyroidism.
Normally, TRH does not stimulate the secretion of other pituitary hormones. However, growth hormone release is stimulated by TRH administration in many patients with acromegaly and in some patients with renal failure, liver disease, anorexia nervosa, and depression. TRH stimulates the release of adrenocorticotropin in some patients with Cushing disease or Nelson syndrome, and the release of intact gonadotropin, a subunit, or free b subunit in patients with pituitary adenoma of gonadotrope origin.26
Serum TSH levels are extremely sensitive to changes in circulating thyroid hormone concentrations. The administration of small doses of T4 or T3 to euthyroid persons suppresses basal TSH levels and blunts the TSH response to TRH. Conversely, the administration of iodide, which slightly decreases thyroid secretion of T4 and T3, causes increased basal TSH concentrations and enhanced TSH responses to TRH.27 An inverse loglinear relationship is seen between changes in TSH and alterations in free T4 or free T3 levels.28
Thyroid hormone suppression of TSH secretion is initiated by T3 binding to a nuclear receptor. T4-induced suppression of TSH is mediated by its intrapituitary deiodination to T3.29 Monodeiodinase activity is high in the pituitary, and 50% to 60% of intrapituitary T3 comes from local conversion of T4 to T3. Hence, the serum TSH concentration may be more dependent on serum T4 than on serum T3.
In addition to inhibiting TSH biosynthesis, T3 administration also reduces the number of TRH receptors on thyrotropes and might thereby reduce their sensitivity to TRH.30
The administration of dopamine, L-dopa, or bromocriptine to normal or hypothyroid individuals decreases their basal TSH concentrations and maximum TSH responses to TRH.21 In addition, the dopamine-receptor blocking agents, metoclopramide and domperidone, increase TSH concentrations in both euthyroid and hypothyroid persons, a finding that supports a physiologic role for endogenous dopamine secretion in suppressing TSH release. Because neither dopamine nor domperidone crosses the blood–brain barrier, the effects of dopamine most likely are mediated directly at the thyrotrope.
Somatostatin may be a physiologic inhibitor of TSH secretion. The infusion of somatostatin lowers TSH levels in hypothyroid patients and suppresses the normal nocturnal rise in TSH.21 In addition, the release of somatostatin from the hypothalamus is stimulated by T3.31 Finally, the administration of anti-somatostatin antiserum to rats causes an increase in basal serum TSH levels, and in cold- or TRH-stimulated TSH release.
Steroid hormones modulate TSH secretion. Corticosteroids inhibit basal and TRH-stimulated TSH levels and block the normal nocturnal surge in TSH. The effects of steroids on pituitary responsiveness to TRH may be mediated by modulation of TRH receptors on thyrotropes.
The secretion of TSH is controlled by the integrated thyrotrope response to humoral signals. The inhibitory effect of thyroid hormones on TSH secretion results in a closed-loop negative-feedback control system for the tight regulation of the concentration of thyroid hormone, which is sensed by the thyrotrope. A deviation of the thyroid hormone concentration from the setpoint of the control system alters TSH release, thereby causing a change in the secretion of thyroid hormones that returns their concentrations toward the setpoint. The setpoint of this “thyrostat” is established by stimulatory and inhibitory hypothalamic releasing hormones (TRH, somatostatin, dopamine) and other mediators that determine the sensitivity of the thyrotrope to inhibition by T3. Thus, differences in thyroid hormone levels among individuals, or differences in responsiveness to environmental or physiologic conditions, reflect differences in the thyrotrope set-points.
Support for this model is provided by the observation that hypothalamic lesions to thyroidectomized rats blunt the expected increase in TSH and enhance the suppressive effects of low doses of thyroid hormones. Chronic intrathecal infusion of TRH in patients with amyotrophic lateral sclerosis produces a sustained rise in serum thyroid hormone and TSH levels, suggesting that the infusion raises the pituitary setpoint.32 In children with hypothyroidism resulting from idiopathic TRH deficiency, TSH release is more sensitive to inhibition by T4, suggesting that thyrotrope sensitivity to thyroid hormone suppression is increased in the absence of TRH.33
TSH is first detectable in fetal serum at ~13 weeks’ gestational age, approximately the same time as the onset of fetal thyroid iodine uptake. The TSH level remains low until the 18th to 20th week of gestation, when it rises abruptly. At birth, the serum TSH concentration is ~10 µU/mL. It then rises rapidly, reaching levels of 75 to 150 µU/mL by 30 minutes after birth.34 Levels then decline and are within the usual childhood range by 2 to 3 days after birth. The serum TSH concentration declines slightly during childhood and adolescence.35
The mean TSH concentration in euthyroid adults is 1.4 to 2.0 µU/mL. Levels do not differ significantly between men and women. Serum TSH levels do not change between adolescence and the age of 60 years. A study of the 24-hour profile of TSH secretion using a sensitive TSH assay found that mean TSH levels were decreased in healthy older men compared to younger control subjects.36 The normal diurnal rhythm was preserved (see Chap. 199).
TSH levels rise to a peak between midnight and the early morning hours; a nadir in TSH concentration occurs in late afternoon.21 TSH secretion is pulsatile, most likely in response to pulsatile release of TRH.37 Six to 10 major pulses per 24 hours are noted. The nocturnal rise in TSH levels is associated with increased TSH pulse amplitude. Alterations in dopaminergic and somatostatinergic tone may modulate the TSH pulse size.
The serum TSH concentration is transiently depressed after stressful medical procedures such as treadmill exercise or gastroscopy, and for 1 to 2 days after elective surgery. These transient decreases may result from the inhibitory effects of increased serum cortisol.
Although exposure to cold is an important stimulus for TSH release in some animals, temperature effects in humans are more limited. Exposure of neonates 3 hours after birth to a decreased ambient temperature causes an increase in serum TSH levels compared to those in age-matched control subjects.34 Elevated serum TSH levels also are noted during hypothermic cardiac surgery in infants.38 In adults, small and inconsistent effects on serum TSH values have been reported as a result of acute or chronic cold exposure.21
Fasting is associated with decreased 5′-monodeiodinase activity, which causes a fall in extrathyroidal conversion of T4 to T3 and an increase in reverse T3 (see Chap. 36). Because similar changes have been observed in patients with numerous acute or chronic illnesses, fasting has been used as a model for the effects of illness on thyroid function. Despite the low T3 concentration, basal TSH levels are either unchanged or decreased, and the TSH response to TRH generally is impaired. Thyrotrope responsiveness to thyroid hormones is intact because the administration of T3 during a fast results in further suppression of TSH, whereas the administration of iodide (to reduce circulating thyroid hormone concentrations) restores normal TSH responsiveness to TRH.39
Basal TSH levels generally have been reported to be normal in euthyroid persons during mild or moderate illness. However, the pituitary-hypothalamic regulation of TSH may be impaired in some severely ill patients. In a study of patients who became severely ill while undergoing bone marrow transplantation, serum TSH decreased to subnormal or undetectable levels in most patients in whom serum T4 values declined.40 The decrease in TSH generally preceded the decline in T4. With recovery, serum T4 and TSH levels returned to normal.
These findings suggest that the setpoint of circulating thyroid hormone is decreased during fasting and severe illness. This could be the result of altered secretion of hypothalamic-releasing hormones, such as TRH or somatostatin. The post-mortem hypothalamic content of TRH mRNA, measured by in situ hybridization, has been reported to be reduced in severely ill individuals.23 Infusion of the cytokines interleukin-1 (IL-1) or tumor necrosis factor-a in rats alters TSH levels and thyroid cell function.41 Also, administration of IL-1b to rats causes a decrease in the hypothalamic content of TRH mRNA.42 These immunomodulators may play a role in the hypothalamic and pituitary responses to stress and illness. During recovery from severe illness, TSH levels may be transiently elevated.43
The radioimmunoassays initially used for routine clinical measurement of TSH have been replaced by more sensitive two-site noncompetitive immunometric assays (IMAs). These assays use two antibodies with specificity toward separate epitopes on TSH. One antibody is attached to a solid-phase support and the other antibody is labeled. Enzymes, luminescent or fluorescent compounds, and iodine-125 have been used as antibody labels.28,44 Luminescent labels now are used most commonly. Binding of the two antibodies to TSH results in the formation of a labeled “sandwich” that is separated from the noncomplexed reagents and measured. IMAs are specific for the measurement of TSH and generally free from interference. Rarely, falsely elevated serum TSH levels have been reported because of the presence in serum of heterophilic antibodies that neutralize the reagent anti-TSH antibody.45
With the introduction of the IMAs, a confusing nomenclature has developed based on the claimed sensitivity (e.g., “highly sensitive,” “ultrasensitive,” “supersensitive”). The American Thyroid Association has proposed that assays should be characterized by a functional criterion and that a TSH assay should be designated as “sensitive” only if sera from thyrotoxic persons yield results >3 log standard deviations below the mean of normal euthyroid persons.46 More than 95% of sera from thyrotoxic persons would be expected to have TSH levels below the lower limit of normal in an assay meeting this criterion. Most commercial IMAs appear capable of meeting that standard.47
Clinical chemists have traditionally reported as the analytic sensitivity or detection limit of an assay the lowest TSH level statistically distinguishable from zero concentration by measurement of replicate samples in the same assay run. Such a definition of sensitivity may be clinically misleading, because a single measurement of a specimen containing TSH at the analytic threshold concentration would yield a result of zero 50% of the time. Furthermore, analytic sensitivity is a function of within-assay variance and does not assess the reliability of between-assay comparisons, which are more likely to be clinically useful in the diagnosis and treatment of an individual patient. As an alternative to analytic sensitivity, the proposal has been made that assay sensitivity be characterized by a criterion based on interassay variability. Specifically, the “lower limit of interassay quantitative measurement,”48 or functional sensitivity, of an assay is the TSH concentration for which the interassay coefficient of variation is less than some preestablished threshold (generally 20%) to permit reliable quantitative comparisons between specimens measured in different assay runs.
A “generational” classification of TSH assays has been proposed49 (Table 15-2). Each generation is approximately an order of magnitude more sensitive than the previous one. Both second- and third-generation assays distinguish suppressed TSH levels in hyperthyroidism from normal values. However, the third-generation assay further differentiates partial suppression of basal TSH concentrations in some patients with subclinical hyperthyroidism, nonthyroid illness, glucocorticoid therapy, and other clinical states (Table 15-3) from the more complete suppression of basal TSH concentrations in overt hyperthyroidism.50

TABLE 15-2. Properties of Thyroid-Stimulating Hormone (TSH) Assays

TABLE 15-3. Clinical Influence on Basal Thyroid-Stimulating Hormone (TSH) and TSH Response to Thyrotropin-Releasing Hormone

Measurement of TSH is frequently used as the initial, and sometimes sole, thyroid function test.51 This approach is generally sensitive and specific in the ambulatory population, in which the finding of a normal TSH level is strong evidence that a patient is euthyroid, and an abnormal TSH has a high likelihood of being due to thyroid dysfunction. However, abnormally high or low TSH values (compared to those of an ambulatory euthyroid control population) are frequently noted in hospitalized patients as a result of the effects of nonthyroid illness, acute psychiatric illness, or glucocorticoid therapy.52,53 Therefore, diagnoses of hypothyroidism or hyperthyroidism in hospitalized patients should be based on clinical evaluation, measurement of free thyroid hormone levels, and other indices of thyroid function, rather than on TSH measurement alone.
The TRH stimulation test has been used in the assessment of mild thyroid dysfunction and in the functional evaluation of the hypothalamic–pituitary–thyroid axis.54 The test entails measuring serum TSH levels at baseline and after the bolus intravenous administration of TRH. A dose-response relation between administered TRH and peak TSH levels is observed for TRH doses of 6.25 to 400 µg. In clinical practice, a TRH dose sufficient to produce a maximal TSH response is used. The peak TSH response occurs 20 to 40 minutes after TRH administration. If a primary thyroid disorder is suspected, measurement of TSH levels at baseline and at 20 or 30 minutes after TRH administration is sufficient (Fig. 15-4). If pituitary or hypothalamic dysfunction is suspected, TSH measurements should be continued for 2 to 3 hours at 30- to 60-minute intervals. During the first 5 minutes after TRH administration, side effects may include mild nausea, headache, a transient rise in blood pressure, light-headedness, a peculiar taste sensation, a flushed feeling, and urinary urgency.54

FIGURE 15-4. Typical thyroid-stimulating hormone (TSH) responses to the administration of thyrotropin-releasing hormone (TRH) under different conditions. Basal TSH is suppressed in overt thyrotoxicosis and does not respond to TRH. The blunted TSH response in patients with nonthyroid illness may be similar to the response in patients with subclinical hyperthyroidism. Patients with subclinical hyperthyroidism or nonthyroid illness may have a basal TSH below the detection threshold for second-generation TSH assays.

TRH testing may be viewed as a means of amplifying and detecting small differences in TSH secretion due, most importantly, to alterations in serum T4 or T3 concentrations. A slight excess of T4 or T3 blunts or completely blocks the TSH response to TRH, whereas small decrements in thyroid hormone levels enhance the response. The peak TSH response to TRH is proportional to the basal serum TSH level.55 Expressed as a multiple of the basal TSH, the peak TSH is a mean 8 to 9.5 times higher. However, considerable variability is seen in individual responses (range: 3- to 23-fold increment in euthyroid persons).
In addition to thyroid hormone concentrations, other factors can alter the TSH response to TRH (see Table 15-3). In patients with severe illnesses, the TSH response to TRH is likely to be diminished. Cortisol and other neurohumoral factors secreted in response to stress, malnutrition, and the administration of glucocorticoids or dopamine all may contribute to the blunted TSH response. In patients with a subnormal basal TSH level, however, the magnitude of the TSH response to TRH does not distinguish those in whom TSH is suppressed as a result of intercurrent illness from those in whom it is suppressed as a result of partial suppression of the pituitary by slight excess of free thyroid hormone (i.e., patients with autonomous thyroid nodules or exogenous thyroid hormone suppression).55
In general, if the basal TSH level exceeds the functional sensitivity threshold of the assay system and, therefore, can be accurately measured, then measurement of the TRH-stimulated TSH level does not provide additional information regarding the cause of the suppressed TSH. With the improvement in sensitivity of TSH assays, the TRH-stimulation test is not generally required in the evaluation of primary hypothyroidism or hyperthyroidism with suppressed TSH. However, the TRH-stimulation test may be useful in the evaluation of central hypothyroidism, in the rare patient with TSH-dependent hyperthyroidism, and in some patients with functioning pituitary tumors that respond to TRH stimulation (e.g., acromegaly).
The basal serum TSH concentration is increased in patients with intrinsic failure of the thyroid gland (primary hypothyroidism) of all causes. The magnitude of the increase is roughly proportional to the severity of disease.56 In general, basal TSH levels show a better inverse correlation with serum T4 levels than with serum T3 levels; this is because of the importance of the uptake of serum T4 and its intracellular deiodination as a source of T3 in the thyrotrope.29 In some persons, elevated TSH levels may be found with normal serum T3 concentrations but decreased serum T4 values. Such findings are common in patients with early thyroid gland failure, patients with mild iodine deficiency, and some patients with Graves disease who have been given long-term antithyroid drug treatment.
The isolated elevation of serum TSH levels with normal serum T4 and T3 concentrations in the absence of clinical signs or symptoms of hypothyroidism has been termed subclinical hypothyroidism. This condition has an overall prevalence of 2% to 7% and is particularly common in older women. Overt hypothyroidism develops at a rate of 5% to 10% per year in persons with elevated TSH levels and positive antithyroid antibodies.57
Measurement of the serum TSH level remains a sensitive test for the diagnosis of primary hypothyroidism in severely ill patients because basal TSH levels, although sometimes partially attenuated, remain higher than normal during intercurrent illness in patients with moderate or severe hypothyroidism. The diagnosis of hypothyroidism should be confirmed by measurement of the free T4 value, however. Patients with mildly elevated TSH and normal free T4 concentrations generally should undergo repeated thyroid function testing after discharge from the hospital to confirm the diagnosis of hypothyroidism.
The TSH response to TRH is exaggerated in patients with primary hypothyroidism. However, TRH testing should not be needed in the evaluation of suspected hypothyroidism if the basal serum TSH level is elevated.
Circulating TSH is suppressed in hyperthyroidism of all causes except in the rare patients with TSH-dependent thyrotoxicosis. In clinically hyperthyroid patients, the basal TSH level measured with a third-generation assay (functional sensitivity of <0.01 µU/mL) is <0.01 µU/mL; in most patients, TSH is undetectable.28,58 Serum TSH generally remains undetectable after TRH stimulation in these patients.
Slight overproduction of T4 and T3 in patients with autonomous nodular goiter or mild Graves disease may suppress TSH values without raising free T4 or free T3 levels above the normal range (subclinical hyperthyroidism). Suppression of the hypothalamic-pituitary axis may be less complete in patients with subclinical hyperthyroidism. In some, the basal TSH level is undetectable, whereas in others, it is detectable but suppressed below the normal range for ambulatory persons. If the basal TSH value is detectable, a TSH increment in response to TRH also is measurable. If the basal TSH level is undetectable, a slight increment after TRH stimulation sometimes may be noted.28,58
A second-generation TSH assay distinguishes suppressed TSH in hyperthyroidism from euthyroid levels. However, patients with partial TSH suppression also may have undetectably low TSH levels with this assay (see Fig. 15-4). If more precise measurement of thyrotrope suppression is required (i.e., to distinguish partial TSH suppression due to nonthyroid illness from thyrotoxicosis in hospitalized patients), measurement with a more sensitive assay or TRH-stimulation testing may be helpful.
The adequacy of thyroid hormone replacement therapy in primary hypothyroidism can be evaluated by measuring the serum TSH concentration. Normalization of serum TSH levels should be sought as a therapeutic end point in adults.59 The threshold for suppression of TSH has been reported to be elevated in infants with congenital hypothyroidism, who may show a persistently elevated TSH level in spite of the administration of adequate doses of replacement T4.60
After the return of free T4 from elevated to normal levels, the thyrotrope may remain suppressed for 4 to 6 weeks.61 Therefore, TSH is not an accurate indicator of thyroid status in thyrotoxic patients whose thyroid hormone levels are changing. Free T4 (and free T3) should be measured in the short-term follow-up of hyperthyroid patients being treated with antithyroid drugs or during the immediate period after treatment with radioactive iodine.
TSH should be measured by a third-generation assay to confirm complete suppression by exogenous thyroid hormone in patients with thyroid cancer. If a second-generation assay is used, then TSH should be measured after TRH stimulation to determine the degree of suppression.28,58
Central hypothyroidism results from failure of the pituitary to secrete biologically active TSH. Central hypothyroidism should be considered in patients who have clinical features of hypothyroidism or hypothalamic-pituitary dysfunction, low serum T4 concentrations, and serum TSH levels that are not elevated. In patients with no clinical manifestations of myxedema and no other evidence of hypopituitarism, other causes of low serum T4 without elevated serum TSH also should be considered, such as decreased thyroid hormone–binding proteins or severe illness. Patients with central hypothyroidism constitute several groups (Table 15-4), as described below.

TABLE 15-4. Causes of Central Hypothyroidism

Combined Pituitary Hormone Deficiency (Idiopathic Hypopituitarism). Patients with combined pituitary hormone deficiency (CPHD) have no antecedent histories of disease or injury that could cause hypopituitarism. Clinical features vary. Cases may be sporadic or familial in occurrence. Hypothyroidism alone is rare; patients generally present in childhood with growth hormone deficiency. Patients then go on to develop varying degrees of TSH, prolactin, and gonadotropin deficiencies. However, the patients do not have diabetes insipidus or neurologic deficits. In some families with CPHD, mutations in pituitary-specific transcriptional factors (Pit-1, Prop-1) have been identified (Table 15-5).62,63 and 64

TABLE 15-5. Identified Molecular Defects in Thyroid-Stimulating Hormone (TSH) and TSH Receptor Function

Isolated Thyroid-Stimulating Hormone Deficiency. In patients with isolated thyroid-stimulating hormone deficiency, basal serum TSH values may be low, normal, or slightly elevated; TRH stimulation generally causes a rise in serum TSH levels. The chronic administration of TRH can restore thyroid hormones to normal levels. Hence, the hypothyroidism is thought to result from impaired release of TRH from the hypothalamus. Rarely, familial cases with mutations in the b-TSH gene (see Table 15-5) have been described. Mutations have included a truncated b-TSH transcript as a result of a premature stop codon; a single amino-acid substitution resulted in a b-TSH that was unable to heterodimerize, and a frame-shift mutation resulted in reduced amounts of TSH with decreased bioactivity.65,66 In another patient, loss-of-function mutations of the TRH receptor were reported (see Table 15-5).67
Hypothalamic Lesions. Destructive lesions of the hypothalamus may result in central hypothyroidism. Generally, multiple pituitary hormones are involved, and patients often have diabetes insipidus. Serum prolactin levels may be mildly elevated because of interruption of the tonic dopaminergic lactotrope inhibitory pathway. In addition to hormone deficiencies, patients may have neurologic abnormalities and other manifestations of hypothalamic disease, such as disturbances of autonomic function, temperature regulation, food and water intake, and sleep cycle, as well as emotional lability.
TSH with reduced bioactivity has been found in the serum of patients with hypothalamic hypothyroidism; long-term treatment with TRH increases the bioactivity of their TSH.68 These findings might explain why some patients with hypothalamic disorders have hypothyroidism despite showing normal or slightly increased levels of immunoreactive TSH.
Pituitary Lesions. Pituitary lesions also cause hypothyroidism. Hypothalamic disturbances, visual field cuts, and parasellar abnormalities may be observed if an extrasellar extension of the lesion is present. Pituitary adenomas rarely cause hypothyroidism if they have not grown large enough to cause distortion and enlargement of the margins of the sella turcica.69
Basal TSH levels may be normal, low, or slightly elevated in patients with central hypothyroidism. Basal TSH values do not correlate with free T4 levels, and TRH-stimulated TSH values are not proportional to basal TSH values.55 Therefore, clinical evaluation and measurement of free T4 should be used in confirming the diagnosis of suspected central hypothyroidism and in titrating thyroid hormone replacement therapy in patients with central hypothyroidism.
Initially, the proposal was made that TRH testing should differentiate pituitary from hypothalamic causes of central hypothyroidism, with pituitary dysfunction causing a blunted or absent TSH response and hypothalamic disease resulting in a normal or exaggerated TSH rise that is delayed or prolonged. Although such classic patterns are found in many patients, the responses often overlap. Normal or “hypothalamic” patterns have been observed in patients with pituitary lesions, and the serum TSH response has been flat in some patients with suprasellar disease.70 Thus, the anatomic site of the central lesion may not always correlate with the expected functional consequences on TRH responsiveness. Abnormal serum TSH responses to TRH (i.e., blunted or delayed peaks) also are noted frequently in patients with pituitary or hypothalamic diseases even when the patients appear clinically euthyroid and their serum thyroid hormone levels are normal.71
Hyperthyroidism induced by TSH has been described in a small group of thyrotoxic patients in whom serum TSH levels are normal or increased (see Chap. 42). If signs and symptoms of thyrotoxicosis are absent in a patient with elevated thyroid hormone concentrations and normal serum TSH levels, other causes of hyperthyroxinemia with nonsuppressed TSH also should be considered (Table 15-6). Patients with TSH-induced hyperthyroidism have clinical evidence of a stimulated thyroid gland, including diffuse goiter and elevated radioactive iodine uptake. Extrathyroidal manifestations of Graves disease are lacking, and the assay of TSI is negative.72 Two groups of abnormalities have been described.

TABLE 15-6. Causes of Hyperthyroxinemia with Nonsuppressed Thyroid-Stimulating Hormone (TSH)

Thyroid-Stimulating Hormone–Producing Pituitary Tumors. In patients with TSH-producing pituitary tumors, basal intact TSH levels are elevated but are not stimulated by TRH or suppressed by exogenous thyroid hormone. Free b-TSH is undetectable; however, free a subunit levels are elevated and the molar ratio of free a subunit to intact TSH is >1.73,74 Computed tomography or magnetic resonance imaging generally reveals a pituitary lesion. However, these patients are best distinguished from those with nonneoplastic hypersecretion of TSH by measurement of the ratio of free a subunit to intact TSH and the response of TSH to TRH. TSH-producing pituitary tumors may cosecrete growth hormone or prolactin. The initial treatment of TSH-producing pituitary tumors is surgical resection, sometimes followed by postoperative irradiation. If hyperthyroidism persists, the long-acting somatostatin analog octreotide acetate has been shown to decrease serum TSH levels and cause reduction in tumor size.73,75 Finally, thyroid ablation can be used for persistent thyrotoxicosis.
Nonneoplastic Hypersecretion of Thyroid-Stimulating Hormone. TSH-dependent hyperthyroidism has been described in the absence of a TSH-secreting pituitary tumor. These patients have selective pituitary resistance to thyroid hormone (PRTH), a variant of the syndrome of generalized resistance to thyroid hormone (GRTH).76,77 The thyroid hormone resistance syndromes are inherited in an autosomal dominant fashion. Considerable clinical overlap is found between GRTH and PRTH. The free thyroid hormone levels are elevated in both. Clinical manifestations of hyperthyroidism in PRTH are variable. Laboratory findings in PRTH and GRTH are similar and are distinguished from the findings in subjects with TSH-secreting pituitary tumors. Basal serum TSH levels are normal or slightly elevated and are stimulated by TRH. The administration of T3 suppresses basal TSH levels and blunts the TSH response to TRH. Serum free a subunit levels are normal, and the molar ratio of free a subunit to intact TSH is <1. Thus, TSH secretory dynamics are qualitatively normal.
The thyroid hormone resistance syndromes are the result of mutations in the T3 nuclear receptor (TR). Similar mutations in the TRb gene have been described in both GRTH and PRTH.74 Hence GRTH and PRTH are alternate phenotypic expressions of a common underlying genotype. The mechanism responsible for this phenotypic variation has not yet been established. Because both the normal and mutant receptor genes may be expressed, the dominant receptor isoform (normal or mutant) may vary in different organs and in different individuals.
The treatment of nonneoplastic TSH-dependent hyperthyroidism is difficult. Antithyroid drug therapy may increase TSH levels further, causing enlargement of the goiter and possibly enhancing abnormal thyrotrope growth. Thyroxine administration may suppress the TSH but worsens symptoms of thyrotoxicosis. The pharmacologic suppression of TSH secretion has been attempted. Some patients have responded to bromocriptine or octreotide. Other patients have been treated successfully with 3,5,3′-triiodothyroacetic acid (TRIAC) or with D-thyroxine.74
A convincing case of ectopic production of TSH by a nonpituitary tumor has not been reported. A patient with hepatocellular carcinoma, thyrotoxicosis, and nonsuppressed TSH has been described.78 Neither TSH nor TRH immunoreactivity could be detected in the tumor, and the hypothesis was made that the tumor was producing a factor with TRH bioactivity.
Hyperthyroidism has been observed in patients with trophoblastic neoplasms such as hydatidiform mole and choriocarcinoma.79 Research has found that the thyrotropic activity isolated from hydatidiform moles copurifies with hCG and that highly purified hCG has weak intrinsic thyrotropic bioactivity75 (see Chap. 42, Chap. 112 and Chap. 219). Because hCG concentration may be high in patients with trophoblastic tumors, even weak intrinsic thyrotropic activity could stimulate the thyroid enough to cause thyrotoxicosis. The TSH bioactivity of hCG is enhanced by the removal of amino acids from its carboxyl terminus and by the removal of sialic acid residues from its carbohydrate side chains.80 Hence, the proposal has been made that the thyroid stimulator in hyperthyroidism resulting from trophoblastic disease may be a structurally variant hCG, either transcribed from an abnormal hCG gene or altered by post-translational modifications.
Since the cloning of the human TSH receptor, a number of mutations and polymorphisms have been reported (see Table 15-5).81,82,83 and 84 Several groups of patients have been described.
Mutations to the TSH receptor or to the Gs protein that result in constitutive activation of the cAMP cascade occur in some autonomously functioning thyroid nodules (AFTNs).85,86,87,88,89,90 and 91 TSH receptor–activating mutations have been reported in 8% to 82% of solitary AFTNs as well as in autonomous nodules within multinodular thyroid glands. These mutations are found only in the autonomous nodule and not in adjacent normal thyroid tissue or in peripheral cells; hence, they are nongermline somatic mutations. Activating somatic mutations to Gsa also have been reported in 0% to 38% of AFTNs. In addition, hyperthyroidism is frequently noted in patients with McCune-Albright syndrome who are mosaics for somatic Gsa-activating mutations acquired during embryogenesis. Not all AFTNs are the result of mutations to these components of the cAMP cascade, however, because autonomous nodules without mutations to either protein are also encountered frequently.
Transfected cells expressing the mutant receptor or Gs protein have elevated basal levels of cAMP compared to cells transfected with the wild-type receptor or Gs. Stimulation by TSH generally causes a further increment in cAMP levels. The receptor-activating mutations are predominantly localized to the membrane-spanning region of the receptor within the trans-membrane segments and connecting loops that interact with Gsa (see Fig. 15-1). Presumably, as a result of the conformational change in the receptor caused by the mutation, it is more effective in constitutively activating Gsa.
Hereditary thyrotoxicosis with diffuse hyperplasia of the thyroid has been described in several families.92,93,94,95,96 and 97 Inheritance of the syndrome is autosomal dominant. It is distinct from Graves disease because no markers of autoimmunity such as TSI, lymphocytic infiltrates, or ophthalmopathy are found. Clinical characteristics vary. Individuals generally present during infancy or early childhood, but some have been young adults at the time of diagnosis; hyperthyroidism ranges from mild to severe. Goiter may not be present initially but tends to grow over time. Hyperthyroidism generally recurs if the patient is treated with subtotal thyroidectomy or with less than complete radioiodine ablation. TSH receptor–activating mutations have been identified and characterized in these patients. The mutations are located in the same regions of the TSH receptor as the activating mutations in AFTNs (see Fig. 15-1); in some cases they are identical. However, the constitutive activity of the TSH receptor in this familial syndrome is generally less than the constitutive activity of the mutated receptors in AFTNs. Severe congenital activating mutations may have a high likelihood of being lethal in utero. In addition to the familial cases, several sporadic cases of congenital hyperthyroidism with activating mutations to the TSH receptor have been reported. These apparently are de novo germline mutations, because neither parent carried the mutated gene.
Constitutive activating mutations of G protein–coupled receptors also have been described in other clinical syndromes, including familial male precocious puberty (LH receptor), continued spermatogenesis after hypophysectomy (FSH receptor), autosomal dominant hypoparathyroidism (calcium receptor), and in a rare form of dwarfism associated with PTH-independent hypercalcemia (PTH receptor).81
Several cases of TSH resistance as a result of TSH receptor loss-of-function mutations have been reported (see Table 15-5).98,99 and 100 All patients have elevated TSH levels; in most, the radioactive iodine uptake and the free T4 are normal or only slightly low, consistent with partial TSH unresponsiveness compensated by the elevated TSH. Cases of severe congenital hypothyroidism with hypoplasia of the thyroid also occur, however. Inheritance is autosomal recessive; affected individuals are compound heterozygous or homozygous for TSH receptor mutations. Heterozygotes are unaffected.
TSH-stimulated cAMP production is reduced or absent in cells transfected with the mutant receptor. Several mechanisms may cause the loss-of-function mutation. Some mutant TSH receptors cannot be detected in the plasma membrane. In some of these mutants, a premature stop codon results in production of a truncated polypeptide; in others an amino acid substitution or deletion may lead to abnormal intracellular processing of the mutant TSH receptor and its consequent failure to appear on the cell surface. A second group of loss-of-function mutations exhibits decreased TSH binding as a result of mutations in the extracellular TSH-binding domain. Finally, in a third group of mutations, TSH binding is normal or near normal, but the cAMP response is impaired. These mutations, which have been localized within the extracellular and membrane-spanning domains (see Fig. 15-1), presumably result in defective coupling to Gsa.
TSH resistance occurs in patients with pseudohypoparathyroidism type 1a, who have Albright hereditary osteodystrophy (brachydactyly, subcutaneous ossifications, short stature, round face; see Chap. 60). These patients are heterozygous for loss-of-function mutations in the Gsa gene that result in partial loss of Gsa activity. They have variable patterns of hormone dysfunction involving end-organ responses to PTH, TSH, and gonadotropins in addition to the skeletal deformities.101
Recombinant human TSH has been produced by cotransfecting Chinese hamster ovary cells with cDNA coding for a and b-TSH.102 Glycosylation of recombinant human TSH is not identical to that of native human TSH. It is bioactive, however, and has undergone initial clinical trials in patients with thyroid cancer.103 Results of whole body radioiodine scans in patients who had undergone thyroidectomy were evaluated after patients were treated with recombinant human TSH to stimulate radio-iodine uptake, and were compared to scans obtained in the same patients after withdrawal of T3 suppression and stimulation by endogenous TSH. In most patients, visualization of residual thyroid activity and metastatic uptake was comparable after both stimulation procedures.104

Pierce JG, Parsons TF. Glycoprotein hormones: structure and function. Annu Rev Biochem 1981; 50:465.

Szkudlinski MW, The NG, Grossmann M, et al. Engineering human glycoprotein hormone superactive analogues. Nature Biotech 1996; 14:1257.

Magner JA. Thyroid-stimulating hormone: biosynthesis, cell biology and bioactivity. Endocr Rev 1990; 11:354.

Lapthom AJ, Harris DC, Littlejohn A, et al. Crystal structure of human chorionic gonadotropin. Nature 1994; 369:455.

Grossmann M, Weintraub BD, Szkudlinski MW. Novel insights into the molecular mechanisms of human thyrotropin action: structural, physiological, and therapeutic implications for the glycoprotein hormone family. Endocr Rev 1997; 18:476.

Chin WW, Can FE, Burnside J, Darling DS. Thyroid hormone regulation of thyrotropin gene expression. Recent Prog Horm Res 1993; 48:393.

Kim MK, McClaskey JH, Bodenner DL, Weintraub BD. An AP-1-like factor and the pituitary-specific factor Pit-1 are both necessary to mediate hormonal induction of human thyrotropin b gene expression. J Biol Chem 1993; 268:23366.

Steinfelder HJ, Wondisford FE. Thyrotropin (TSH) b-subunit gene expression—an example for the complex regulation of pituitary hormone genes. Exp Clin Endocrinol Diabetes 1997; 105:196.

Shupnik MA, Ridgway EC. Triiodothyronine rapidly decreases transcription of the thyrotropin subunit genes in thyrotropic tumor explants. Endocrinology 1985; 117:1940.

Can FE, Wong NCW. Characteristics of a negative thyroid hormone response element. J Biol Chem 1994; 269:4175.

Magner JA, Kane J, Chou ET. Intravenous thyrotropin (TSH)-releasing hormone releases human TSH that is structurally different from basal TSH. J Clin Endocrinol Metab 1992; 74:1306.

Boume HR, Sanders DA, McCormick F. The GTPase superfamily: a conserved switch for diverse cell functions. Nature 1990; 348:125.

Ji TH, Grossmann M, Ji I. G protein-coupled receptors. I. Diversity of receptor-ligand interactions. J Biol Chem 1998; 273:17299.

Laugwitz KL, Allgeier A, Offermanns S, et al. The human thyrotropin receptor: a heptahelical receptor capable of stimulating members of all four G protein families. Proc Natl Acad Sci U S A 1996; 93:116.

Parmentier M, Libert F, Maenhaut C, et al. Molecular cloning of the thyrotropin receptor. Science 1989; 246:1620.

Vassart G, Dumont JE. The thyrotropin receptor and the regulation of thyrocyte function and growth. Endocr Rev 1992; 13:596.

Kobe B, Deisenhofer J. A structural basis of the interactions between leucine-rich repeats and protein ligands. Nature 1995; 374:183.

Jiang X, Dreano M, Buckler DR, et al. Structural predictions for the ligand-binding region of glycoprotein hormone receptors and the nature of hormone-receptor interactions. Structure 1995; 3:1341.

Tong W. Actions of thyroid-stimulating hormone. In: Greep RO, Astwood EB, eds. Handbook of physiology, section 7, Endocrinology; vol III, Thyroid. Baltimore: Williams & Wilkins, 1974:255.

Toni R, Lechan RM. Neuroendocrine regulation of thyrotropin-releasing hormone (TRH) in the tuberoinfundibular system. J Endocrinol Invest 1993; 16:715.

Morley JE. Neuroendocrine control of thyrotropin secretion. Endocr Rev 1981; 2:396.

Lechan RM, Wu P, Jackson IMD, et al. Thyrotropin-releasing hormone precursor: characterization in rat brain. Science 1986; 231:159.

Fliers E, Wiersinga WM, Swaab DF. Physiological and pathophysiological aspects of thyrotropin-releasing hormone gene expression in the human hypothalamus. Thyroid 1998; 8:921.

Wilber JF, Xu AH. The thyrotropin-releasing hormone gene cloning, characterization, and transcriptional regulation in the central nervous system, heart and testis. Thyroid 1998; 8:897.

Gershengorn MC. Mechanism of thyrotropin releasing hormone stimulation of pituitary hormone secretion. Annu Rev Physiol 1986; 48:515.

Daneshdoost L, Gennarelli TA, Bashey HM, et al. Recognition of gonadotroph adenomas in women. N Engl J Med 1991; 324:589.

Vagenakis AG, Rapoport B, Azizi F, et al. Hyperresponse to thyrotropin-releasing hormone accompanying small decreases in serum thyroid hormone concentrations. J Clin Invest 1974; 54:913.

Spencer CA, LoPresti JS, Patel A, et al. Applications of a new chemiluminometric thyrotropin assay to subnormal measurement. J Clin Endocrinol Metab 1990; 70:453.

Larsen PR. Thyroid-pituitary interaction. N Engl J Med 1982; 306:23.

Gershengorn MC. Thyrotropin-releasing hormone receptor: cloning and regulation of its expression. Recent Prog Horm Res 1993; 48:341

Berelowitz M, Maeda K, Harris S, Frohman LA. The effect of alterations in the pituitary-thyroid axis on hypothalamic content and in vitro release of somatostatin-like immunoreactivity. Endocrinology 1980; 107:24.

Kaplan MM, Taft JA, Reichlin S. Munsat TL. Sustained rises in serum thyrotropin, thyroxine, and triiodothyronine during long term, continuous thyrotropin-releasing hormone treatment in patients with amyotrophic lateral sclerosis. J Clin Endocrinol Metab 1986; 63:808.

Sato T, Ishiguro K, Suzuki Y, et al. Low setting of feedback regulation of TSH secretion by thyroxine in pituitary dwarfism with TSH-releasing hormone deficiency. J Clin Endocrinol Metab 1976; 42:385.

Fisher DA, Odell WD. Acute release of thyrotropin in the newborn. J Clin Invest 1969; 48:1670.

Penny R, Spencer CA, Frasier SD, Nicoloff JT. Thyroid-stimulating hormone and thyroglobulin levels decrease with chronological age in children and adolescents. J Clin Endocrinol Metab 1983; 56:177.

Van Coevorden A, Laurent E, Decoster C, et al. Decreased basal and stimulated thyrotropin secretion in healthy elderly men. J Clin Endocrinol Metab 1989; 69:177.

Brabant G, Prank K, Ranft U, et al. Physiological regulation of circadian and pulsatile thyrotropin secretion in normal men and women. J Clin Endocrinol Metab 1990; 70:403.

Wilber JF, Baum D. Elevation of plasma TSH during surgical hypothermia. J Clin Endocrinol Metab 1970; 31:372.

Gardner DF, Kaplan MM, Stanley CA, Utiger RD. Effect of tri-iodothyronine replacement on the metabolic and pituitary response to starvation. N Engl J Med 1979; 300:579.

Wehmann RE, Gregerman RI, Burns WH, et al. Suppression of thyrotropin in the low-thyroxine state of severe nonthyroidal illness. N Engl J Med 1985; 312:546.

Pang X-P, Hershman JM, Mirrel CJ, Pekary AE. Impairment of hypothalamic-pituitary-thyroid function in rats treated with human recombinant tumor necrosis factor-a (cachectin). Endocrinology 1989; 125:76.

Kakucska I, Romero LI, Clark BD, et al. Suppression of thyrotropin releasing hormone gene expression by interleukin 1-beta in the rat: implications for nonthyroid illness. Neuroendocrinology 1994; 59:129.

Bacci V, Schussler GC, Kaplan TB. The relationship between serum tri-iodothyronine and thyrotropin during systemic illness. J Clin Endocrinol Metab 1982; 54:1229.

van Heyningen V, Abbott SR, Daniel SG, et al. Development and utility of a monoclonal-antibody-based, highly sensitive immunoradiometric assay of thyrotropin. Clin Chem 1987; 33:1387.

Brennan MD, Klee GO, Preissner CM, Hay ID. Heterophilic serum antibodies: a cause for falsely elevated serum thyrotropin levels. Mayo Clin Proc 1987; 62:894.

Hay ID, Bayer MF, Kaplan MM, et al. American Thyroid Association assessment of current free thyroid hormone and thyrotropin measurements and guidelines for future clinical assays. Clin Chem 1991; 37:2002.

Spencer CA, Takeuchi M, Kazarosyan M. Current status and performance goals for serum thyrotropin (TSH) assays. Clin Chem 1996; 42:140.

Bayer MF. Performance criteria for appropriate characterization of “(highly) sensitive” thyrotropin assays. Clin Chem 1987; 33:630.

Nicoloff JT, Spencer CA. The use and misuse of the sensitive thyrotropin assays. J Clin Endocrinol Metab 1990; 71:553.

Saller B, Brod’a N, Heydarian R, et al. Utility of third generation thyrotropin assays in thyroid function testing. Exp Clin Endocrinol Diabetes 1998; 106:S29.

Ross DS, Daniels GH, Gouveia D. The use and limitations of a chemiluminescent thyrotropin assay as a single thyroid function test in an outpatient endocrine clinic. J Clin Endocrinol Metab 1990; 71:764.

Attia J, Margetts P, Guyatt G. Diagnosis of thyroid disease in hospitalized patients: a systematic review. Arch Intern Med 1999; 159:658.

Spencer C, Eigen A, Shen D, et al. Specificity of sensitive assays of thyrotropin (TSH) used as a screen for thyroid disease in hospitalized patients. Clin Chem 1987; 33:1391.

Hershman JM. Clinical application of thyrotropin-releasing hormone. N Engl J Med 1974; 290:886.

Spencer CA, Schwarzbein D, Guttler RB, et al. Thyrotropin (TSH)-releasing hormone stimulation test responses employing third and fourth generation TSH assays. J Clin Endocrinol Metab 1993; 76:494.

Bigos ST, Ridgway EC, Kourides IA, Maloof F. Spectrum of pituitary alterations with mild and severe thyroid impairment. J Clin Endocrinol Metab 1978; 46:317.

Tunbridge WMG, Brewis M, French JM, et al. Natural history of autoimmune thyroiditis. BMJ 1981; 282:258.

Ross DS, Ardisson U, Meskell MJ. Measurement of thyrotropin in clinical and subclinical hyperthyroidism using a new chemiluminescent assay. J Clin Endocrinol Metab 1989; 69:684.

Helfand M, Crapo LM. Monitoring therapy in patients taking levothyroxine. Ann Intern Med 1990; 113:450.

Schultz RM, Glassman MS, MacGillivray MH. Elevated threshold for thyrotropin suppression in congenital hypothyroidism. Am J Dis Child 1980; 134:19.

Vagenakis AG, Braverman LE, Azizi F, et al. Recovery of pituitary thyrotropic function after withdrawal of prolonged thyroid-suppression therapy. N Engl J Med 1975; 293:681.

Cohen LE, Wondisford FE, Radovick S. Role of Pit-1 in the gene expression of growth hormone, prolactin, and thyrotropin. Endocrinol Metab Clin North Am 1996; 25:523.

Pellegrini-Bouiller I, Bélicar P, Barlier A, et al. A new mutation of the gene encoding transcription factor Pit-1 is responsible for combined pituitary hormone deficiency. J Clin Endocrinol Metab 1996; 81:2790.

Deladoëy J, Flück C, Büyükgebiz A, et al. “Hot spot” in the PROP1 gene responsible for combined pituitary hormone deficiency. J Clin Endocrinol Metab 1999; 84:1645.

Doeker BM, Pfäffle RW, Pohlenz J, Andler W. Congenital central hypothyroidism due to a homozygous mutation in the thyrotropin b–subunit gene follows an autosomal recessive inheritance. J Clin Endocrinol Metab 1998; 83: 1762.

Hayashizaki Y, Hiraoka Y, Endo Y, Matsubara K. Thyroid stimulating hormone (TSH) deficiency caused by a single base substitution in the CAGYC region of the b-subunit. EMBO J 1989; 8:2291.

Collu R, Tang J, Castagné J, et al. A novel mechanism for isolated central hypothyroidism: inactivating mutations in the thyrotropin-releasing hormone receptor gene. J Clin Endocrinol Metab 1997; 82:1561.

Beck-Peccoz P, Amr S, Menzezes-Ferreira MM, et al. Decreased receptor binding of biologically inactive thyrotropin in central hypothyroidism. N Engl J Med 1985; 312:1085.

Klijn JGM, Lamberts SWJ, De Jong FH, et al. The importance of pituitary tumour size in patients with hyperprolactinaemia in relation to hormonal variables and extrasellar extension of tumour. Clin Endocrinol (Oxf) 1980; 12:341.

Patel YC, Burger HG. Serum thyrotropin (TSH) in pituitary and/or hypothalamic hypothyroidism: normal or elevated basal levels and paradoxical responses to thyrotropin-releasing hormone. J Clin Endocrinol Metab 1973; 37:190.

Snyder PJ, Jacobs LS, Rabello MM, et al. Diagnostic value of thyrotrophin-releasing hormone in pituitary and hypothalamic diseases. Ann Intern Med 1974; 81:751.

Weintraub BD, Gershengorn MC, Kourides IA, Fein H. Inappropriate secretion of thyroid stimulating hormone. Ann Intern Med 1981; 95:339.

Brucker-Davis F, Oldfield EH, Skarulis MC, et al. Thyrotropin-secreting pituitary tumors: diagnostic criteria, thyroid hormone sensitivity, and treatment outcome in 25 patients followed at the National Institutes of Health. J Clin Endocrinol Metab 1999; 84:476.

McDermott MT, Ridgway EC. Central hyperthyroidism. Endocrinol Metab Clin North Am 1998; 27:187

Gesundheit N, Petrick PA, Nissim M, et al. Thyrotropin-secreting pituitary adenomas: clinical and biochemical heterogeneity. Ann Intern Med 1989; 111:827.

Refetoff S, Weiss RE, Usala SJ. The syndromes of resistance to thyroid hormone. Endocr Rev 1993; 14:348.

Beck-Pecoz P, Forloni F, Cortelazz D, et al. Pituitary resistance to thyroid hormones. Horm Res 1992; 38:66.

Helzberg JH, McPhee MS, Zarling EJ, Lukert BP. Hepatocellular carcinoma: an unusual course with hyperthyroidism and inappropriate thyroid-stimulating hormone production. Gastroenterology 1985; 88:181.

Higgins HP, Hershman JM, Kenimer JG, et al. The thyrotoxicosis of hydatidiform mole. Ann Intern Med 1975; 83:307.

Hoermann R, Broecker M, Grossmann M, et al. Interaction of human chorionic gonadotropin (hCG) and asialo-hCG with recombinant human thyrotropin receptor. J Clin Endocrinol Metab 1994; 77: 1009.

Spiegel AM. Mutations in G proteins and G protein–coupled receptors in endocrine disease. J Clin Endocrinol Metab 1996; 81:2434.

Van Sande J, Parma J, Tonacchera M, et al. Somatic and germline mutations of the TSH receptor gene in thyroid diseases. J Clin Endocrinol Metab 1995; 80:2577.

Bodenner DL, Lash RW. Thyroid disease mediated by molecular defects in cell surface and nuclear receptors. Am J Med 1998; 105:524.

Morris JC. The clinical expression of thyrotropin receptor mutations. Endocrinologist 1998; 8:195.

Parma J, Duprez L, Van Sande J, et al. Somatic mutations in the thyrotropin receptor gene cause hyperfunctioning thyroid adenomas. Nature 1993; 365:649.

Holzapfel HP, Führer D, Wonerow P, et al. Identification of constitutively activating somatic thyrotropin receptor mutations in a subset of toxic multinodular goiters. J Clin Endocrinol Metab 1997; 82:4229.

Parma J, Duprez L, Van Sande J, et al. Diversity and prevalence of somatic mutations in the thyrotropin receptor and Gsa genes as a cause of toxic thyroid adenomas. J Clin Endocrinol Metab 1997; 82:2695.

Russo D, Arturi F, Wicker R, et al. Genetic alterations in thyroid hyperfunctioning adenomas. J Clin Endocrinol Metab 1995; 80:1347.

Duprez L, Parma J, Costagliola S, et al. Constitutive activation of the TSH receptor by spontaneous mutations affecting the N-terminal extracellular domain. FEBS Lett 1997; 409:469.

Tonacchera M, Chiovato L, Pinchera A, et al. Hyperfunctioning thyroid nodules in toxic multinodular goiter share activating thyrotropin receptor mutations with solitary toxic adenoma. J Clin Endocrinol Metab 1998; 83:492.

Führer D, Holzapfel HP, Wonerow P, et al. Somatic mutations in the thyrotropin receptor gene and not in the Gsa protein gene in 31 toxic thyroid nodules. J Clin Endocrinol Metab 1997; 82:3885.

Leclère J, Béné MC, Aubert V. Clinical consequences of activating germline mutations of TSH receptor, the concept of toxic hyperplasia. Horm Res 1997; 47:158.

Duprez L, Parma J, Van Sande J, et al. Germline mutations in the thyrotropin receptor gene cause non-autoimmune autosomal dominant hyperthyroidism. Nat Genet 1994; 7:396.

Führer D, Wonerow P, Willgerodt H, Paschke R. Identification of a new thyrotropin receptor germline mutation (Leu629Phe) in a family with neonatal onset of autosomal dominant nonautoimmune hyperthyroidism. J Clin Endocrinol Metab 1997; 82:4234.

Schwab KO, Gerlich M, Broecker M, et al. Constitutively active germline mutation of the thyrotropin receptor gene as a cause of congenital hyperthyroidism. J Pediatr 1997; 131:899.

Grüters A, Schöneberg T, Biebermann H, et al. Severe congenital hyperthyroidism caused by a germ-line neo mutation in the extracellular portion of the thyrotropin receptor. J Clin Endocrinol Metab 1998; 83:1431.

Khoo DHC, Parma J, Rajasoorya C, et al. A germline mutation of the thyrotropin receptor gene associated with thyrotoxicosis and mitral valve prolapse in a Chinese family. J Clin Endocrinol Metab 1999; 84:1459.

Sunthoruthepvarakui T, Gottschalk ME, Hayashi Y, Refetoff S. Resistance to thyrotropin caused by mutations in the thyrotropin-receptor gene. N Engl J Med 1995; 332:155.

de Roux N, Misrahi M, Brauner R, et al. Four families with loss of function mutations of the thyrotropin receptor. J Clin Endocrinol Metab 1996; 81:4229.

Gagné N, Parma J, Deal C, et al. Apparent congenital athyreosis contrasting with normal plasma thyroglobulin levels and associated with inactivating mutations in the thyrotropin receptor gene: are athyreosis and ectopic thyroid distinct entities? J Clin Endocrinol Metab 1998; 83:1771.

Levine MA, Downs RW Jr, Moses AM, et al. Resistance to multiple hormones in patients with pseudohypoparathyroidism. Am J Med 1983; 74:545.

Thotakura NR, Desai BK, Bates LG, et al. Biological activity and metabolic clearance of a recombinant human thyrotropin produced in Chinese hamster ovary cells. Endocrinology 1991; 128:341.

Meier CA, Braverman LE, Ebner SA, et al. Diagnostic use of recombinant human thyrotropin in patients with thyroid carcinoma (phase I/II study). J Clin Endocrinol Metab 1994; 78:188.

Haugen BR, Pacini F, Reiners C, et al. A comparison of recombinant human thyrotropin and thyroid hormone withdrawal for the detection of thyroid remnant or cancer. J Clin Endocrinol Metab 1999; 84:3877.

Spiegel AM, Weinstein US, Shenker A. Abnormalities in G protein coupled signal transduction pathways in human disease. J Clin Invest 1993; 92:1119.




  2. […] Whats the difference between the various synthetic thyroid hormonesTSH – Thyroid Stimulating HormoneHypothyroidism and Diet – Good and Bad Foods4 Keys To Successful Weight Loss With Hypothyroidism and Hashimoto's thyroid diseaseCHAPTER 15 THYROID-STIMULATING HORMONE AND ITS DISORDERS […]

  3. swift transportation
    Very interesting subject , regards for putting up.

  4. It truly is rare to come across a professional in whom you may have some trust. In the world today, nobody absolutely cares about showing others exactly how in this subject matter. How happy I am to have found a real wonderful blog as this. It’s people like you exactly who make a true difference these days through the tips they discuss.

  5. F*ckin’ awesome things here. I am very glad to see your post. Thanks a lot and i’m looking forward to contact you. Will you please drop me a mail?

  6. […] About What Causes Weight Gain After 40It’s Hard to Get Excited About Reduced Carb Diet PlansCHAPTER 15 THYROID-STIMULATING HORMONE AND ITS DISORDERS ul.legalfooter li{ list-style:none; float:left; padding-right:20px; } .accept{ display:none; […]

Leave a Reply

Fill in your details below or click an icon to log in:

WordPress.com Logo

You are commenting using your WordPress.com account. Log Out / Change )

Twitter picture

You are commenting using your Twitter account. Log Out / Change )

Facebook photo

You are commenting using your Facebook account. Log Out / Change )

Google+ photo

You are commenting using your Google+ account. Log Out / Change )

Connecting to %s

%d bloggers like this: