CHAPTER 34 Pituitary, Thyroid, and Parathyroid Pharmacology
The pituitary gland consists of an anterior lobe (adenohypophysis) and a posterior lobe (neurohypophysis). It is connected to the hypothalamus, which lies above it, by the stalk that contains neurosecretory fibers and capillaries. The hypophyseal portal system drains the hypothalamus and perfuses the anterior pituitary. Numerous releasing factors or regulating hormones that are produced by the hypothalamus are carried to the anterior pituitary by this portal system. These hypothalamic releasing factors stimulate the anterior pituitary to produce and secrete numerous tropic hormones, which stimulate target glands to produce hormones. The hypothalamic releasing factors, anterior pituitary hormones produced, target glands, and target gland hormones are presented in Table 34-1. Pituitary hormone secretion is regulated by negative feedback. For anterior pituitary hormones, secretion of releasing factors from the hypothalamus is decreased when the concentration of target gland hormones is high and increased when it is low.
The posterior lobe of the pituitary secretes two homologous peptide hormones, vasopressin and oxytocin. These hormones are synthesized in the hypothalamus and transported via the neurosecretory fibers of the stalk to the posterior pituitary, where they are stored and released. Both of these hormones are nonapeptides, and their structures are similar.
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 Gq/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 Gs 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.
Vasopressin and desmopressin acetate, a long-acting synthetic analogue that acts predominantly at V2 receptors, are used to treat diabetes insipidus. The receptors mediating this effect are located on the cells of the collecting duct in the kidney. Vasopressin is also used to control bleeding in certain conditions (e.g., colonic diverticular bleeding). Vasopressin stimulates the release of von Willebrand factor and clotting factor VIII and is used to treat deficiencies of these factors in certain types of hemophilia. Desmopressin is also used to decrease nocturnal enuresis. Felypressin, a synthetic analogue of vasopressin, is a vasoconstrictor that is used outside the United States with local anesthetics as an alternative to epinephrine.
Oxytocin receptors are Gq/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.
Oxytocin is used intravenously for stimulation of labor and to induce postpartum lactation in cases of breast engorgement. Investigations are underway for its use in therapeutic interventions in a variety of conditions, especially those characterized by anxiety and aberrations in social function, such as autism.12
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.
GH has direct and indirect effects. Its action is through cell surface receptors (JAK/STAT family). The direct actions of GH include lipolysis in fat cells and stimulation of hepatic glucose output. These effects are opposite to those of insulin. The anabolic and growth-promoting effects of GH are indirect and are mediated by insulin-like growth factor type I (IGF-I). IGF-I stimulates chondrogenesis and skeletal and soft tissue growth. IGF-I increases mitogenesis, increasing cell number rather than cell size. GH-releasing hormone from the hypothalamus stimulates GH release. Somatostatin from the hypothalamus inhibits GH release and release of gastrointestinal secretions.
In contrast to the direct effects of GH, the effects mediated by IGF-I are insulin-like. IGF-I acts through cell membrane receptors that resemble those of insulin. Insulin at high doses may act at IGF-I receptors and vice versa (see Chapter 36). In pharmacologic doses, GH causes an initial insulin-like effect followed by an effect antagonistic to that of insulin.
Circulating endogenous GH has a half-life of 20 to 25 minutes, although slow-release forms are available allowing injections once or twice a month. Human GH can be given subcutaneously, with peak plasma levels reached in 2 to 4 hours. Metabolism occurs in the liver and the kidney.
GH (somatrem, somatropin) is used in the treatment of growth failure in children (pituitary dwarfism), wasting in acquired immunodeficiency syndrome (AIDS), and somatotropin deficiency syndrome. Short-term treatment of GH-deficient adults results in increased lean body mass, decreased fat mass, increased exercise tolerance, and improved psychological well-being. It is sometimes abused by athletes6 or used for its antiaging effect. GH is a potent anabolic agent and may have a role in clinical management of burn injuries. The GH-releasing hormone analogue sermorelin is used to treat GH deficiency in children who have growth retardation and diagnostically to determine the GH-releasing capacity of the pituitary. Octreotide, a somatostatin analogue that inhibits GH release, is approved for use in treating symptoms of vasoactive intestinal tumors, metastatic carcinoid tumors, and acromegaly. Other uses include AIDS-associated diarrhea and esophageal varices. Pegvisomant, a competitive antagonist of GH, is used to treat acromegaly.
GH may induce relative insulin resistance. It has been documented to cause diabetes in AIDS patients16 and decreased insulin sensitivity that is dose-dependent, with a possible increase in type 2 diabetes in children.5 It may cause scoliosis in children. Arthralgia, especially in the hands and wrist, may occur. Patients may have headaches, especially in the first few months of therapy, and should be carefully observed (monitored) because of the possibility of intracranial hypertension.
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.
|HYPOTHALAMIC HORMONE||PITUITARY HORMONE INHIBITED||TARGET ORGAN|
|Somatostatin||Growth hormone||Liver, bone, other|
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 (Gs–adenylyl cyclase–cAMP) in the thyroid cell. TSH also causes activation of phospholipase C (Gq-PLC). TSH is used for diagnostic purposes and to stimulate iodine (131I) uptake in some patients with thyroid cancer (see later).
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.
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.
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
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.
Worldwide, the most common cause of thyroid disorders is iodine deficiency. In the United States, the leading cause of hypothyroidism is Hashimoto’s thyroiditis, an autoimmune disease. Graves’ disease (diffuse toxic goiter), also an autoimmune disorder, is the most common cause of hyperthyroidism in the United States.
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
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.
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.
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.
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 />