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MD Consult: Books: Goldman: Cecil Medicine: THYROID-STIMULATING HORMONE

Goldman: Cecil Medicine, 23rd ed.

Copyright © 2007 Saunders, An Imprint of Elsevier


Like the other glycoprotein hormones, TSH is a heterodimer composed of the common α subunit and the unique TSH β subunit. TSH is produced in thyrotroph cells. TSH is measured by highly sensitive immunoradiometric assays that use antisera directed toward the TSH β subunit. Normal levels of TSH range from 0.4 to 4.0 μU/mL. The detection limit for current TSH assays is less than 0.01 μU/mL, thus allowing measurement of suppressed TSH levels in patients with hyperthyroidism.

TSH controls thyroid hormone (T4 and T3) synthesis and secretion from the thyroid gland. TSH stimulates cyclic adenosine monophosphate production and acts as a trophic hormone as well as stimulating hormone synthesis. TSH secretion from the pituitary gland is regulated by the hypothalamic-pituitary-thyroid axis. Hypothalamic TRH is a tripeptide that stimulates TSH synthesis and secretion. Various other hypothalamic hormones including somatostatin and dopamine can inhibit TSH secretion, but their roles in normal physiology have not been clearly elucidated.

Thyroid hormones have an inhibitory effect on the production of TRH and TSH and constitute a powerful negative feedback loop in the hypothalamic-pituitary-thyroid axis. The direct effects of thyroid hormone at the level of the pituitary gland are well illustrated by TSH responses to TRH stimulation tests. In hypothyroidism, TSH responses to exogenous TRH are exaggerated. In hyperthyroidism, TSH responses to TRH are blunted or flat, a finding indicating that the inhibitory effects of thyroid hormone override the stimulatory effects of TRH. Thyroid hormones act through nuclear receptors that function at the transcriptional level to suppress expression of the TRH gene as well as the α- and β-subunit genes of TSH. In hypothyroidism, expression of the TSHα and TSHβ genes is stimulated, and hormone production is markedly enhanced.

Secretion of TSH is pulsatile, but the amplitude of the pulses is relatively small and does not create the difficulties in measurement of TSH that are encountered with measurements of other pituitary hormones. TSH levels are elevated in infants in the immediate postpartum period. Thereafter, thyroid function tests remain remarkably constant throughout life. TSH secretion has a diurnal rhythm with a small increase at night. Because of the integrated nature of the hypothalamic-pituitary-thyroid axis, thyroid function tests are best interpreted when concentrations of TSH, free T4, and free T3 levels are known. Except in conditions of secondary hypothyroidism or TSH-secreting pituitary tumors, TSH levels provide an excellent screening test for thyroid dysfunction. In cases of primary hypothyroidism, TSH levels are elevated as TSH increases logarithmically in response to falling thyroid hormone levels. In hyperthyroidism, TSH is suppressed to levels lower than or near the detection limits of most sensitive assays.


Central forms of hypothyroidism include secondary hypothyroidism, which is caused by TSH deficiency, and tertiary hypothyroidism, which is caused by TRH deficiency. Three different types of congenital TSH deficiency are caused by genetic mutations. One type involves mutations in the TSHβ gene, in which several different types of mutations have been described. A second involves mutations in Pit-1, which causes combined deficiencies of GH, PRL, and TSH (see earlier). A third involves a mutation in the gene for TRH. Acquired, central forms of hypothyroidism are often associated with other pituitary hormone deficiencies, and usually goiter is absent because of low TSH levels.

Tests for TSH deficiency are best interpreted by analyzing free T4 levels in combination with TSH. Low free T4 without elevated TSH is consistent with central hypothyroidism. Free T4 measurements should be used, rather than total T4, to avoid confusion caused by thyroxine-binding globulin deficiency. In some patients with hypothalamic disease, the TSH level is partially elevated in the presence of low levels of free T4, but the bioactivity of the TSH is reduced. Central forms of hypothyroidism must be distinguished from the sick-euthyroid condition ( Chapter 244 ). Laboratory tests in patients with the sick-euthyroid syndrome progress through several phases but can include prolonged periods when both TSH and free thyroid hormone levels are low. It can be very difficult in these patients to exclude central hypothyroidism unequivocally. In addition to the clinical setting in which thyroid function tests are measured, the presence of normal thyroid function tests before the illness and the absence of known hypothalamic or pituitary disease make true central hypothyroidism unlikely. Increased levels of reverse T3 are suggestive of sick-euthyroidism, and free T4 and T3 may be in the normal or low normal range in sick-euthyroid patients. When TSH deficiency is documented, thyroid hormone is replaced using daily doses of l-thyroxine (0.05 to 0.15 mg/day). Because TSH cannot be used as an end point, one monitors serum levels of free T4 and T3.


Etiology and Pathogenesis

TSH-secreting tumors are rare and account for 1 to 3% of pituitary tumors. TSH-producing tumors may be plurihormonal. GH and PRL are co-secreted most often, a finding perhaps reflecting the common cellular lineage for thyrotrophs, somatotrophs, and lactotrophs. Long-standing severe hypothyroidism can cause thyrotroph hyperplasia and pituitary enlargement. These hyperplastic masses regress with thyroid hormone replacement therapy. Most true TSH-producing tumors are relatively autonomous and respond weakly to TRH stimulation or to thyroid hormone suppression.

Clinical Manifestations

TSH-secreting tumors are usually macroadenomas by the time a diagnosis has been made. Consequently, many patients exhibit mass effects of the tumor and hyperthyroidism. Now that measurement of TSH is used as the initial assessment for hyperthyroidism, however, smaller tumors are seen more commonly than previously. The clinical features of TSH-secreting tumors resemble those of Graves’ disease, except features of autoimmunity such as ophthalmopathy are absent. Circulating levels of T4 and T3 range widely but can be elevated as much as two- to threefold. Diffuse goiter is present in the majority of patients with TSH-producing tumors, and the 24-hour uptake of radioiodine is elevated.


Because feedback inhibition of TSH is impaired in TSH-producing tumors, TSH levels are inappropriately elevated in the presence of high levels of T4 and T3. TSH levels produced by tumors range from the low normal to as high as 500 μU/mL, but most levels are minimally elevated. Free α-subunit measurements can be very helpful in confirming the diagnosis of a TSH-secreting tumor. Most TSH-producing tumors (>80%) secrete excess free α subunit. Thus, the diagnosis of a TSH-secreting tumor can usually be made by demonstrating that a hyperthyroid patient has a detectable serum TSH level associated with excess secretion of the free α subunit. The finding of a mass lesion on CT or MRI confirms the diagnosis. Several other causes of inappropriate TSH secretion should be considered, including resistance to thyroid hormone and familial dysalbuminemic hyperthyroxinemia and other disorders that alter serum thyroid hormone–binding proteins.


The goals of therapy are to treat the underlying TSH-secreting tumor and to correct the hyperthyroidism. Transsphenoidal surgery alone is rarely curative because of the large size of most tumors, but it can alleviate mass effects and lower TSH levels. As in other large pituitary tumors, adjunctive irradiation may be required to control tumor growth. Somatostatin analogues have been used as adjunctive medical therapy, and they decrease TSH and α-subunit levels in approximately 80% of patients with TSH-secreting tumors. However, consistent effects on tumor growth have not been demonstrated. Hyperthyroidism caused by TSH-secreting tumors can be treated using antithyroid drugs or radioiodine.


Null cell adenomas, or clinically nonfunctioning tumors, are variably defined depending on the criteria used to analyze tumor cell phenotype. The majority of clinically nonfunctioning adenomas can be shown to produce low levels of the free α subunit, free β subunits of FSH and LH, and intact FSH and LH when analyzed by immunocytochemistry or for messenger RNA expression. A smaller fraction can be shown to produce low levels of other pituitary hormones, particularly ACTH or GH. Even with detailed analyses of hormone production, a subset (10 to 20%) of nonfunctioning adenomas does not appear to produce one of the major pituitary hormones.

The clinical features and management of null cell tumors are similar to those for gonadotropin-producing tumors. The major signs and symptoms result from tumor mass effects that cause visual field defects, headache and other neurologic symptoms, and hypopituitarism. Transsphenoidal surgery is the primary mode of treatment, with a goal of debulking the tumor to relieve mass effects. Because no serum tumor markers are known, patients must be followed by CT or MRI in conjunction with visual field tests.

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