The pituitary regulates the synthesis and secretion of thyroid hormones through the release of thyrotropin—also known as thyroid-stimulating hormone (TSH)—from the anterior pituitary. The hypothalamus, in turn, stimulates the release of TSH through thyrotropin-releasing hormone (TRH). Finally, circulating thyroid hormones exert feedback control on both TRH and TSH secretion.
TRH from the hypothalamus stimulates thyrotrophs of the anterior pituitary to secrete TSH, which stimulates T4/T3 synthesis
TRH is a tripeptide pyro-Glu-His-Pro containing the modified amino acid pyro-Glu. It is found in many tissues, including the cerebral cortex, multiple areas of the GI tract, and the β cells of the pancreas. However, the arcuate nucleus and the median eminence of the hypothalamus appear to be the major sources of the TRH that stimulates TSH synthesis and secretion (Fig. 49-8). TRH released by neurons in the hypothalamus travels to the anterior pituitary through the hypophyseal portal system (see p. 978). Hypothalamic lesions that interrupt TRH release or delivery cause a fall in basal TSH levels. Conversely, administering TRH intravenously can cause a rapid, dose-dependent release of TSH from the anterior pituitary. However, it is not clear that such bursts of TRH release and TSH secretion occur physiologically.
FIGURE 49-8 Hypothalamic-pituitary-thyroid axis. Small-bodied neurons in the arcuate nucleus and median eminence of the hypothalamus secrete TRH, a tripeptide that reaches the thyrotrophs in the anterior pituitary via the long portal veins. TRH binds to a G protein–coupled receptor on the thyrotroph membrane, triggering the DAG/IP3 pathway; stimulation of this pathway leads to protein phosphorylation and a rise in [Ca2+]i. These pathways stimulate the thyrotrophs to synthesize and release TSH, which is a 28-kDa glycoprotein stored in secretory granules. The TSH binds to receptors on the basolateral membrane of thyroid follicular cells, stimulating Gαs, which in turn activates adenylyl cyclase and raises [cAMP]i. As outlined in Figure 49-3, TSH stimulates a number of steps in the synthesis and release of T4 and T3. Inside the pituitary, the type 2 form of 5′/3′-monodeiodinase converts T4 to T3, which negatively feeds back on the thyrotrophs as well as on the TRH-secreting neurons. Somatostatin and dopamine—released by hypothalamic neurons—inhibit TSH release and thus can influence the set-point at which TSH is released in response to a given amount of T3 in the pituitary. AC, adenylyl cyclase; MCT8, monocarboxylate transporter 8; PKC, protein kinase C; PLC, phospholipase C.
Once it reaches the thyrotrophs in the anterior pituitary, TRH binds to the TRH receptor, a G protein–coupled receptor on the cell membranes of the thyrotrophs. TRH binding triggers the phospholipase C pathway (see p. 58). The formation of diacylglycerols (DAGs) stimulates protein kinase C and leads to protein phosphorylation. The simultaneous release of inositol trisphosphate (IP3) triggers Ca2+ release from internal stores, raising [Ca2+]i. The result is an increase in both the synthesis and release of TSH, which is stored in secretory granules. TRH produces some of its effects by activating phospholipase A2, a process leading to the release of arachidonic acid and the formation of a variety of biologically active eicosanoids (see pp. 62–64). In healthy humans, administering TRH also raises plasma [prolactin] by stimulating lactotrophs in the anterior pituitary (see p. 1150). However, no evidence indicates a regulatory role for TRH in prolactin secretion or milk production.
The thyrotrophs represent a relatively small number of cells in the anterior pituitary. The TSH that they release is a 28-kDa glycoprotein with α and β chains. The α chain of TSH is identical to that of the other glycoprotein hormones: the gonadotropins luteinizing hormone (LH), follicle-stimulating hormone (FSH), and human chorionic gonadotropin (hCG). The β chain is unique to TSH and confers the specificity of the hormone. Once secreted, TSH acts on the thyroid follicular cell via a specific receptor.
The TSH receptor on the thyroid follicular cells is a G protein–coupled receptor. Like receptors for the other glycoprotein hormones (LH, FSH, and hCG), the TSH receptor, via Gαs, activates adenylyl cyclase (see p. 53). The rise in [cAMP]i stimulates a diverse range of physiological processes or events, summarized in Figure 49-3:
1. Iodide uptake by NIS on the basolateral membrane of the thyroid follicular cell. Stimulation of this cotransporter allows for trapping of dietary iodine within the thyroid gland (including follicular cells and colloid). The ratio of thyroid to serum iodine (the so-called thyroid/serum or T/S ratio) is 30 : 1 in euthyroid individuals. The T/S ratio decreases under conditions of low TSH (e.g., hypophysectomy), and increases under conditions of high TSH (e.g., a TSH-secreting pituitary adenoma).
2. Iodination of thyroglobulin in the follicular lumen.
3. Conjugation of iodinated tyrosines to form T4 and T3 within the thyroglobulin molecule.
4. Endocytosis of iodinated thyroglobulin into the follicular cells from thyroid colloid.
5. Proteolysis of the iodinated thyroglobulin in the follicular cell.
6. Secretion of T4 and T3 into the circulation.
7. Hyperplasia of the thyroid gland because of the growth-promoting effects of TSH.
Figure 49-9 illustrates the goiter that occurs when TSH concentrations are elevated for a prolonged period and stimulate an otherwise normal thyroid gland (see Box 49-1). Hyperplasia of the thyroid gland also occurs in Graves disease (Box 49-4) because of stimulation of the TSH receptor by a thyroid-stimulating immunoglobulin (see p. 1017). In contrast, the chronic elevation of TSH typically seen when the thyroid gland undergoes autoimmune destruction of follicular cells (Hashimoto thyroiditis) does not lead to follicular hypertrophy, but the gland may increase modestly in size from infiltration by immune cells.
FIGURE 49-9 Goiter in iodine deficiency. A young woman from a region in Central Africa where iodine deficiency is prevalent exhibits a large goiter secondary to iodine deficiency and the growth-promoting effects of TSH, the levels of which are part of a feedback mechanism for achieving a sufficient amount of thyroid hormone.
Surprisingly, it is not uncommon for B lymphocytes to synthesize immunoglobulins that bind to and activate the TSH receptor, thereby reproducing all the actions of TSH on the thyroid. Unfortunately, these errant lymphocytes do not regulate the production of these immunoglobulins in a manner analogous to the regulation of TSH secretion by the pituitary. As a result, iodine trapping by the thyroid increases, the synthesis and secretion of both T3 and T4 increase, and the thyroid enlarges to produce a goiter. Untreated, the affected individual becomes increasingly hyperthyroid. N49-4 The clinical manifestations of hyperthyroidism include an increased metabolic rate with associated weight loss, sweating and heat intolerance, a rapid and more forceful heartbeat, muscle weakness and wasting, tremulousness, difficulty concentrating, and changes in hair growth and skin texture. Because TSH stimulates all areas of the thyroid, the thyroid is symmetrically enlarged, and even the isthmus is frequently palpable and visible on clinical examination.
The abnormal immunoglobulin is designated thyroid-stimulating immunoglobulin (TSI). The constellation of symptoms noted previously, together with a symmetrical goiter, is called Graves disease after Robert Graves, who provided one of the first detailed descriptions of the disorder in the early 19th century. In some patients these antibodies are also able to stimulate connective tissue in the extraocular muscles and in the dermis of the lower extremity to synthesize mucopolysaccharides, which leads to thickening of both the muscle and the dermis. Therefore, in addition to the abnormalities of thyroid growth and hyperfunction, a minority of individuals with Graves disease develop a peculiar infiltrative abnormality in the extraocular muscles. When severe, this infiltrative ophthalmopathy impairs muscle function and causes diplopia (double vision) and a forward protrusion of the eyes (exophthalmos). Even less frequently, patients with Graves disease develop infiltrating dermopathy in the skin over the lower legs called pretibial myxedema. This thickening of the skin occurs in localized patches and is pathologically distinct from the generalized thickening and coarsening of the skin seen in hypothyroidism (generalized myxedema).
Contributed by Eugene Barrett
Some patients with hyperthyroidism become extremely ill and are said to be in thyroid storm. These individuals usually have a severe illness superimposed on their hyperthyroidism, and they develop high fevers, a profound tachycardia, sweating, and restlessness. Altered mental status is common. If untreated, these patients can develop severe circulatory collapse resulting in death. Thyroid storm can be the initial presentation of hyperthyroidism or it can occur in patients already known to be hyperthyroid and treated appropriately. However, when these latter individuals experience the severe stress of a major operation, trauma, or illness, they can develop thyroid storm. This condition is a true emergency. Treatment consists of giving sodium iodide, which over the long term encourages thyroid hormone synthesis but in the short term blocks the release of already-synthesized thyroid hormones; a β blocker to inhibit the β adrenoceptors, whose expression is increased by the elevated levels of thyroid hormones in the blood; and a drug such as propylthiouracil (PTU), which blocks the manufacture of additional thyroid hormone by inhibiting the iodination and conjugation steps. Fluid replacement and stress doses of corticosteroids are also given to support the circulation.
T3 exerts negative feedback on TSH secretion
Circulating free T4 and T3 inhibit both the synthesis of TRH by hypothalamic neurons and the release of TSH by the thyrotrophs in the anterior pituitary. Plasma [TSH] is very sensitive to alteration in the levels of free T4 and T3; a 50% decline in free T4 levels can cause plasma [TSH] to increase 50- to 100-fold. Conversely, as may be expected of a well-functioning feedback system, an excess of thyroid hormone leads to a decrease in plasma [TSH].
At the level of the thyrotroph, the sensor in this feedback system monitors the concentration of T3 inside the thyrotroph (see Fig. 49-8). As noted above, either T3 can enter directly from the blood plasma, or T3can form inside the thyrotroph by deiodination of T4. The negative feedback of T4 and T3 on TSH release occurs at the level of the pituitary thyrotroph by both indirect and direct mechanisms. In the indirect feedback pathway, intracellular T3 decreases the number of TRH receptors on the surface of the thyrotroph. As a result, thyroid hormones indirectly inhibit TSH release by reducing the sensitivity of the thyrotrophs to TRH. In the direct feedback pathway, intracellular T3 inhibits the synthesis of both the α and the β chains of TSH. Indeed, both the α and β TSH genes have T3 response elements in their promoter regions. These response elements, which are inhibitory, differ from those found in genes that are positively regulated by T3 (e.g., Na-K pump).
Free T4 and T3 concentrations in the plasma, which determine intracellular T3 levels in the thyrotroph, are relatively constant over the course of 24 hours, a finding reflecting the long half-lives of both T4 and T3(see p. 1009). Given that the levels of T4 and T3 are the primary triggers in the afferent limb of the negative feedback for the hypothalamic-pituitary-thyroid axis, the feedback regulation of TSH secretion by thyroid hormones appears to be a slow process—essentially integrating thyroid hormone levels over time. Indeed, T3 feeds back on the thyrotroph by modulating gene transcription, which by its very nature is a slow process.
The feedback of T4 and T3 on the release of TSH may also be under the control of somatostatin and dopamine, which travel from the hypothalamus to the thyrotrophs through the portal vessels (see Fig. 49-8). Somatostatin and dopamine both inhibit TSH secretion, apparently by making the thyrotroph more sensitive to inhibition by intracellular T3—that is, shifting the set-point for T3. Thus, somatostatin and dopamine appear to counterbalance the stimulatory effect of TRH. Although these inhibitory effects are readily demonstrated with pharmacological infusion of these agents, their physiological role in the regulation of TSH secretion appears small. In particular, with long-term administration of somatostatin or dopamine, compensatory mechanisms appear to override any inhibition.
A special example of feedback between T3 and TSH is seen in neonates of mothers with abnormal levels of T3. If the mother is hyperthyroid, both she and the fetus will have low TSH levels because T3 crosses the placenta. After birth, the newborn rapidly metabolizes its T3, but its TSH remains suppressed, so that the infant temporarily becomes hypothyroid. Conversely, if the mother's thyroid gland has been removed and she is hypothyroid because she is not receiving sufficient thyroid hormone replacement therapy, both she and the fetus will have high levels of circulating TSH. Immediately after birth, the newborn will be temporarily hyperthyroid (Box 49-5).
Clinical Assessment of Thyroid Function
Plasma TSH Levels
Direct measurements of T4/T3 provide a measure of total circulating hormone (i.e., the sum of free T4 and T3, as well as T4 and T3 bound to TBG, TTR, and albumin; see pp. 1008–1009). However, these direct measurements do not allow one to distinguish between bound and free T4/T3. The sensitive response of TSH to changes in thyroid hormone levels provides an extremely valuable tool for assessing whether the free T4/T3 levels in the circulation are deficient, sufficient, or excessive. Indeed, the level of TSH reflects the amount of free, biologically active thyroid hormone in the target tissue. As a result, in recent years, measurements of plasma TSH, using very sensitive immunoassay methods, have come to be regarded as the single best measure of thyroid hormone status. Obviously, this approach is valid only if the thyrotrophs themselves are able to respond to T3/T4—that is, if patients show no evidence of pituitary dysfunction.
The health of the thyrotrophs themselves can be tested by injecting a bolus of synthetic TRH and monitoring changes in plasma [TSH]. In hypothyroid patients, the subsequent rise in plasma [TSH] is more dramatic than in physiologically normal individuals. This test was of great value in confirming the diagnosis of hypothyroidism before the advent of today's ultrasensitive assays, but it has largely been abandoned.
Radioactive Iodine Uptake
Determining the amount of a standard bolus of radioactive iodine—123I (half-life, 13 hours) or 131I (half-life, 8 days)—that the thyroid can take up was also once widespread as a measure of thyroid function. A hyperactive gland will take up increased amounts of the tracer, whereas an underactive gland will take up subnormal amounts. Today, the test is used mostly for three other purposes. First, radioactive iodine uptake can show whether a solitary thyroid nodule, detected on physical examination, is “hot” (functioning) or “cold” (nonfunctioning). Cold nodules are more likely than hot ones to harbor a malignancy. Second, radioactive iodine uptake can show whether hyperthyroidism is the result of thyroid inflammation (i.e., thyroiditis), in which tracer uptake is minimal because of TSH suppression, or Graves disease, in which tracer uptake is increased because thyroid-stimulating immunoglobulin (see p. 1017) mimics TSH. Third, higher doses of radioactive iodine are commonly used to treat patients with hyperthyroidism. In this circumstance, the use of 131I causes radiolytic destruction of the overactive thyroid tissue. In the setting of thyroid cancer, therapists give very high doses of 131I to deliver sufficient radiation to tumors that retain only a little of the iodine-concentrating ability of the normal thyroid.