Vasopressin

Vasopressin (antidiuretic hormone [ADH]) acts on the kidney to increase water reabsorption. It increases total peripheral resistance and has an important role in the long-term control of blood pressure. Vasopressin also has a vasoconstrictor action that plays a role in the short-term regulation of arterial pressure. There are two subtypes of vasopressin receptors. V₁ receptors, which are G_q/11 protein–linked, produce their action by stimulation of phospholipase C and formation of inositol triphosphate. This is the pathway responsible for the vasoconstrictor action of vasopressin. V₂ receptors, which are G_s protein–linked, cause stimulation of adenylyl cyclase and increase cyclic adenosine 3′,5′-monophosphate (cAMP) formation. Stimulation of V₂ receptors by vasopressin leads to its antidiuretic effect. Lack of ADH leads to diabetes insipidus, resulting in polyuria and polydipsia.

Oxytocin

Oxytocin receptors are G_q/11 protein–linked receptors that, when stimulated, lead to an increase in intracellular Ca⁺⁺ and muscle contraction. Oxytocin causes contraction of uterine smooth muscle and may play a role in the initiation of labor. Oxytocin also stimulates milk ejection in lactating mothers by stimulating myoepithelial cells around the alveoli of the mammary glands. Recent data suggests that oxytocin is a neuropeptide involved in a wide array of social behaviors in diverse species. Maternal bonding, social decision making, and processing of social stimuli and social memory are enhanced by increased levels of oxytocin.

Growth Hormone

Growth hormone (GH), also known as somatotropin, is the most abundant of the anterior pituitary hormones. The principal form of GH is a 191-amino acid single-peptide chain with two sulfhydryl bridges. GH for pharmacologic use is produced by recombinant DNA techniques and contains the 191-amino acid sequence of somatotropin, recombinant human GH, or 192 amino acids consisting of somatotropin plus an extra methionine at the amino terminal end. These preparations are equipotent.

Prolactin

Prolactin is an anterior pituitary hormone that is similar in structure to GH. Prolactin increases the growth of the secretory epithelium in the breast and stimulates the production of milk. Although prolactin is not used clinically, the secretion of prolactin can be altered by certain drugs. Because dopamine inhibits prolactin release (Table 34-2), drugs that affect dopamine levels or dopamine receptors in the pituitary affect prolactin release. Bromocriptine and cabergoline are dopamine-receptor agonists that are used to inhibit prolactin release and reduce the size of pituitary prolactin-releasing tumors.

TABLE 34-2 Hypothalamic Inhibitory Releasing Factors, Anterior Pituitary Hormones Inhibited, and Target Glands

Thyrotropin (Thyroid-Stimulating Hormone)

Thyrotropin (thyroid-stimulating hormone [TSH]) is a glycoprotein hormone consisting of two subunits (α and β). Secretion is pulsatile and follows a circadian rhythm, with levels of TSH being highest during sleep at night. TSH secretion is controlled by thyrotropin-releasing hormone (TRH), which is inhibited by thyroid hormone negative feedback. Because TRH is stimulated by cold and decreased by severe stress, TSH is also affected by these conditions. TSH stimulates the thyroid to synthesize thyroglobulin and the thyroid hormones thyroxine (T₄) and triiodothyronine (T₃). An increase in the amount of free thyroid hormone in the circulation results in decreased TSH gene transcription and decreased TSH secretion.

The TSH receptor is G protein–coupled. The effects of TSH are mediated by stimulation of adenylyl cyclase and increased cAMP (G_s–adenylyl cyclase–cAMP) in the thyroid cell. TSH also causes activation of phospholipase C (G_q-PLC). TSH is used for diagnostic purposes and to stimulate iodine (¹³¹I) uptake in some patients with thyroid cancer (see later).

Synthesis of Thyroid Hormones

The synthesis of thyroid hormones is shown schematically in Figure 34-2. The first step is uptake of iodide by the thyroid gland. This step may be inhibited by ions of similar size and charge such as perchlorate. Iodide uptake is followed by oxidation of iodide to hypoiodite and iodination of tyrosyl groups of thyroglobulin to form iodotyrosyl groups. Tyrosine residues within the thyroglobulin molecule may be monoiodinated to monoiodotyrosine (MIT) or diiodinated to form diiodotyrosine (DIT). This step is catalyzed by thyroperoxidase and is rapid. Iodotyrosyl residues are coupled to form iodothyronyl residues within thyroglobulin. This may be either MIT plus DIT to form T₃ or DIT plus DIT to form T₄. The ratio of T₄ to T₃ formed is approximately 4 : 1. The coupling of iodotyrosyl groups is also catalyzed by peroxidase enzyme. Thyroid hormones are released by proteolysis of thyroglobulin. Most of the hormone released is T₄, which is converted to T₃ in peripheral tissues by iodothyronine deiodinases. T₃ is about four times more potent than T₄.

FIGURE 34-2 Synthesis of thyroid hormones and sites of action of various antithyroid drugs. DIT, Diiodotyrosine; MIT, monoiodotyrosine; T₃, triiodothyronine; T₄, thyroxine.

Control of Thyroid Hormone Secretion

The effect of TSH on the thyroid gland is to stimulate the synthesis and secretion of thyroid hormones T₄ and T₃ (see previous discussion). In addition to TSH, the iodine concentration in the blood plays an important role in regulating the uptake of iodide and formation of thyroid hormones in the thyroid gland. Iodination and thyroid hormone release can be inhibited by larger doses of iodides.

The hypothalamic-pituitary-thyroid axis is stimulated by cold and decreased in severe stress. It is under negative feedback control of the thyroid hormones, which act on the hypothalamus to decrease TRH synthesis and secretion, and on the pituitary to block the action of TRH.

Actions of Thyroid Hormones

Thyroid hormones act by diffusing across the cell membrane and binding to intracellular receptors in target tissues. T₄ is converted to T₃ inside the cell. T₃ has greater affinity than T₄ for the receptors. The action of thyroid hormones leads to an increase in transcription, resulting in synthesis of proteins that produce many of the actions of thyroid hormones. Thyroid hormones are crucial in normal development and metabolism. They have a critical effect on growth, partly by direct action and partly by potentiating GH. Thyroid hormones are important for a normal response to parathyroid hormone (PTH) and calcitonin. They are crucial for nervous and skeletal tissues. Thyroid deficiency during development causes cretinism, characterized by mental retardation and dwarfism.

In addition, thyroid hormones are regulators of metabolism in most tissues. They increase basal metabolic rate and resting respiratory rate. Thyroid hormones stimulate the heart, resulting in the heart beating more rapidly and with greater force and an increase in cardiac output. Energy use in skeletal muscle, liver, and kidney is also markedly stimulated. T₃ sensitizes the heart to the effects of circulating endogenous catecholamines by a direct effect on Ca⁺⁺ channels,⁸ and thyroid hormones cause an increase in myocardial β-adrenergic receptors.¹⁷

Pharmacokinetics

The thyroid hormones are highly protein-bound; the major plasma-binding protein is thyroxine-binding globulin. They are also bound by thyroxine-binding prealbumin and albumin. The half-life of T₄ is normally 6 to 7 days; this is shortened to 3 to 4 days in hyperthyroidism. T₃ binds more loosely to plasma proteins and has a half-life of approximately 2 days.

Hypothyroidism

Thyroid deficiency during development causes cretinism, which is characterized by gross retardation of growth and mental deficiency. In an adult, thyroid deficiency results in hypothyroidism and, in more severe cases, myxedema. Hypothyroidism is a common endocrine disorder affecting 1.4% to 2% of women and 0.1% to 0.2% of men. The prevalence of overt and subclinical hypothyroidism is significantly greater in women than in men and increases dramatically in women after age 40 years, affecting 5% to 10% of women older than 50 years.² Subclinical hypothyroidism is common, especially among older women.¹⁵ It has been suggested that this condition may be associated with an increased mortality rate, particularly from cardiovascular disease and a subtle decrease in myocardial contractility.¹¹ Subclinical hypothyroidism is associated with a small increase in low-density lipoprotein cholesterol and a decrease in high-density lipoprotein cholesterol, changes that increase risk of atherosclerosis and coronary artery disease.¹⁰ Cognitive impairment occurs in hypothyroidism, and attention, motor speed, memory, and visual spatial organization all are significantly impaired.⁴ In addition, hypothyroidism is an important risk factor for carpal tunnel syndrome.¹⁴

Signs and Symptoms of Hypothyroidism

Typical symptoms of hypothyroidism include lethargy; fatigue; loss of energy and ambition; slowing of intellectual and motor activity; decreased appetite; increased weight; and skin that is dry, cold, and coarse. Hair loss, including loss of the outer third of eyebrows, occurs. Hypothyroid patients have cold intolerance, bradycardia, hypotension, and increased capillary fragility. They also show an exaggerated response to central nervous system depressants such as sedatives and narcotic analgesics.

Replacement Therapy

Animal products include desiccated thyroid, which is composed of animal thyroid glands. Numerous preparations of levothyroxine sodium (T₄) are available. Liothyronine sodium (T₃) and liotrix, a mixture of T₄ and T₃ in a 4 : 1 ratio, are also available. Synthetic T₄ has a uniform content and a long half-life and is the preferred and most widely used thyroid replacement medication. Because of its greater potential for cardiotoxicity and its shorter half-life, the use of T₃ is controversial and much less frequent. Nevertheless, for some patients, the combination of T₃ and T₄ is better than T₄ alone.³ Animal experiments have shown that in rats, only replacement of T₃ and T₄ ensures euthyroidism in all tissues.

The thyroid hormones are well absorbed after oral administration. Absorption of T₄ may be decreased, however, by food, Ca⁺⁺ preparations, and aluminum-containing antacids. Absorption of T₄ is best if it is taken on an empty stomach in the morning. Absorption of T₃, which is almost completely absorbed, is not affected by food.

Levothyroxine has a half-life of approximately 7 days. It takes about 1 month to reach steady state. The half-life of liothyronine is shorter (<2 days), as is its duration of action.

Hyperthyroidism

Hyperthyroidism may be caused by Graves’ disease (diffuse toxic goiter), an autoimmune disorder, or toxic nodular goiter. Graves’ disease is the most common cause of hyperthyroidism in the United States. In hyperthyroidism (thyrotoxicosis), there is an excess of thyroid hormones, resulting in a high metabolic rate, increased heart rate and contractility, and increased sensitivity to catecholamines. Other signs and symptoms include increased appetite but decreased weight, weakened skeletal muscles or muscle wasting, increased body temperature, sensitivity to heat, nervousness, and tremor. Exophthalmus may be present in Graves’ disease.

Hyperthyroidism may be treated surgically or pharmacologically. The most common treatments are described subsequently.

Radioactive Iodine

The ¹³¹I isotope has a half-life of 8 days and emits γ radiation and β particles. Given orally, it is concentrated in the thyroid, where the β particles destroy the gland. Symptoms of hyperthyroidism begin to improve in a few />