Human Physiology - William F. Ganong 2002

Endocrine System, Metabolism, and Reproduction
Thyroid Gland
Regulation of Thyroid Secretion

Thyroid Gland function is regulated primarily by Changes in the circulating levels of pituitary TSH. TSH secretion is stimulated by hypophysiotropic thyrotropin-releasing hormone (TRH; see Chapter 14) and inhibited via a negative feedback mechanism exerted by circulating free T₄ and T₃. The action of circulating T₄ is enhanced when it is converted to T₃ within the Cytoplasm of pituitary Cells by the enzyme 5"-DII. TSH secretion is also suppressed by stress; in experimental animals, it is stimulated by cold and inhibited by heat.

Chemistry and METABOLISM of TSH

Human TSH is a glycoprotein containing 211 amino acid residues along with hexoses, hexosamines, and sialic acid. It consists of two subunits, a and ß. The a-subunit is encoded by a Gene on chromosome 6, and the ß-subunit by a gene on chromosome 1. The two subunits are noncovalently linked. The TSH a-subunit is identical to the a-subunits of LH, FSH, and hCG (see Chapters 22 and 23). The functional Specificity of TSH resides in the ß-subunit. While The Structure of TSH varies across species, TSH from other mammals is also active in humans.

The biological half-life of human TSH is approximately 60 minutes. Most TSH is degraded in the Kidneys, with a smaller portion broken down in the Liver. Its secretion is pulsatile, with mean output beginning to rise around 9:00 PM, peaking at midnight, and declining throughout the day. The normal secretion rate is about 110 µg/day, and the mean plasma level is 2 µIU/mL (Fig. 18-12).

Because the a-subunit of hCG is identical to that of TSH, high levels of hCG can activate thyroid receptors. In some patients with benign or malignant placental tumors, plasma hCG levels may rise high enough to cause mild hyperthyroidism.

Effects of TSH on The Thyroid Gland

Hypophysectomy leads to depression of thyroid function and glandular atrophy, whereas administration of TSH stimulates the gland. Within minutes of TSH administration, there is an increase in iodide binding, the synthesis of T₃, T₄, and iodotyrosines, the secretion of thyroglobulin into the colloid, and colloid endocytosis. Iodine concentration increases after several hours, resulting in accelerated Blood flow; with chronic TSH Treatment, the cells undergo hypertrophy, and the mass of the gland increases.

Prolonged stimulation by TSH causes a marked enlargement of the thyroid gland, a condition known as a goiter (also referred to as a struma).

TSH Receptors

The TSH receptor is a typical serpentine receptor that activates adenylyl cyclase via a G protein. It also triggers the activation of PLC. Like the receptors for other glycoprotein Hormones, it possesses an elongated, glycosylated extracellular domain.

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Fig. 18-12. Relationship between plasma TSH levels, measured by a ultrasensitive radioimmunoassay, and plasma free T levels determined by dialysis (FT₄). Note that the TSH scale is logarithmic.

Other Factors Affecting Thyroid Growth

In addition to TSH receptors, thyroid cells contain receptors for IGF-I, EGF, and other growth factors. IGF-I and EGF promote growth, whereas y-interferon and tumor necrosis factor inhibit it. The exact Physiological Role of these factors in the thyroid gland remains to be fully elucidated.

Regulatory Mechanisms

The mechanisms regulating thyroid secretion are illustrated in Fig. 18-13. The negative feedback regulation—The Effect of THYROID HORMONES on TSH secretion—acts partly at the hypothalamic level, but is also largely a pituitary effect, as T₄ and T₃ block the TRH-induced increase in TSH secretion. The relationship between plasma TSH levels and the FT₄ index is shown in Fig. 18-12. Infusion of T₄, much like T₃, decreases circulating TSH levels, which drop markedly within an hour. In experimental animals, an initial increase in pituitary TSH content persists before secretion begins to fall, indicating that thyroid hormones inhibit secretion before they slow down synthesis. The effects on TSH secretion and synthesis are known to depend on Protein Synthesis, even though the initial response is relatively rapid. The daily maintenance of appropriate thyroid secretion depends on the negative feedback loop between thyroid hormones, TSH, and TRH (see Fig. 18-13). Regulation, likely mediated via TRH, includes cold-induced increases in thyroid hormone secretion and, potentially, heat-induced decreases. Notably, cold exposure causes a distinct rise in blood TSH in experimental animals and newborns, but has little effect on this response in adults. Consequently, in adults, increased heat production driven by elevated thyroid hormone secretion (thyroid hormone thermogenesis) plays only a minor role in the response to cold. Stress inhibits TRH secretion. Dopamine and Somatostatin act at the pituitary level to suppress TSH secretion, though it remains unclear whether they play a physiological role in regulating TSH output.

Fig. 18-13. Feedback regulation of thyroid secretion. Dashed arrows indicate inhibitory effects, and solid arrows indicate stimulatory effects. Compare with Figs. 20-20, 22-11, 23-24, and 23-38.

The amount of thyroid hormone required to maintain normal cellular function in thyroidectomized individuals was traditionally determined as the dose needed to normalize the basal metabolic rate. Today, however, it is defined as the amount necessary to return plasma TSH levels to normal. In fact, given the exceptional precision and sensitivity of modern TSH assays and the marked inverse relationship between plasma free thyroid hormones and plasma TSH, TSH measurement is now practiced as one of the best tests for assessing thyroid function. The amount of T₄ that normalizes plasma TSH levels in athyreotic individuals averages 112 µg of oral T₄ per day for adults. About 80% of this dose is absorbed from the gastrointestinal tract. It produces a slightly elevated FT₄ index, but a normal FT₃ index, indicating that in humans—unlike in some experimental animals—plasma T₃ rather than T₄ serves as the primary regulator of TSH secretion via negative feedback.