Textbook Chapter 11: Endocrine System PDF

Page 320 In Chapters 6–8 and 10, you learned that the nervous system is one of the two major control systems of the body, and now we turn our attention to the other—the endocrine system. The endocrine system consists of ductless glands called endocrine glands that secrete hormones, as well as hormo...

Page 320 In Chapters 6–8 and 10, you learned that the nervous system is one of the two major control systems of the body, and now we turn our attention to the other—the endocrine system. The endocrine system consists of ductless glands called endocrine glands that secrete hormones, as well as hormone-secreting cells located in various organs such as the brain, heart, kidneys, liver, and stomach. You will learn about exocrine (ducted) glands in Chapter 15. Hormones are chemical messengers that enter the blood, which carries them from their site of secretion to the cells upon which they act. The cells a particular hormone influences are known as the target cells for that hormone. The aim of this chapter is to first present a detailed overview of endocrinology—that is, a structural and functional analysis of general features of hormones—followed by a more detailed analysis of several important hormonal systems. Before continuing, you should review the principles of ligand-receptor interactions and cell signaling that were described in Chapters 3 and 5— they pertain to the mechanisms by which hormones exert their actions. Hormones functionally link various organ systems together. As such, several of the general principles of physiology first introduced in Chapter 1 apply to the study of the endocrine system, including the principle that the functions of organ systems are coordinated with each other. This coordination is key to the maintenance of homeostasis, which is important for health and survival, another important general principle of physiology that will be covered in subsequent sections of this chapter. In many cases, the actions of one hormone can be potentiated, inhibited, or counterbalanced by the actions of another. This illustrates the general principle of physiology that most physiological functions are controlled by multiple regulatory systems, often working in opposition, which will be especially relevant in the sections on the endocrine control of metabolism and the control of pituitary gland function. The binding of hormones to their carrier proteins and receptors illustrates the general principle of physiology that physiological processes are dictated by the laws of chemistry and physics. The anatomy of the connection of the hypothalamus and anterior pituitary demonstrates that structure is a determinant of—and has coevolved with—function (hypothalamic control of anterior pituitary function). The regulated uptake of iodine into the cells of the thyroid gland that synthesize thyroid hormones demonstrates the general principle of physiology that controlled exchange of materials occurs between compartments and across cellular membranes. Finally, this chapter exemplifies the general principle of physiology that information flow between cells, tissues, and organs is an essential feature of homeostasis and allows for integration of physiological processes. General Characteristics of Hormones and Hormonal Control Systems 11.1 Hormones and Endocrine Glands Endocrine glands are distinguished from another type of gland in the body called exocrine glands. Exocrine glands secrete their products into a duct, from where the secretions either exit the body (as in sweat) or enter the lumen of another organ, such as the intestines. By contrast, endocrine glands are ductless and release hormones into the blood (Figure 11.1). Hormones are actually released first into interstitial fluid, from where they diffuse into the blood, but for simplicity we will often omit the interstitial fluid step in our discussion. Figure 11.1 Exocrine gland secretions enter ducts from where their secretions either exit the body or, as shown here, connect to the lumen of a structure such as the intestines or to the surface of the skin. By contrast, endocrine glands secrete hormones that enter the interstitial fluid and diffuse into the blood, from where they can reach distant target cells. Figure 11.2 summarizes most of the endocrine glands and other hormone-secreting organs, the hormones they secrete, and some of the major functions the hormones control. The endocrine system differs from most of the other organ systems of the body in that the various components are not anatomically connected; however, they do form a system in the functional sense. You may be puzzled to see some organs—the heart, for instance—that clearly have other functions yet are listed as part of the endocrine system. The explanation is that, in addition to the cells that carry out other functions, the organ also contains cells that secrete hormones.  Figure 11.2 Overview of the major hormones and their sites of production, and some of their important functions. Page 321 Note also in Figure 11.2 that the hypothalamus, a part of the brain, is considered part of the endocrine system. This is because the chemical messengers released by certain axon terminals in both the hypothalamus and its extension, the posterior pituitary, do not function as neurotransmitters affecting adjacent cells but, rather, enter the blood as hormones. The blood then carries these hormones to their sites of action. Figure 11.2 demonstrates that there are a large number of endocrine glands and hormones. This chapter is not all inclusive. Some of the hormones listed in Figure 11.2 are best considered in the context of the control systems in which they participate. For example, the pancreatic hormones (insulin and glucagon) are described in Chapter 16 in the context of organic metabolism, and the reproductive hormones are extensively covered in Chapter 17. Page 322 Also evident from Figure 11.2 is that a single gland may secrete multiple hormones. The usual pattern in such cases is that a single cell type secretes only one hormone, so that multiple-hormone secretion reflects the presence of different types of endocrine cells in the same gland. In a few cases, however, a single cell may secrete more than one hormone or different forms of the same hormone. Finally, in some cases, a hormone secreted by an endocrine gland cell may also be secreted by other cell types and serves in these other locations as a neurotransmitter or paracrine or autocrine substance. For example, somatostatin, a hormone produced by neurons in the hypothalamus, is also secreted by cells of the stomach and pancreas, where it has local paracrine actions. Study and Review 11.1 Endocrine glands: Ductless organs or groups of cells that secrete hormones directly into the blood or other body fluids. A single gland may secrete multiple hormones. Review Question: Give an example of an endocrine gland and an exocrine gland and explain the major anatomical feature that distinguishes them. What organ contains both endocrine and exocrine glands? 11.2 Hormone Structures and Synthesis Hormones fall into three major structural classes: amines peptides and proteins steroids Amine Hormones The amine hormones are derivatives of the amino acid tyrosine. They include the thyroid hormones (produced by the thyroid gland) and the catecholamines epinephrine and norepinephrine (produced by the adrenal medulla) and dopamine (produced by the hypothalamus). The structure and synthesis of the iodine-containing thyroid hormones will be described in detail in Section 11.9 of this chapter. For now, their structures are included in Figure 11.3. Chapter 6 described the structures of catecholamines and the steps of their synthesis; the structures are reproduced here in Figure 11.3.  Figure 11.3 Chemical structures of the amine hormones: thyroxine and triiodothyronine (thyroid hormones), and norepinephrine, epinephrine, and dopamine (catecholamines). The two thyroid hormones differ by only one iodine atom, a difference noted in the abbreviations T3 and T4. The position of the carbon atoms in the two rings of T3 and T4 are numbered; this provides the basis for the complete names of T3 and T4 as shown in the figure. T4 is the primary secretory product of the thyroid gland, but is activated to the much more potent T3 in target tissue. There are two adrenal glands, one above each kidney. Each adrenal gland is composed of an inner adrenal medulla, which secretes catecholamines, and a surrounding adrenal cortex, which secretes steroid hormones. The adrenal medulla is really a modified sympathetic ganglion whose cell bodies do not have axons. Instead, they release their secretions into the blood, thereby fulfilling a criterion for an endocrine gland. The adrenal medulla secretes mainly two catecholamines, epinephrine and norepinephrine. In humans, the adrenal medulla secretes approximately four times more epinephrine than norepinephrine. This is because the adrenal medulla expresses high amounts of an enzyme called phenylethanolamine-N-methyltransferase (PNMT), which catalyzes the reaction that converts norepinephrine to epinephrine (refer back to Figure 6.35). Epinephrine and norepinephrine exert actions similar to those of the sympathetic nerves, which, because they do not express PNMT, make only norepinephrine. These actions are described in various chapters and summarized in Section 11.16 of this chapter. The other catecholamine hormone, dopamine, is synthesized by neurons in the hypothalamus. Dopamine is released into a special circulatory system called a portal system (see Section 11.8), which carries the hormone to the pituitary gland; there, it acts to inhibit the activity of certain endocrine cells. Peptide and Protein Hormones Most hormones are polypeptides. Short polypeptides with a known function are often referred to simply as peptides; longer polypeptides with tertiary structure and a known function are called proteins. Hormones in this class range in size from small peptides having only three amino acids to large proteins, some of which contain carbohydrate and thus are glycoproteins. For convenience, we will simply refer to all these hormones as peptide hormones. Page 323 In many cases, peptide hormones are initially synthesized on the ribosomes of endocrine cells as larger molecules known as preprohormones, which are then cleaved to prohormones by proteolytic enzymes in the rough endoplasmic reticulum (Figure 11.4a). The prohormone is then packaged into secretory vesicles by the Golgi apparatus. In this process (called post- translational modification), the prohormone is cleaved to yield the active hormone and other peptide chains found in the prohormone. Consequently, when the cell is stimulated to release the contents of the secretory vesicles by exocytosis, the other peptides are secreted along with the hormone. In certain cases, these other peptides may also exert hormonal effects. In other words, instead of just one peptide hormone, the cell may secrete multiple peptide hormones—derived from the same prohormone—each of which differs in its effects on target cells. One well-studied example of this is the synthesis of insulin in the pancreas (Figure 11.4b). Insulin is synthesized as a polypeptide preprohormone, then processed to the prohormone. Enzymes clip off a portion of the prohormone resulting in insulin and another product called C-peptide. Both insulin and C-peptide are secreted into the circulation in roughly equimolar amounts. Insulin is a key regulator of metabolism, while C-peptide may have several actions on a variety of cell types.  Figure 11.4 Typical synthesis and secretion of peptide hormones. (a) Peptide hormones typically are processed by enzymes from preprohormones containing a signal peptide to become prohormones; further processing results in one or more active hormones that are stored in secretory vesicles. Secretion of stored secretory vesicles occurs by the process of exocytosis. (b) An example of peptide hormone synthesis. Insulin is synthesized as a preprohormone (not shown) that is cleaved to the prohormone shown here. Each bead represents an amino acid. The action of proteolytic enzymes cleaves the prohormone into insulin and C-peptide (plus four amino acids that are removed altogether; not shown). Note that this cleavage results in two chains of insulin, which are connected by disulfide bridges. DIG DEEPER What is the advantage of packaging peptide hormones in secretory vesicles? Answer found in Appendix A. Steroid Hormones Steroid hormones make up the third family of hormones. Figure 11.5 shows some examples of steroid hormones; their ringlike structure was described in Chapter 2. Steroid hormones are primarily produced by the adrenal cortex and the gonads (testes and ovaries), as well as by the placenta during pregnancy. In addition, vitamin D is enzymatically converted in the body to an active steroid hormone, as you will learn in Section 11.21.  Figure 11.5 Structures of representative steroid hormones and their structural relationship to cholesterol. The general process of steroid hormone synthesis is illustrated in Figure 11.6a. In both the gonads and the adrenal cortex, the hormone-producing cells are stimulated by the binding of an anterior pituitary gland hormone to its plasma membrane receptor. These receptors are linked to Gs proteins (refer back to Figure 5.6), which activate adenylyl cyclase and cAMP production. The subsequent activation of protein kinase A by cAMP results in phosphorylation of numerous intracellular proteins, which facilitate the subsequent steps in the process. Figure 11.6 (a) Schematic overview of steps commonly involved in steroid synthesis. (b) The five hormones shown in boxes are the major hormones secreted from the adrenal cortex. Dehydroepiandrosterone (DHEA) and androstenedione are androgens—that is, testosterone-like hormones. Cortisol and corticosterone are glucocorticoids, and aldosterone is a mineralocorticoid that is produced by only one part of the adrenal cortex. Note: For simplicity, not all enzymatic steps are indicated.  DIG DEEPER Why are steroid hormones not packaged into secretory vesicles, such as those depicted in Figure 11.4? Answer found in Appendix A. Page 324 All of the steroid hormones are derived from cholesterol, which is either taken up from the extracellular fluid by the cells or synthesized by intracellular enzymes. The final steroid hormone product depends upon the cell type and the types and amounts of the enzymes it expresses. Cells in the ovary, for example, express large amounts of the enzyme needed to convert testosterone to estradiol, whereas cells in the testes do not express significant amounts of this enzyme and therefore make primarily testosterone. Once formed, steroid hormones are not stored in the cytosol in membrane-bound vesicles, because the lipophilic nature of the steroids allows them to freely diffuse across lipid bilayers. As a result, once they are synthesized, steroid hormones diffuse across the plasma membrane into the circulation. Because of their lipid nature, steroid hormones are not highly soluble in blood. Consequently, the majority of steroid hormones are reversibly bound in plasma to carrier proteins such as albumin and various other specific proteins. The next sections describe the pathways for steroid synthesis in the adrenal cortex and gonads. Those for the placenta are somewhat unusual and are briefly discussed in Chapter 17. Hormones of the Adrenal Cortex The five major hormones secreted by the adrenal cortex are aldosterone, cortisol, corticosterone, dehydroepiandrosterone (DHEA), and androstenedione (Figure 11.6b). Aldosterone is known as a mineralocorticoid because its effects are on salt (mineral) balance, mainly on the kidneys’ handling of sodium, potassium, and hydrogen ions. Its actions are described in detail in Chapter 14. Briefly, production of aldosterone is under the control of another hormone called angiotensin II, which binds to plasma membrane receptors in the adrenal cortex to activate the inositol trisphosphate second-messenger pathway (see Chapter 5). This is different from the more common cAMP-mediated mechanism by which most steroid hormones are produced, as previously described. Once synthesized, aldosterone enters the circulation and acts on cells of the kidneys to stimulate Na+ and H2O retention, and K+ and H+ excretion in the urine. Cortisol and the related but less functional steroid corticosterone are called glucocorticoids because they have important effects on the metabolism of glucose and other organic nutrients. Cortisol is the predominant glucocorticoid in humans and is the only one we will discuss. In addition to its effects on organic metabolism, cortisol exerts many other effects, including facilitation of the body’s responses to stress and regulation of the immune system (see Section 11.14). Dehydroepiandrosterone (DHEA) and androstenedione belong to the class of steroid hormones known as androgens; this class also includes the major male sex steroid testosterone, produced by the testes. The adrenal androgens are much less potent than testosterone, and they are usually of little physiological significance in the adult male. They do, however, have functions in the adult female and in both sexes in the fetus and at puberty, as described in Chapter 17. The adrenal cortex is composed of three distinct layers (Figure 11.7). The cells of the outermost layer—the zona glomerulosa—express the enzymes required to synthesize corticosterone and then convert it to aldosterone (see Figure 11.6b) but do not express the genes that code for the enzymes required for the formation of cortisol and androgens. Therefore, this layer synthesizes and secretes aldosterone but not the other major adrenocortical hormones. In contrast, the zona fasciculata and zona reticularis have the opposite enzyme profile. They secrete no aldosterone but do secrete cortisol and androgens. In humans, the zona fasciculata primarily produces cortisol and the zona reticularis primarily produces androgens. Figure 11.7 Section through an adrenal gland showing both the medulla and the zones of the cortex, as well as the hormones they secrete. Figure 11.8 Gonadal production of steroids. Only the ovaries have high concentrations of the enzyme (aromatase) required to produce the estrogens estrone and estradiol.  In certain diseases, the adrenal cortex may secrete decreased or increased amounts of various steroids. For example, the absence of an enzyme required for the formation of cortisol by the adrenal cortex can result in the shunting of the cortisol precursors into the androgen pathway. (Look at Figure 11.6b to imagine how this might happen.) One example of an inherited disease of this type is congenital adrenal hyperplasia (CAH) (see Chapter 17 for more details). In CAH, the excess adrenal androgen production results in virilization of the genitalia of female fetuses; at birth, it may not be obvious whether the baby is phenotypically male or female. Fortunately, the most common form of this disease is routinely screened for at birth in many countries and appropriate therapeutic measures can be initiated immediately. Page 325 Hormones of the Gonads Compared to the adrenal cortex, the gonads express different enzymes in their steroid pathways. Endocrine cells in both the testes and the ovaries do not express the enzymes required to produce aldosterone and cortisol. They possess high concentrations of enzymes in the androgen pathways leading to androstenedione, as in the adrenal cortex. In addition, the endocrine cells in the testes express large amounts of an enzyme that converts androstenedione to testosterone, which is the major androgen secreted by the testes (Figure 11.8). The ovarian endocrine cells synthesize the female sex hormones, which are collectively known as estrogens (primarily estradiol and estrone). Estradiol is the predominant estrogen present during a woman’s lifetime. The ovarian endocrine cells express large amounts of the enzyme aromatase, which catalyzes the conversion of androgens to estrogens (see Figure 11.8). Consequently, estradiol—rather than testosterone—is the major steroid hormone secreted by the ovaries. Page 326 Very small amounts of testosterone do diffuse out of ovarian endocrine cells, however, and very small amounts of estradiol are produced from testosterone in the testes. Moreover, following their release into the blood by the gonads and the adrenal cortex, steroid hormones may undergo further conversion in other organs. For example, testosterone is converted to estradiol in some of its target cells. Consequently, the major male and female sex hormones —testosterone and estradiol, respectively—are not unique to males and females. The ratio of the concentrations of the hormones, however, is very different in the two sexes. Finally, endocrine cells of the corpus luteum, an ovarian structure that arises following each ovulation, secrete another major steroid hormone, progesterone. This steroid is critically important for maintaining a pregnancy (see Chapter 17). Progesterone is also synthesized in other parts of the body—notably, the placenta in pregnant women and the adrenal cortex in both males and females. Study and Review 11.2 Amine hormones: amino acid derivatives iodine-containing thyroid hormones Catecholamines: secreted by the adrenal medulla and the hypothalamus Peptides and proteins: strings of amino acids typically synthesized as larger (inactive) molecules that are cleaved into active fragments by post-translational processing modification Steroid hormones: produced from cholesterol by the adrenal cortex and the gonads and from steroid precursors by the placenta Adrenal cortex produces the mineralocorticoid aldosterone; the glucocorticoid cortisol; and two androgens, DHEA and androstenedione. Ovaries produce mainly estradiol and progesterone. Testes produce mainly testosterone. Review Question: What are the three general chemical classes of hormones? Give examples of each and their gland of origin. (Answer found in Appendix A.) 11.3 Hormone Transport in the Blood Most peptide and all catecholamine hormones are water-soluble. Therefore, with the exception of a few peptides, these hormones are transported simply dissolved in plasma (Table 11.1). In contrast, steroid hormones and thyroid hormones are poorly soluble; consequently, they circulate in the blood largely bound to plasma proteins. Even though the steroid and thyroid hormones exist in plasma mainly bound to large proteins, small concentrations of these hormones do exist dissolved in the plasma. The dissolved, or free, hormone is in equilibrium with the bound hormone: This reaction is an excellent example of the general principle of physiology that physiological processes are dictated by the laws of chemistry and physics. The balance of this equilibrium will shift to the right as the endocrine gland secretes more free hormone and to the left in the target gland as hormone dissociates from its binding protein in plasma and diffuses into the target gland cell. The total hormone concentration in plasma is the sum of the free and bound hormones. However, only the free hormone can diffuse out of capillaries and encounter its target cells. Therefore, the concentration of the free hormone is what is biologically important rather than the concentration of the total hormone, most of which is bound. As we will see next, the degree of protein binding also influences the rate of metabolism and the excretion of the hormone. Study and Review 11.3 Peptide hormones and catecholamines: soluble in plasma Steroid and thyroid hormones: poorly soluble; mostly bound to plasma proteins Review Question: Which classes of hormones are carried in the blood mainly as unbound, dissolved hormone? Mainly bound to plasma proteins? What accounts for the differences? (Answer found in Appendix A.) TABLE 11.1 Categories of Hormones Major Location Chemical Form in of Most Common Signaling Rate of Class Plasma Receptors Mechanisms* Excretion/Metabolism Peptides and Free Plasma 1. Second messengers (e.g., Fast (minutes) catecholamines (unbound) membrane cAMP, Ca2+, IP3) 2. Enzyme activation by receptor (e.g., JAK) 3. Intrinsic enzymatic activity of receptor (e.g., tyrosine autophosphorylation) Steroids and Protein- Intracellular Intracellular receptors Slow (hours to days) thyroid bound directly alter gene hormone transcription *The diverse mechanisms of action of chemical messengers such as hormones were discussed in detail in Chapter 5. Page 327 11.4 Hormone Metabolism and Excretion Once a hormone has been synthesized and secreted into the blood, has acted on a target tissue, and its increased activity is no longer required, the concentration of the hormone in the blood usually returns to normal. This is necessary to prevent excessive, possibly harmful effects from the prolonged exposure of target cells to hormones. A hormone’s concentration in the plasma depends upon:  its rate of secretion by the endocrine gland its rate of removal from the blood Removal, or “clearance,” of the hormone occurs either by excretion or by metabolic transformation. The liver and the kidneys are the major organs that metabolize or excrete hormones. A more detailed explanation of clearance can be found in Chapter 14, Section 14.4. The liver and kidneys, however, are not the only routes for eliminating hormones. Sometimes a hormone is metabolized by the cells upon which it acts. In the case of some peptide hormones, for example, endocytosis of hormone–receptor complexes on plasma membranes enables cells to remove the hormones rapidly from their surfaces and catabolize them intracellularly. The receptors are then often recycled to the plasma membrane. In addition, enzymes in the blood and tissues rapidly break down catecholamine and peptide hormones. These hormones therefore tend to remain in the bloodstream for only brief periods—minutes to an hour. In contrast, protein-bound hormones are protected from excretion or metabolism by enzymes as long as they remain bound. Therefore, removal of the circulating steroid and thyroid hormones generally takes longer, often several hours to days. In some cases, metabolism of a hormone activates the hormone rather than inactivates it. In other words, the secreted hormone may be relatively inactive until metabolism transforms it. One example is T4 produced by the thyroid gland, which is converted to the much more active hormone T3 inside the target cell. Figure 11.9 summarizes the possible fates of hormones after their secretion. Figure 11.9 Possible fates and actions of a hormone following its secretion by an endocrine cell. Not all paths apply to all hormones. Many hormones are activated by metabolism inside target cells. Study and Review 11.4 The liver and kidneys remove hormones from the plasma by metabolizing or excreting them. Peptide hormones and catecholamines are rapidly removed from the blood Steroid and thyroid hormones are removed more slowly, mainly because they circulate bound to plasma proteins. Some hormones are metabolized to more active molecules in target cells and other organs.  Review Question: Other than by the liver and kidneys, how else can a hormone be metabolized and cleared from the circulation? (Answer found in Appendix A.) 11.5 Mechanisms of Hormone Action Hormone Receptors Because hormones are transported in the blood, they can reach all tissues. Yet, the response to a hormone is highly specific, involving only the target cells for that hormone. The ability to respond depends upon the presence of specific receptors for those hormones on or in the target cells. As emphasized in Chapter 5, the response of a target cell to a chemical messenger is the final event in a sequence that begins when the messenger binds to specific cell receptors. As that chapter described, the receptors for water-soluble chemical messengers like peptide hormones and catecholamines are proteins located in the plasma membranes of the target cells. In contrast, the receptors for lipid-soluble chemical messengers like steroid and thyroid hormones are proteins located mainly inside the target cells. Hormones can influence the response of target cells by regulating hormone receptors. Again, Chapter 5 described basic concepts of receptor modulation such as up-regulation and down-regulation. In the context of hormones, up-regulation is an increase in the number of a hormone’s receptors in a cell, often resulting from a prolonged exposure to a low concentration of the hormone. This has the effect of increasing target-cell responsiveness to the hormone. Down-regulation is a decrease in receptor number, often from exposure to high concentrations of the hormone. This temporarily decreases target-cell responsiveness to the hormone, thereby preventing overstimulation. In some cases, hormones can down-regulate or up-regulate not only their own receptors but the receptors for other hormones as well. If one hormone induces down-regulation of a second hormone’s receptors, the result will be a reduction of the second hormone’s effectiveness. On the other hand, a hormone may induce an increase in the number of receptors for a second hormone. In this case, the effectiveness of the second hormone is increased. This latter phenomenon, in some cases, underlies the important hormone–hormone interaction known as permissiveness. Page 328 In general terms, permissiveness means that hormone A must be present in order for hormone B to exert its full effect. A low concentration of hormone A is usually all that is needed for this permissive effect, which may be due to A’s ability to up-regulate B’s receptors. For example, epinephrine stimulates the release of fatty acids into the blood from adipocytes, an important function in times of increased energy requirements. However, epinephrine cannot do this effectively in the absence of permissive amounts of thyroid hormones (Figure 11.10). One reason is that thyroid hormones stimulate the synthesis of beta-adrenergic receptors for epinephrine in adipose tissue; as a result, the tissue becomes much more sensitive to epinephrine. However, receptor up-regulation does not explain all cases of permissiveness. Sometimes, the effect may be due to changes in the signaling pathway that mediates the actions of a given hormone. Figure 11.10 The ability of thyroid hormone to “permit” epinephrine-induced release of fatty acids from adipose tissue cells. Thyroid hormone exerts this effect by causing an increased number of beta- adrenergic receptors on the cell. Thyroid hormone by itself stimulates only a small amount of fatty acid release. DIG DEEPER A patient is observed to have symptoms that are consistent with increased concentrations of epinephrine in the blood, including a rapid heart rate, anxiety, and elevated fatty acid concentrations. However, the circulating epinephrine concentrations are measured and found to be in the normal range. What might explain this? Answer found in Appendix A. Events Elicited by Hormone–Receptor Binding The events initiated when a hormone binds to its receptor—that is, the mechanisms by which the hormone elicits a cellular response—are one or more of the signal transduction pathways that apply to all chemical messengers, as described in Chapter 5. In other words, there is nothing unique about the mechanisms that hormones initiate as compared to those used by neurotransmitters and paracrine or autocrine substances, and so we will review them only briefly here (see Table 11.1). Effects of Peptide Hormones and Catecholamines As stated previously, the receptors for peptide hormones and catecholamines are located on the extracellular surface of the target cell’s plasma membrane. This location is important because these hormones are too hydrophilic to diffuse through the plasma membrane. When activated by hormone binding, the receptors trigger one or more of the signal transduction pathways for plasma membrane receptors described in Chapter 5. That is, the activated receptors directly influence: enzyme activity that is part of the receptor activity of cytoplasmic janus kinases associated with the receptor G proteins coupled in the plasma membrane to effector proteins—ion channels and enzymes—that generate second messengers such as cAMP and Ca2+ (see Figure 11.6a as an example) The opening or closing of ion channels changes the electrical potential across the membrane. When a Ca2+ channel is involved, the cytosolic concentration of this important ionic second-messenger changes. The changes in enzyme activity are usually very rapid (e.g., due to phosphorylation) and produce changes in the activity of various cellular proteins. In some cases, the signal transduction pathways also lead to activation or inhibition of particular genes, causing a change in the synthesis rate of the proteins encoded by these genes. Thus, peptide hormones and catecholamines may exert both rapid (nongenomic) and slower (gene transcription) actions on the same target cell. Effects of Steroid and Thyroid Hormone The steroid hormones and thyroid hormone are lipophilic, and their receptors, which are intracellular, are members of the nuclear receptor superfamily. As described for lipid-soluble messengers in Chapter 5, the binding of hormone to its receptor leads to the activation (or in some cases, inhibition) of the transcription of particular genes, causing a change in the synthesis rate of the proteins coded for by those genes. The ultimate result of changes in the concentrations of these proteins is an enhancement or inhibition of particular processes the cell carries out or a change in the cell’s rate of protein secretion. Evidence exists for plasma membrane receptors for these hormones, but their physiological significance in humans is not established. Pharmacological Effects of Hormones The administration of very large quantities of a hormone for medical purposes may have effects on an individual that are not usually observed at physiological concentrations. These pharmacological effects can also occur in diseases involving the secretion of excessive amounts of hormones. Pharmacological effects are of great importance in medicine because hormones are often used in large doses as therapeutic agents. Perhaps the most common example is that of very potent synthetic forms of cortisol, such as prednisone, which is administered to suppress allergic and inflammatory reactions. In such situations, a host of unwanted effects may be observed (as described in Section 11.15). Page 329 Study and Review 11.5 Receptors: bind to hormones and exert an action Steroids and thyroid hormones: inside target cells Peptide hormones and catecholamines: on plasma membrane Up-regulation and down-regulation: increases or decreases hormone’s effectiveness, respectively Review Question: Contrast the cellular locations and mechanism and rapidity of action of receptors for the various classes of hormones. (Answer found in Appendix A.) 11.6 Inputs That Control Hormone Secretion Hormone secretion is mainly under the control of three types of inputs to endocrine cells (Figure 11.11): changes in the plasma concentrations of mineral ions or organic nutrients neurotransmitters released from neurons ending on the endocrine cell another hormone (or, in some cases, a paracrine substance) acting on the endocrine cell Figure 11.11 Inputs that act directly on endocrine gland cells to stimulate or inhibit hormone secretion. Before we look more closely at each category, we must stress that more than one input may influence hormone secretion. For example, insulin secretion is stimulated by the extracellular concentrations of glucose and other nutrients, and is either stimulated or inhibited by the different branches of the autonomic nervous system. Thus, the control of endocrine cells illustrates the general principle of physiology that most physiological functions are controlled by multiple regulatory systems, often working in opposition. The resulting output—the rate of hormone secretion—depends upon the relative amounts of stimulatory and inhibitory inputs. The term secretion applied to a hormone denotes its release by exocytosis from the cell. In some cases, hormones such as steroid hormones are not secreted, per se, but instead diffuse through the cell’s plasma membrane into the extracellular space. Secretion or release by diffusion is sometimes accompanied by increased synthesis of the hormone. For simplicity in this chapter and the rest of the book, we will usually not distinguish between these possibilities when we refer to stimulation or inhibition of hormone “secretion.” Control by Plasma Concentrations of Mineral Ions or Organic Nutrients The secretion of several hormones is directly controlled—at least in part—by the plasma concentrations of specific mineral ions or organic nutrients. In each case, a major function of the hormone is to regulate through negative feedback (see Chapter 1, Section 1.5) the plasma concentration of the ion or nutrient controlling its secretion. For example, insulin secretion is stimulated by an increase in plasma glucose concentration. Insulin, in turn, acts on skeletal muscle and adipose tissue to promote facilitated diffusion of glucose through the plasma membranes into the cytosol. Consequently, the action of insulin restores plasma glucose concentration to normal (Figure 11.12). Another example is the regulation of calcium ion balance by parathyroid hormone (PTH), as described in detail in Section 11.21. This hormone is produced by cells of the parathyroid glands, which, as their name implies, are located in close proximity to the thyroid gland. A decrease in the plasma Ca2+ concentration directly stimulates PTH secretion. PTH then exerts several actions on bone and other tissue that increase calcium release into the blood, thereby restoring plasma Ca2+ to normal. Figure 11.12 Example of how the direct control of hormone secretion by the plasma concentration of a substance—in this case, an organic nutrient—results in negative feedback control of the substance’s plasma concentration. In other cases, the regulated plasma substance may be an ion, such as Ca2+. Control by Neurons As stated, the adrenal medulla is a modified sympathetic ganglion and thus is stimulated by sympathetic preganglionic fibers (refer back to Chapter 6 for a discussion of the autonomic nervous system). In addition to controlling the adrenal medulla, the autonomic nervous system influences other endocrine glands (Figure 11.13). Both parasympathetic and sympathetic inputs to these other glands may occur, some inhibitory and some stimulatory. Examples are the secretions of insulin and the gastrointestinal hormones, which are stimulated by neurons of the parasympathetic nervous system and inhibited by sympathetic neurons. Figure 11.13 Pathways by which the nervous system influences hormone secretion. The autonomic nervous system controls hormone secretion by the adrenal medulla and many other endocrine glands. Certain neurons in the hypothalamus, some of which terminate in the posterior pituitary, secrete hormones. The secretion of hypothalamic hormones from the posterior pituitary and the effects of other hypothalamic hormones on the anterior pituitary gland are described later in this chapter. The and symbols indicate stimulatory and inhibitory actions, respectively. DIG DEEPER: General Principle of Physiology List the several ways this figure illustrates the general principle of physiology described in Chapter 1 that information flow between cells, tissues, and organs is an essential feature of homeostasis and allows for integration of physiological processes. Answer found in Appendix A. Page 330 One large group of hormones—those secreted by the hypothalamus and the posterior pituitary—is under the direct control of neurons in the brain itself (see Figure 11.13). This category will be described in detail in Section 11.8. Control by Other Hormones In many cases, the secretion of a particular hormone is directly controlled by the blood concentration of another hormone. Often, the only function of the first hormone in a sequence is to directly stimulate the secretion of the next. A hormone that stimulates the secretion of another hormone is often referred to as a tropic hormone. The tropic hormones usually stimulate not only secretion but also the growth of the stimulated gland. (When specifically referring to growth-promoting actions, the term trophic is often used, but for simplicity we will usually use only the general term tropic.) These types of hormonal sequences are covered in detail in Section 11.8. In addition to stimulatory actions, however, some hormones such as those in a multihormone sequence inhibit secretion of other hormones. Study and Review 11.6 Hormone secretion: controlled by different inputs: ion or nutrient that the hormone regulates neural input to the endocrine cells one or more other hormones Autonomic nervous system controls the secretion of many hormones. Neurons from the sympathetic and parasympathetic nervous systems terminate directly on cells within some endocrine glands, thereby regulating hormone secretion. Review Question: What are the three direct inputs to endocrine glands that control hormone secretion? Give one or more specific examples of each. (Answer found in Appendix A.) 11.7 Types of Endocrine Disorders Because there is such a wide variety of hormones and endocrine glands, the features of disorders of the endocrine system may vary considerably. For example, endocrine disease may manifest as an imbalance in metabolism, leading to weight gain or loss; as a failure to grow or develop normally in early life; as an abnormally high or low blood pressure; as a loss of reproductive fertility; or as mental and emotional changes, to name a few. Despite these varied features, which depend upon the particular hormone affected, essentially all endocrine diseases can be categorized in one of four ways. These include: too little hormone (hyposecretion) too much hormone (hypersecretion) decreased responsiveness of the target cells to hormone (hyporesponsiveness) increased responsiveness of the target cells to hormone (hyperresponsiveness) Page 331 Hyposecretion An endocrine gland may be secreting too little hormone because the gland is not functioning normally, a condition termed primary hyposecretion. Examples include: partial or total destruction of a gland, leading to decreased hormone secretion  an enzyme deficiency resulting in decreased synthesis of the hormone dietary deficiency of iodine, specifically leading to decreased secretion of thyroid hormones Many other causes, such as infections and exposure to toxic chemicals, have the common denominator of damaging the endocrine gland or reducing its ability to synthesize or secrete the hormone. The other major cause of hyposecretion is secondary hyposecretion. In this case, the endocrine gland is not damaged (at least at first) but is receiving too little stimulation by its tropic hormone or, rarely, excessive amounts of an inhibitory hormone. This might occur, for example, if the tropic hormone was being synthesized and released at an abnormally low rate. In the long term, lack of the trophic action of the tropic hormones invariably leads to atrophy of the target gland that can be reversed over time if the concentration of the trophic hormone in the blood returns to normal. To distinguish between primary and secondary hyposecretion, one measures the concentration of the tropic hormone in the blood. If increased, the cause is primary; if not increased or lower than normal, the cause is secondary. The most common means of treating hormone hyposecretion is to administer the missing hormone or a synthetic analog of the hormone. This is normally done by oral (pill), topical (gel applied to skin), or by injection. The route of administration typically depends upon the chemical nature of the hormone being replaced. For example, individuals with low thyroid hormone take a daily pill to restore normal hormone concentrations, because thyroid hormone is readily absorbed from the intestines. By contrast, people with diabetes mellitus who require insulin typically obtain it via injection; insulin is a peptide that would be digested by the enzymes of the gastrointestinal tract if it were ingested. Hypersecretion A hormone can also undergo either primary hypersecretion (the gland is secreting too much of the hormone on its own) or secondary hypersecretion (excessive stimulation of the gland by its tropic hormone). One cause of primary or secondary hypersecretion is the presence of a hormone-secreting, endocrine-cell tumor. These tumors are often benign (that is, not malignant cancers) and tend to produce their hormones continually at a high rate, even in the absence of stimulation or in the presence of increased negative feedback. When an endocrine tumor causes hypersecretion, the tumor can often be removed surgically or destroyed with radiation if it is confined to a small area. These procedures are also useful in certain cases where an endocrine gland is hypersecreting for reasons unrelated to the presence of a tumor. Both of these procedures can be used, for example, in treating hypersecretion from an overactive thyroid gland (see Section 11.12). In many cases, drugs that inhibit a hormone’s synthesis can block hypersecretion. Alternatively, the situation can be treated with drugs that do not alter the hormone’s secretion but instead block the hormone’s actions on its target cells (receptor antagonists). Hyporesponsiveness and Hyperresponsiveness In some cases, a component of the endocrine system may not be functioning normally, even though there is nothing wrong with hormone secretion. The problem is that the target cells do not respond normally to the hormone, a condition termed hyporesponsiveness, or hormone resistance. An important example of a disease resulting from hyporesponsiveness is the most common form of diabetes mellitus (called type 2 diabetes mellitus), in which the target cells of the hormone insulin are hyporesponsive to this hormone. Hyporesponsiveness can result from deficiency or loss of function of receptors for the hormone. For example, some individuals who are genetically male have a defect manifested by the absence of receptors for androgens. Consequently, their target cells are unable to bind androgens, and the result is lack of development of certain male characteristics, as though the hormones were not being produced (see Chapter 17 for additional details). In a second type of hyporesponsiveness, the receptors for a hormone may be normal but some signaling event that occurs within the cell after the hormone binds to its receptors may be defective. For example, the activated receptor may be unable to stimulate formation of cyclic AMP or another component of the signaling pathway for that hormone. A third cause of hyporesponsiveness applies to hormones that require metabolic activation by some other tissue after secretion. There may be a deficiency of the enzymes that catalyze the activation. For example, some men secrete testosterone (the major circulating androgen) normally and have normal receptors for androgens. However, these men are missing the intracellular enzyme that converts testosterone to dihydrotestosterone, a potent metabolite of testosterone that binds to androgen receptors and mediates some of the actions of testosterone on secondary sex characteristics such as the growth of facial and body hair. By contrast, hyperresponsiveness to a hormone can also occur and cause problems. For example, as you learned earlier, thyroid hormone causes an up-regulation of beta-adrenergic receptors for epinephrine; therefore, hypersecretion of thyroid hormone causes, in turn, a hyperresponsiveness of target cells to epinephrine. One result of this is the increased heart rate typical of people with increased plasma concentrations of thyroid hormone. Study and Review 11.7 Classes: hyposecretion, hypersecretion, and target-cell hyporesponsiveness or hyperresponsiveness Primary: defect in the cells that secrete the hormone Secondary: too much or too little tropic/trophic hormone Hyporesponsiveness: decreased sensitivity to a stimulus Hyperresponsiveness: increased sensitivity to a stimulus Review Question: How would you distinguish between primary and secondary hyposecretion of a hormone? (Answer found in Appendix A.)  Page 332 The Hypothalamus and Pituitary Gland 11.8 Control Systems Involving the Hypothalamus and Pituitary Gland The pituitary gland, or hypophysis (from a Greek term meaning “to grow underneath”), lies in a pocket (called the sella turcica) of the sphenoid bone at the base of the brain (Figure 11.14) just below the hypothalamus. The pituitary gland is connected to the hypothalamus by the infundibulum, or pituitary stalk, containing axons from neurons in the hypothalamus and small blood vessels. In humans, the pituitary gland is primarily composed of two adjacent lobes called the anterior lobe—usually referred to as the anterior pituitary gland or adenohypophysis—and the posterior lobe—usually called the posterior pituitary or neurohypophysis. The anterior pituitary gland arises embryologically from an invagination of the pharynx called Rathke’s pouch, whereas the posterior pituitary is not actually a gland but, rather, an extension of the neural components of the hypothalamus. Figure 11.14 (a) Relation of the pituitary gland to the brain and hypothalamus. (b) Neural and vascular connections between the hypothalamus and pituitary gland. Hypothalamic neurons from the paraventricular and supraoptic nuclei travel down the infundibulum to end in the posterior pituitary, whereas others (shown for simplicity as a single nucleus, but in reality several nuclei, including some cells from the paraventricular nuclei) end in the median eminence. Almost the entire blood supply to the anterior pituitary gland comes via the hypothalamo–hypophyseal portal vessels, which originate in the median eminence. Long portal vessels connect the capillaries in the median eminence with those in the anterior pituitary gland. (The short portal vessels, which originate in the posterior pituitary, carry only a small fraction of the blood leaving the posterior pituitary and supply only a small fraction of the blood received by the anterior pituitary gland.) Arrows indicate direction of blood flow.  DIG DEEPER Why does it take only very small quantities of hypophysiotropic hormones to achieve concentrations that are effective in regulating anterior pituitary gland hormone secretion? Answer found in Appendix A. The axons of two well-defined clusters of hypothalamic neurons (the supraoptic and paraventricular nuclei) pass down the infundibulum and end within the posterior pituitary in close proximity to capillaries (small blood vessels where exchange of solutes occurs between the blood and interstitium) (Figure 11.14b). Therefore, these neurons do not form a synapse with other neurons. Instead, their terminals end directly on capillaries. The terminals release hormones into these capillaries, which then drain into veins and the general circulation. In contrast to the neural connections between the hypothalamus and posterior pituitary, there are no important neural connections between the hypothalamus and anterior pituitary gland. There is, however, a special type of vascular connection (see Figure 11.14b). The junction of the hypothalamus and infundibulum is known as the median eminence. Capillaries in the median eminence recombine to form the hypothalamo–hypophyseal portal vessels (or portal veins). The term portal denotes veins that connect two sets of capillaries; normally, as you will learn in Chapter 12, capillaries drain into veins that return blood to the heart. Only in portal systems does one set of capillaries drain into veins that then form a second set of capillaries before eventually emptying again into veins that return to the heart. The hypothalamo–hypophyseal portal vessels pass down the infundibulum and enter the anterior pituitary gland, where they drain into a second set of capillaries, the anterior pituitary gland capillaries. Thus, the hypothalamo–hypophyseal portal vessels offer a local route for blood to be delivered directly from the median eminence to the cells of the anterior pituitary gland. As we will see shortly, this local blood system provides a mechanism for hormones synthesized in cell bodies in the hypothalamus to directly alter the activity of the cells of the anterior pituitary gland, bypassing the general circulation and thus efficiently and specifically regulating hormone release from that gland. We begin our survey of pituitary gland hormones and their major physiological actions with the two hormones of the posterior pituitary. Posterior Pituitary Hormones We emphasized that the posterior pituitary is really a neural extension of the hypothalamus (see Figure 11.14). The hormones are synthesized not in the posterior pituitary itself but in the hypothalamus—specifically, in the cell bodies of the supraoptic and paraventricular nuclei, whose axons pass down the infundibulum and terminate in the posterior pituitary. Enclosed in small vesicles, the hormone is transported down the axons to accumulate at the axon terminals in the posterior pituitary. Various stimuli activate inputs to these neurons, causing action potentials that propagate to the axon terminals and trigger the release of the stored hormone by exocytosis. The hormone then enters capillaries to be carried away by the blood returning to the heart. In this way, the brain can receive stimuli and respond as if it were an endocrine organ. By releasing its hormones into the general circulation, the posterior pituitary can modify the functions of distant organs. The two posterior pituitary hormones are the peptides oxytocin and vasopressin. Oxytocin is involved in two reflexes related to reproduction. In one case, oxytocin stimulates contraction of smooth muscle cells in the breasts, which results in milk ejection during lactation. This occurs in response to stimulation of the nipples of the breast during nursing of the infant. Sensory cells within the nipples send stimulatory neural signals to the brain that terminate on the hypothalamic cells that make oxytocin, causing their activation and thus release of the hormone. In a second reflex, one that occurs during labor in a pregnant woman, stretch receptors in the cervix send neural signals back to the hypothalamus, which releases oxytocin in response. Oxytocin then stimulates contraction of uterine smooth muscle cells, until eventually the fetus is delivered (see Chapter 17 for details). Although oxytocin is also present in males, its systemic endocrine functions in males are uncertain. Recent research suggests that oxytocin may be involved in various aspects of memory and behavior in male and female mammals, possibly including humans. These include such things as pair bonding, maternal behavior, and emotions such as love. If true in humans, this is likely due to oxytocin-containing neurons in other parts of the brain, as it is unclear whether any systemic oxytocin can cross the blood–brain barrier and enter the brain. Page 333 The other posterior pituitary hormone, vasopressin, acts on smooth muscle cells around blood vessels to cause their contraction, which constricts the blood vessels and thereby increases blood pressure. This may occur, for example, in response to a decrease in blood pressure that resulted from a loss of blood due to an injury. Vasopressin also acts within the kidneys to decrease water excretion in the urine, thereby retaining fluid in the body and helping to maintain blood volume. One way in which this would occur would be if a person were to become dehydrated. Because of its kidney function, vasopressin is also known as antidiuretic hormone (ADH). (An increase in the volume of water excreted in the urine is known as diuresis, and because vasopressin decreases water loss in the urine, it has antidiuretic properties.) The actions of vasopressin will be discussed in the context of circulatory control (Chapter 12, Section 12.10) and fluid balance (Chapter 14, Section 14.7). Page 334 Anterior Pituitary Gland Hormones and the Hypothalamus Other nuclei of hypothalamic neurons secrete hormones that control the secretion of all the anterior pituitary gland hormones. For simplicity’s sake, Figure 11.14 depicts these neurons as arising from a single nucleus, but in fact several hypothalamic nuclei send axons whose terminals end in the median eminence. The hypothalamic hormones that regulate anterior pituitary gland function are collectively termed hypophysiotropic hormones (recall that another name for the pituitary gland is hypophysis); they are also commonly called hypothalamic releasing or inhibiting hormones. With one exception (dopamine), each of the hypophysiotropic hormones is the first in a three-hormone sequence (Figure 11.15): 1. A hypophysiotropic hormone controls the secretion of 2. an anterior pituitary gland hormone, which controls the secretion of 3. a hormone from some other endocrine gland Figure 11.15 Typical sequential pattern by which a hypophysiotropic hormone (hormone 1 from the hypothalamus) controls the secretion of an anterior pituitary gland hormone (hormone 2), which in turn controls the secretion of a hormone by a third endocrine gland (hormone 3). The hypothalamo–hypophyseal portal vessels are illustrated in Figure 11.14. This last hormone then acts on its target cells. The adaptive value of such sequences is that they permit a variety of types of important hormonal feedback (described in detail later in this chapter). They also allow amplification of a response of a small number of hypothalamic neurons into a large peripheral hormonal signal. We begin our description of these sequences in the middle—that is, with the anterior pituitary gland hormones—because the names of the hypophysiotropic hormones are mostly based on the names of the anterior pituitary gland hormones. Overview of Anterior Pituitary Gland Hormones As shown in Figure 11.16, the anterior pituitary gland secretes at least six hormones that have well-established functions in humans. These six hormones—all peptides—are follicle- stimulating hormone (FSH), luteinizing hormone (LH), growth hormone (GH, also known as somatotropin), thyroid-stimulating hormone (TSH, also known as thyrotropin), prolactin, and adrenocorticotropic hormone (ACTH, also known as corticotropin). Each of the last four is secreted by a distinct cell type in the anterior pituitary gland, whereas FSH and LH, collectively termed gonadotropic hormones (or gonadotropins) because they stimulate the gonads, are often secreted by the same cells. Figure 11.16 Targets and major functions of the six classical anterior pituitary gland hormones. Two other peptides—beta-lipotropin and beta-endorphin—are both derived from the same prohormone as ACTH, but their physiological roles in humans are unclear. In animal studies, however, beta-endorphin has been shown to have pain-killing effects, and beta- lipotropin can mobilize fats in the circulation to provide a source of energy. Both of these functions may contribute to the ability to cope with stressful challenges. Page 335 Figure 11.16 summarizes the target organs and major functions of the six classical anterior pituitary gland hormones. Note that the only major function of two of the six is to stimulate their target cells to synthesize and secrete other hormones (and to maintain the growth and function of these cells). Thyroid-stimulating hormone induces the thyroid to secrete thyroxine and triiodothyronine. Adrenocorticotropic hormone stimulates the adrenal cortex to secrete cortisol. Three other anterior pituitary gland hormones also stimulate the secretion of another hormone but have additional functions as well. Growth hormone stimulates the liver to secrete a growth-promoting peptide hormone known as insulin-like growth factor-1 (IGF- 1) and, in addition, exerts direct effects on bone and on metabolism (Section 11.19). Follicle- stimulating hormone and luteinizing hormone stimulate the gonads to secrete the sex hormones—estradiol and progesterone from the ovaries, or testosterone from the testes; in addition, however, they regulate the growth and development of ova and sperm. The actions of FSH and LH are described in detail in Chapter 17 and therefore are not covered further here.  Prolactin is unique among the six classical anterior pituitary gland hormones in that its major function is not to exert control over the secretion of a hormone by another endocrine gland. Its most important action is to stimulate development of the mammary glands during pregnancy and milk production when a woman is nursing (lactating); this occurs by direct effects upon gland cells in the breasts. During lactation, prolactin exerts a secondary action to inhibit gonadotropin secretion, thereby decreasing fertility when a woman is nursing. In the male, the physiological functions of prolactin are still under investigation. Hypophysiotropic Hormones As stated, secretion of the anterior pituitary gland hormones is largely regulated by hormones produced by the hypothalamus and collectively called hypophysiotropic hormones. These hormones are secreted by neurons that originate in discrete nuclei of the hypothalamus and terminate in the median eminence around the capillaries that are the origins of the hypothalamo–hypophyseal portal vessels. The generation of action potentials in these neurons causes them to secrete their hormones by exocytosis, much as action potentials cause other neurons to release neurotransmitters by exocytosis. Hypothalamic hormones, however, enter the median eminence capillaries and are carried by the hypothalamo–hypophyseal portal vessels to the anterior pituitary gland (Figure 11.17). There, they diffuse out of the anterior pituitary gland capillaries into the interstitial fluid surrounding the various anterior pituitary gland cells. Upon binding to specific membrane-bound receptors, the hypothalamic hormones act to stimulate or inhibit the secretion of the different anterior pituitary gland hormones. Figure 11.17 Hormone secretion by the anterior pituitary gland is controlled by hypophysiotropic hormones released by hypothalamic neurons and reaching the anterior pituitary gland by way of the hypothalamo–hypophyseal portal vessels. The hypophysiotropic hormones stimulate the anterior pituitary cells, which then release their hormones into the general circulation. These hypothalamic neurons secrete hormones in a manner identical to that described previously for the hypothalamic neurons whose axons end in the posterior pituitary. In both cases, the hormones are synthesized in cell bodies of the hypothalamic neurons, pass down axons to the neuron terminals, and are released in response to action potentials in the neurons. Two crucial differences, however, distinguish the two systems. First, the axons of the hypothalamic neurons that secrete the posterior pituitary hormones leave the hypothalamus and end in the posterior pituitary, whereas those that secrete the hypophysiotropic hormones are much shorter and remain in the hypothalamus, ending on capillaries in the median eminence. Second, most of the capillaries into which the posterior pituitary hormones are secreted immediately drain into the general circulation, which carries the hormones to the heart for distribution to the entire body. In contrast, the hypophysiotropic hormones enter capillaries in the median eminence of the hypothalamus that do not directly join the main bloodstream but empty into the hypothalamo–hypophyseal portal vessels, which carry them to the cells of the anterior pituitary gland. When an anterior pituitary gland hormone is secreted, it will diffuse into the same capillaries that delivered the hypophysiotropic hormone. These capillaries then drain into veins, which enter the general blood circulation, from which the anterior pituitary gland hormones come into contact with their target cells. The portal circulatory system ensures that hypophysiotropic hormones can reach the cells of the anterior pituitary gland at a high concentration and with very little delay. The small total blood flow in the portal veins allows extremely small amounts of hypophysiotropic hormones from relatively few hypothalamic neurons to control the secretion of anterior pituitary hormones without dilution in the systemic circulation. This is an excellent illustration of the general principle of physiology that structure is a determinant of—and has coevolved with—function. By releasing hypophysiotropic factors into relatively few veins with a low total blood flow, the concentration of hypophysiotropic factors can increase rapidly leading to a larger increase in the release of anterior pituitary hormones (amplification). Also, the total amount of hypophysiotropic hormones entering the general circulation is very low, which prevents them from having unintended effects in the rest of the body. Page 336 There are multiple hypophysiotropic hormones, each influencing the release of one or, in at least one case, two of the anterior pituitary gland hormones. For simplicity, Figure 11.18 and the text of this chapter summarize only those hypophysiotropic hormones that have clearly documented physiological roles in humans.  Figure 11.18 The effects of definitively established hypophysiotropic hormones on the anterior pituitary gland. The hypophysiotropic hormones reach the anterior pituitary gland via the hypothalamo– hypophyseal portal vessels. The and symbols indicate stimulatory and inhibitory actions, respectively. Several of the hypophysiotropic hormones are named for the anterior pituitary gland hormone whose secretion they control. Thus, secretion of ACTH (corticotropin) is stimulated by corticotropin-releasing hormone (CRH), secretion of growth hormone is stimulated by growth hormone–releasing hormone (GHRH), secretion of thyroid-stimulating hormone (thyrotropin) is stimulated by thyrotropin-releasing hormone (TRH), and secretion of both luteinizing hormone and follicle-stimulating hormone (the gonadotropins) is stimulated by gonadotropin-releasing hormone (GnRH). However, note in Figure 11.18 that two of the hypophysiotropic hormones do not stimulate the release of an anterior pituitary gland hormone but, rather, inhibit its release. One of them, somatostatin (SST), inhibits the secretion of growth hormone. The other, dopamine (DA), inhibits the secretion of prolactin. As Figure 11.18 shows, growth hormone is controlled by two hypophysiotropic hormones —somatostatin, which inhibits its release, and growth hormone–releasing hormone, which stimulates it. The rate of growth hormone secretion depends, therefore, upon the relative amounts of the opposing hormones released by the hypothalamic neurons, as well as upon the relative sensitivities to them of the GH-producing cells of the anterior pituitary gland. This is a key example of the general principle of physiology that most physiological functions are controlled by multiple regulatory systems, often working in opposition. Such dual controls may also exist for the other anterior pituitary gland hormones. This is particularly true in the case of prolactin where the evidence for a prolactin-releasing hormone in laboratory animals is reasonably strong (the importance of such physiological control for prolactin in humans, if it exists, is uncertain). Figure 11.19 summarizes the information presented in Figures 11.16 and 11.18 to illustrate the full sequence of hypothalamic control of endocrine function.  Figure 11.19 A combination of Figures 11.16 and 11.18 summarizes the hypothalamic–anterior pituitary gland system. The and symbols indicate stimulatory and inhibitory actions, respectively. Given that the hypophysiotropic hormones control anterior pituitary gland function, we must now ask: What controls secretion of the hypophysiotropic hormones themselves? Some of the neurons that secrete hypophysiotropic hormones may possess spontaneous activity, but the firing of most of them requires neural and hormonal input. Page 337 Neural Control of Hypophysiotropic Hormones Neurons of the hypothalamus receive stimulatory and inhibitory synaptic input from virtually all areas of the central nervous system, and specific neural pathways influence the secretion of the individual hypophysiotropic hormones. A large number of neurotransmitters, such as the catecholamines and serotonin, are released at synapses on the hypothalamic neurons that produce hypophysiotropic hormones. Not surprisingly, drugs that influence these neurotransmitters can alter the secretion of the hypophysiotropic hormones. In addition, there is a strong circadian influence (see Chapter 1) over the secretion of certain hypophysiotropic hormones. The neural inputs to these cells arise from other regions of the hypothalamus, which in turn are linked to inputs from visual pathways that recognize the presence or absence of light. A good example of this type of neural control is that of CRH, the secretion of which is tied to the day/night cycle in mammals. This pattern results in ACTH and cortisol concentrations in the blood that begin to increase in the hours just prior to awakening. Hormonal Feedback Control of the Hypothalamus and Anterior Pituitary Gland A prominent feature of each of the hormonal sequences initiated by a hypophysiotropic hormone is negative feedback exerted upon the hypothalamo–hypophyseal system by one or more of the hormones in its sequence. Negative feedback is a key component of most homeostatic control systems, as introduced in Chapter 1. In this case, it is effective in dampening hormonal responses—that is, in limiting the extremes of hormone secretory rates. For example, when a stressful stimulus elicits increased secretion, in turn, of CRH, ACTH, and cortisol, the resulting increase in plasma cortisol concentration feeds back to inhibit the CRH-secreting neurons of the hypothalamus and the ACTH-secreting cells of the anterior pituitary gland. Therefore, cortisol secretion does not increase as much as it would without negative feedback. Cortisol negative feedback is also critical in terminating the ACTH response to stress. As you will see in Section 11.15, this is important because of the potentially damaging effects of excess cortisol on immune function and metabolic reactions, among others. The situation described for cortisol, in which the hormone secreted by the third endocrine gland in a sequence exerts a negative feedback effect over the anterior pituitary gland and/or hypothalamus, is known as a long-loop negative feedback (Figure 11.20). Figure 11.20 Short-loop and long-loop feedbacks. Long-loop feedback is exerted on the hypothalamus and/or anterior pituitary gland by the third hormone in the sequence. Short-loop feedback is exerted by the anterior pituitary gland hormone on the hypothalamus. Long-loop feedback does not exist for prolactin because this is one anterior pituitary gland hormone that does not have major control over another endocrine gland—that is, it does not participate in a three-hormone sequence. Nonetheless, there is negative feedback in the prolactin system, for this hormone itself acts upon the hypothalamus to stimulate the secretion of dopamine, which then inhibits the secretion of prolactin. The influence of an anterior pituitary gland hormone on the hypothalamus is known as a short-loop negative feedback (see Figure 11.20). Like prolactin, several other anterior pituitary gland hormones, including growth hormone, also exert such feedback on the hypothalamus. The Role of “Nonsequence” Hormones on the Hypothalamus and Anterior Pituitary Gland There are many stimulatory and inhibitory hormonal influences on the hypothalamus and/or anterior pituitary gland other than those that fit the feedback patterns just described. In other words, a hormone that is not itself in a particular hormonal sequence may nevertheless exert important influences on the secretion of the hypophysiotropic or anterior pituitary gland hormones in that sequence. For example, estradiol markedly enhances the secretion of prolactin by the anterior pituitary gland, even though estradiol secretion is not normally controlled by prolactin. Thus, the sequences we have been describing should not be viewed as isolated units. Study and Review 11.8 Pituitary gland: anterior pituitary gland and posterior pituitary connected to the hypothalamus by a stalk or infundibulum (containing neuron axons and blood vessels called portal veins) Axons with cell bodies in the hypothalamus terminate in the posterior pituitary release oxytocin and vasopressin (antidiuretic hormone) into the blood (not into the portal circulation) Anterior pituitary gland secretes: growth hormone (GH) thyroid-stimulating hormone (TSH) adrenocorticotropic hormone (ACTH) prolactin (PRL) follicle-stimulating hormone (FSH) and luteinizing hormone (LH) (gonadotropins) Anterior pituitary gland hormone control: Hypophysiotropic hormones: stimulatory or inhibitory hormones secreted into capillaries in the median eminence of the hypothalamus and reaching the anterior pituitary gland via the portal vessels hormonal feedback (typically negative feedback) Hypophysiotropic hormone control: neuronal and hormonal input to the hypothalamic neurons Two- and three-hormone sequences Long-loop negative feedback: The “target gland” hormone exerts negative feedback on the secretion of the hypothalamic and/or anterior pituitary gland hormone in the pathway. Short-loop negative feedback: A given anterior pituitary hormone inhibits the hypophysiotropic hormone(s) that control its secretion. Review Question: Compare and contrast long-loop and short-loop negative feedback. Give an example of each. (Answer found in Appendix A.)  Page 338 The Thyroid Gland 11.9 Synthesis of Thyroid Hormone Thyroid hormone exerts diverse effects throughout much of the body. The actions of this hormone are so widespread—and the consequences of imbalances in its concentration so significant—that it is worth examining thyroid gland function in detail. As mentioned earlier, the thyroid gland produces two iodine-containing molecules of physiological importance, thyroxine (called T4 because it contains four iodines) and triiodothyronine (T3, three iodines; review Figure 11.3). A considerable about of T4 is converted to T3 in target tissues by enzymes known as deiodinases. We will therefore consider T3 to be the major thyroid hormone, even though the concentration of T4 in the blood is usually greater than that of T3. (You may think of T4 as a sort of reservoir for additional T3.) Because of its lower clearance rate, T4 is typically prescribed in situations where thyroid function is decreased in a person for any reason. The thyroid gland sits within the neck in front of and straddling the trachea (Figure 11.21a). It first becomes functional early in fetal life. Within the thyroid gland are numerous follicles, each composed of an enclosed sphere of epithelial cells surrounding a core containing a protein-rich material called the colloid (Figure 11.21b). The follicular epithelial cells participate in almost all phases of thyroid hormone synthesis and secretion. Synthesis begins when circulating iodide is actively cotransported with sodium ions across the basolateral membranes of the epithelial cells (step 1 in Figure 11.22), a process known as iodide trapping. The Na+ is pumped back out of the cell by Na+/K+-ATPases.  Figure 11.21 (a) Location of the bilobed thyroid gland. (b) A cross section through several adjoining follicles filled with colloid. (b) Biophoto Associates/Science Source Figure 11.22 Steps involved in T3 and T4 formation. Steps are keyed to the text. Growing evidence suggests that the final step (7) requires one or more transporter proteins, not shown here. DIG DEEPER What is the benefit of storing iodinated thyroglobulin in the colloid? Answer found in Appendix A. The negatively charged iodide ions diffuse to the apical membrane of the follicular epithelial cells and are transported into the colloid by an integral membrane protein called pendrin (step 2 ). Pendrin is a sodium-independent chloride/iodide transporter. The colloid of the follicles contains large amounts of a protein called thyroglobulin. Once in the colloid, iodide is rapidly oxidized at the luminal surface of the follicular epithelial cells to iodine, which is then attached to the phenolic rings of tyrosine residues within thyroglobulin (step 3 ). This process is called organification of iodine. Thyroglobulin itself is synthesized by the follicular epithelial cells and secreted by exocytosis into the colloid. Page 339 Page 340 The enzyme responsible for oxidizing iodides and attaching them to tyrosines on thyroglobulin in the colloid is called thyroid peroxidase, and it, too, is synthesized by follicular epithelial cells. Iodine may be added to either of two positions on a given tyrosine within thyroglobulin. A tyrosine with one iodine attached is called monoiodotyrosine (MIT); if two iodines are attached, the product is diiodotyrosine (DIT). Next, the phenolic ring of a molecule of MIT or DIT is removed from the remainder of its tyrosine and coupled to another DIT on the thyroglobulin molecule (step 4 ). This reaction may also be mediated by thyroid peroxidase. If two DIT molecules are coupled, the result is thyroxine (T4). If one MIT and one DIT are coupled, the result is T3. Therefore, the synthesis of T4 and T3 is unique in that it actually occurs in the extracellular (colloidal) space within the thyroid follicles. Finally, for thyroid hormone to be secreted into the blood, extensions of the colloid- facing membranes of follicular epithelial cells engulf portions of the colloid (with its iodinated thyroglobulin) by endocytosis (step 5 ). The thyroglobulin, which contains T4 and T3, is brought into contact with lysosomes in the cell interior (step 6 ). Proteolysis of thyroglobulin releases T4 and T3, which then diffuse out of the follicular epithelial cell (likely with the aid of membrane-bound transporters) into the interstitial fluid and from there to the blood (step 7 ). There is sufficient iodinated thyroglobulin stored within the follicles of the thyroid to provide thyroid hormone for several weeks even in the absence of dietary iodine. This storage capacity makes the thyroid gland unique among endocrine glands but is an essential adaptation considering the unpredictable intake of iodine in the diets of most animals. The processes shown in Figure 11.22 are an important example of the general principle of physiology that controlled exchange of materials occurs between compartments and across cellular membranes. A pump is necessary to transport iodide from the interstitial space against a concentration gradient across the cell membrane into the cytosol of the follicular cell, and pendrin is necessary to mediate the efflux of iodide from the cytoplasm into the colloidal space. These processes can be exploited clinically by administering very low doses of radioactive iodine to a patient suspected of having thyroid disease. The radioactive iodine is concentrated in the thyroid gland, allowing the gland to be visualized by a nuclear medicine scan. Study and Review 11.9 Thyroid hormones (T3 and T4): sequential additions of iodine (catalyzed by thyroid peroxidase) to tyrosines within the thyroglobulin molecule sequence in the thyroid follicle lumen (colloid), a process called organification of iodine Iodinated tyrosines on thyroglobulin are coupled to produce either T3 or T4. T4: main secretory product T3: active hormone; produced from T4 in target tissue Review Question: How could you decrease the action of T4 in the body without directly altering thyroid function? (Answer found in Appendix A.) 11.10 Control of Thyroid Function Essentially all of the actions of the follicular epithelial cells just described are stimulated by TSH, which, as we have seen, is stimulated by TRH. The basic control mechanism of TSH production is the negative feedback action of T3 and T4 on the anterior pituitary gland and, to a lesser extent, the hypothalamus (Figure 11.23). However, TSH does more than just stimulate T3 and T4 production. TSH also increases protein synthesis in follicular epithelial cells, increases DNA replication and cell division, and increases the amount of rough endoplasmic reticulum and other cellular machinery required by follicular epithelial cells for protein synthesis. Therefore, if thyroid cells are exposed to greater TSH concentrations than normal, they will undergo hypertrophy—that is, they will increase in size. An enlarged thyroid gland from any cause is called a goiter. There are several other ways in which goiters can occur that will be described later in Section 11.12 and in one of the case studies in Chapter 19. Figure 11.23 TRH-TSH-thyroid hormone sequence. T3 and T4 inhibit secretion of TSH and TRH by negative feedback, indicated by the symbol. Study and Review 11.10 Thyroid hormone synthesis and thyroidal iodine uptake (trapped in follicle) stimulated by TSH Negative feedback: Thyroid hormones inhibit TSH (and TRH). TSH causes thyroid growth (hypertrophy). Goiter: enlarged thyroid from any cause  Review Question: Why does iodine deficiency lead to goiter? (Answer found in Appendix A.) Page 341 11.11 Actions of Thyroid Hormone Receptors for thyroid hormone are present in the nuclei of most of the cells of the body, unlike receptors for many other hormones, whose distribution is more limited. Therefore, the actions of T3 are widespread and affect many organs and tissues. Like steroid hormones, T3 acts by inducing gene transcription and protein synthesis. Metabolic Actions T3 has several effects on carbohydrate and lipid metabolism, although not to the extent of other hormones such as insulin. Nonetheless, T3 stimulates carbohydrate absorption from the small intestine and increases fatty acid release from adipocytes. These actions provide energy that helps maintain metabolism at a high rate. Much of that energy is used to support the activity of Na+/K+-ATPases throughout the body; these enzymes are stimulated by T3. The cellular concentration of ATP, therefore, is critical for the ability of cells to maintain Na+/K+- ATPase activity in response to thyroid hormone stimulation. ATP concentrations are controlled in part by a negative feedback mechanism; ATP negatively feeds back on the glycolytic enzymes within cells that participate in ATP generation. A decrease in cellular stores of ATP, therefore, releases the feedback and triggers an increase in glycolysis; this results in the metabolism of additional glucose that restores ATP concentrations. One of the by-products of these processes is heat. Thus, as ATP is consumed in cells by Na+/K+-ATPases at a high rate due to T3 stimulation, the cellular stores of ATP must be maintained by increased metabolism of fuels. This calorigenic action of T3 represents a significant fraction of the total heat produced each day in a typical person. This action is essential for body temperature homeostasis, just one of many ways in which the actions of thyroid hormone demonstrate the general principle of physiology that homeostasis is essential for health and survival. Without thyroid hormone, heat production would decrease and body temperature (and most physiological processes) would be compromised. Permissive Actions Some of the actions of T3 are attributable to its permissive effects on the actions of catecholamines. T3 up-regulates beta-adrenergic receptors in many tissues, notably the heart and nervous system. It should not be surprising, therefore, that the symptoms of excess thyroid hormone concentration closely resemble some of the symptoms of excess epinephrine and norepinephrine (sympathetic nervous system activity). That is because the increased T3 potentiates the actions of the catecholamines, even though the latter are within normal concentrations. Because of this potentiating effect, people with excess T3 are often treated with drugs that block beta-adrenergic receptors to alleviate the anxiety, nervousness, and “racing heart” associated with excessive sympathetic activity. Growth and Development T3 is required for normal production of growth hormone from the anterior pituitary gland. Therefore, when T3 is very low, growth in children is decreased. In addition, T3 is a very important developmental hormone for the nervous system. T3 exerts many effects on the central nervous system during development, including the formation of axon terminals and the production of synapses, the growth of dendrites and dendritic extensions (called “spines”), and the formation of myelin. Absence of T3 results in the syndrome called congenital hypothyroidism. This syndrome is characterized by a poorly developed nervous system and severely compromised intellectual function (mental retardation). In the United States, the most common cause is the failure of the thyroid gland to develop normally. With neonatal screening, it can be treated with T4 at birth, which prevents long-term impairment of growth and mental development. The most common cause of congenital hypothyroidism around the world (although rare in the United States) is dietary iodine deficiency in the mother. Without iodine in her diet, iodine is not available to the fetus. Thus, even though the fetal thyroid gland may be normal, it cannot synthesize sufficient thyroid hormone. If the condition is discovered and corrected with iodine and thyroid hormone administration shortly after birth, mental and physical abnormalities can be minimized. If the treatment is not initiated in the neonatal period, the intellectual impairment resulting from congenital hypothyroidism cannot be reversed. The availability of iodized salt products has essentially eliminated congenital hypothyroidism in many countries, but it is still a common disorder in some parts of the world where iodized salt is not available. The effects of T3 on nervous system function are not limited to fetal and neonatal life. For example, T3 is required for proper nerve and muscle reflexes and for normal cognition in adults. Study and Review 11.11 Thyroid hormone effects: increases metabolic rate (calorigenic effect) and thus heat production exerts permissive actions: increases the effectiveness of actions of the sympathetic nervous system important for normal growth and development during fetal life and childhood  Review Question: Why can the symptoms of excessive thyroid hormone be confused with increased activity of the sympathetic nervous system? (Answer found in Appendix A.) Page 342 11.12 Hypothyroidism and Hyperthyroidism Any condition characterized by plasma concentrations of thyroid hormones that are chronically below normal is known as hypothyroidism. Most cases of hypothyroidism are caused by primary defects resulting from damage to or loss of functional thyroid tissue or from inadequate iodine consumption. In iodine deficiency, the synthesis of thyroid hormone is compromised, leading to a decrease in the plasma concentration of this hormone. This, in turn, releases the hypothalamus and anterior pituitary gland from negative feedback inhibition. This leads to an increase in TRH concentration in the portal circulation that drains into the anterior pituitary gland. Plasma TSH concentration is increased due to the increased TRH and loss of thyroid hormone negative feedback on the anterior pituitary gland. The resulting overstimulation of the thyroid gland can produce goiters that can achieve astounding sizes if untreated (Figure 11.24). This form of hypothyroidism is reversible if iodine is added to the diet. It is rare in the United States because of the widespread use of iodized salt, in which a small fraction of NaCl molecules is replaced with NaI. Figure 11.24 Goiter at an advanced stage. domonabikebali/Alamy Stock Photo The most common cause of hypothyroidism in the United States is autoimmune disruption of the normal function of the thyroid gland, a condition known as autoimmune thyroiditis. One form of autoimmune thyroiditis results from Hashimoto’s disease, in which cells of the immune system attack thyroid tissue. Like many other autoimmune diseases, Hashimoto’s disease is more common in women and can slowly progress with age. As thyroid hormone begins to decrease because of the decrease in thyroid function due to inflammation of the gland, TSH concentrations increase due to the decreased negative feedback. The consequent overstimulation of the thyroid gland results in cellular hypertrophy, and a goiter can develop. The usual treatment for autoimmune thyroiditis is daily replacement with a pill containing T4. This causes the TSH concentration to decrease to normal due to negative feedback. Another cause of hypothyroidism can occur when the release of TSH from the anterior pituitary is inadequate for long periods of time. This is called secondary hypothyroidism and can lead to atrophy of the thyroid gland due to the long-term loss of the trophic effects of TSH. The features of hypothyroidism in adults may be mild or severe, depending on the degree of hormone deficiency. These include an increased sensitivity to cold (cold intolerance) and a tendency toward weight gain. Both of these symptoms are related to the decreased calorigenic actions normally produced by thyroid hormone. Many of the other symptoms appear to be diffuse and nonspecific, such as fatigue and changes in skin tone, hair, appetite, gastrointestinal function, and neurological function (for example, depression). The basis of the last effect in humans is uncertain, but it is now clear from work on laboratory animals that thyroid hormone has widespread effects on the adult mammalian brain. In severe, untreated hypothyroidism, certain hydrophilic polymers called glycosaminoglycans accumulate in the interstitial space in scattered regions of the body. Normally, thyroid hormone acts to prevent overexpression of these extracellular compounds that are secreted by connective tissue cells. When T3 is too low, therefore, these hydrophilic molecules accumulate and water tends to be trapped with them. This combination causes a characteristic puffiness of the face and other regions that is known as myxedema. As in the case of hypothyroidism, there are a variety of ways in which hyperthyroidism, or thyrotoxicosis, can develop. Among these are hormone-secreting tumors of the thyroid gland (rare), but the most common form of hyperthyroidism is an autoimmune disease called Graves’ disease. This disease is characterized by the production of antibodies that bind to and activate the TSH receptors on thyroid gland cells, leading to chronic overstimulation of the growth and activity of the thyroid gland (see Chapter 19 for a case study related to this disease). The signs and symptoms of thyrotoxicosis can be predicted in part from the previous discussion about hypothyroidism. Hyperthyroid patients tend to have heat intolerance, weight loss, and increased appetite, and they often show signs of increased sympathetic nervous system activity (anxiety, tremors, jumpiness, increased heart rate). Hyperthyroidism can be very serious, particularly because of its effects on the cardiovascular system (largely secondary to its permissive actions on catecholamines). It may be treated with drugs that inhibit thyroid hormone synthesis, by surgical removal of the thyroid gland, or by destroying a portion of the thyroid gland using radioactive iodine. In the last case, the radioactive iodine is ingested. Because the thyroid gland is the chief region of iodine uptake in the body, most of the radioactive iodine appears within the gland, where its high-energy radiation partly destroys the tissue.  Study and Review 11.12 Hypothyroidism: decreased thyroid function due to autoimmune destruction of thyroid (e.g., Hashimoto’s disease) or to iodine deficiency characterized by weight gain, fatigue, cold intolerance, and changes in cognition and skin tone goiter due to inflammation and/or increased TSH Hyperthyroidism: increased thyroid function almost always caused by autoimmune disease (Graves’ disease) in which TSH receptor is chronically activated by immunoglobulins characterized by weight loss, heat intolerance, irritability, and anxiety results in goiter if untreated: due to immunological stimulation of thyroid function (TSH independent) Review Question: What will happen to the concentration of TSH in the blood in primary hypothyroidism (autoimmune destruction of the thyroid gland) and why? (Answer found in Appendix A.) Page 343 The Endocrine Response to Stress 11.13 Physiological Functions of Cortisol Much of this book is concerned with the body’s response to stress in its broadest meaning as a real or perceived threat to homeostasis. Thus, any change in external temperature, water intake, or other homeostatic factors sets into motion responses designed to minimize a significant change in some physiological variable. In this section, the basic endocrine response to stress is described. These threats to homeostasis comprise a large number of situations, including physical trauma, prolonged exposure to cold, prolonged heavy exercise, infection, shock, decreased oxygen supply, sleep deprivation, pain, and emotional stresses. It may seem obvious that the physiological response to cold exposure must be very different from that to infection or emotional stresses such as fright, but in one respect the response to all these situations is the same: Invariably, the secretion from the adrenal cortex of the glucocorticoid hormone cortisol is increased. Activity of the sympathetic nervous system, including release of the hormone epinephrine from the adrenal medulla, also increases in response to many types of stress. The increased cortisol secretion during stress is mediated by the hypothalamus–anterior pituitary gland system described earlier. As illustrated in Figure 11.25, neural input to the hypothalamus from portions of the nervous system responding to a particular stress induces secretion of CRH. This hormone is carried by the hypothalamo–hypophyseal portal vessels to the anterior pituitary gland, where it stimulates ACTH secretion. ACTH in turn circulates through the blood, r