Vander's Human Physiology - The Endocrine System PDF

Page 319 CHAPTER 11 The Endocrine System Sagital MRI of a human brain showin...

Page 319 CHAPTER 11 The Endocrine System Sagital MRI of a human brain showing the connection between the hypothalamus, the pituitary stalk, and the pituitary gland (white structures in center of image). Living Art Enterprises/Science Source General Characteristics of Hormones and Hormonal Control Systems Copyright © 2022. McGraw-Hill US Higher Ed ISE. All rights reserved. 11.1 Hormones and Endocrine Glands 11.2 Hormone Structures and Synthesis 11.3 Hormone Transport in the Blood 11.4 Hormone Metabolism and Excretion 11.5 Mechanisms of Hormone Action 11.6 Inputs That Control Hormone Secretion 11.7 Types of Endocrine Disorders Widmaier, Eric, et al. Vander's Human Physiology, McGraw-Hill US Higher Ed ISE, 2022. ProQuest Ebook Central, http://ebookcentral.proquest.com/lib/twc-ebooks/detail.action?docID=6861910. Created from twc-ebooks on 2024-10-03 14:33:47.  The Hypothalamus and Pituitary Gland 11.8 Control Systems Involving the Hypothalamus and Pituitary Gland The Thyroid Gland 11.9 Synthesis of Thyroid Hormone 11.10 Control of Thyroid Function 11.11 Actions of Thyroid Hormone 11.12 Hypothyroidism and Hyperthyroidism The Endocrine Response to Stress 11.13 Physiological Functions of Cortisol 11.14 Functions of Cortisol in Stress 11.15 Adrenal Insufficiency and Cushing’s Syndrome 11.16 Other Hormones Released During Stress Endocrine Control of Growth 11.17 Bone Growth 11.18 Environmental Factors Influencing Growth 11.19 Hormonal Influences on Growth Copyright © 2022. McGraw-Hill US Higher Ed ISE. All rights reserved. Endocrine Control of Ca2+ Homeostasis 11.20 Effector Sites for Ca2+ Homeostasis 11.21 Hormonal Controls 11.22 Metabolic Bone Diseases Chapter 11 Clinical Case Study Widmaier, Eric, et al. Vander's Human Physiology, McGraw-Hill US Higher Ed ISE, 2022. ProQuest Ebook Central, http://ebookcentral.proquest.com/lib/twc-ebooks/detail.action?docID=6861910. Created from twc-ebooks on 2024-10-03 14:33:47.  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 Copyright © 2022. McGraw-Hill US Higher Ed ISE. All rights reserved. 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 Widmaier, Eric, et al. Vander's Human Physiology, McGraw-Hill US Higher Ed ISE, 2022. ProQuest Ebook Central, http://ebookcentral.proquest.com/lib/twc-ebooks/detail.action?docID=6861910. Created from twc-ebooks on 2024-10-03 14:33:47.  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 Copyright © 2022. McGraw-Hill US Higher Ed ISE. All rights reserved. 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. Widmaier, Eric, et al. Vander's Human Physiology, McGraw-Hill US Higher Ed ISE, 2022. ProQuest Ebook Central, http://ebookcentral.proquest.com/lib/twc-ebooks/detail.action?docID=6861910. Created from twc-ebooks on 2024-10-03 14:33:47.  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. Copyright © 2022. McGraw-Hill US Higher Ed ISE. All rights reserved. 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 Widmaier, Eric, et al. Vander's Human Physiology, McGraw-Hill US Higher Ed ISE, 2022. ProQuest Ebook Central, http://ebookcentral.proquest.com/lib/twc-ebooks/detail.action?docID=6861910. Created from twc-ebooks on 2024-10-03 14:33:47.  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. Copyright © 2022. McGraw-Hill US Higher Ed ISE. All rights reserved. Widmaier, Eric, et al. Vander's Human Physiology, McGraw-Hill US Higher Ed ISE, 2022. ProQuest Ebook Central, http://ebookcentral.proquest.com/lib/twc-ebooks/detail.action?docID=6861910. Created from twc-ebooks on 2024-10-03 14:33:47.  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 Copyright © 2022. McGraw-Hill US Higher Ed ISE. All rights reserved. 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. Widmaier, Eric, et al. Vander's Human Physiology, McGraw-Hill US Higher Ed ISE, 2022. ProQuest Ebook Central, http://ebookcentral.proquest.com/lib/twc-ebooks/detail.action?docID=6861910. Created from twc-ebooks on 2024-10-03 14:33:47.  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. Copyright © 2022. McGraw-Hill US Higher Ed ISE. All rights reserved. Widmaier, Eric, et al. Vander's Human Physiology, McGraw-Hill US Higher Ed ISE, 2022. ProQuest Ebook Central, http://ebookcentral.proquest.com/lib/twc-ebooks/detail.action?docID=6861910. Created from twc-ebooks on 2024-10-03 14:33:47.  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 Copyright © 2022. McGraw-Hill US Higher Ed ISE. All rights reserved. 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. Widmaier, Eric, et al. Vander's Human Physiology, McGraw-Hill US Higher Ed ISE, 2022. ProQuest Ebook Central, http://ebookcentral.proquest.com/lib/twc-ebooks/detail.action?docID=6861910. Created from twc-ebooks on 2024-10-03 14:33:47.  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. Copyright © 2022. McGraw-Hill US Higher Ed ISE. All rights reserved. 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. Widmaier, Eric, et al. Vander's Human Physiology, McGraw-Hill US Higher Ed ISE, 2022. ProQuest Ebook Central, http://ebookcentral.proquest.com/lib/twc-ebooks/detail.action?docID=6861910. Created from twc-ebooks on 2024-10-03 14:33:47.  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 Copyright © 2022. McGraw-Hill US Higher Ed ISE. All rights reserved. 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 Widmaier, Eric, et al. Vander's Human Physiology, McGraw-Hill US Higher Ed ISE, 2022. ProQuest Ebook Central, http://ebookcentral.proquest.com/lib/twc-ebooks/detail.action?docID=6861910. Created from twc-ebooks on 2024-10-03 14:33:47.  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. Copyright © 2022. McGraw-Hill US Higher Ed ISE. All rights reserved. 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. Widmaier, Eric, et al. Vander's Human Physiology, McGraw-Hill US Higher Ed ISE, 2022. ProQuest Ebook Central, http://ebookcentral.proquest.com/lib/twc-ebooks/detail.action?docID=6861910. Created from twc-ebooks on 2024-10-03 14:33:47.  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 Copyright © 2022. McGraw-Hill US Higher Ed ISE. All rights reserved. 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 Widmaier, Eric, et al. Vander's Human Physiology, McGraw-Hill US Higher Ed ISE, 2022. ProQuest Ebook Central, http://ebookcentral.proquest.com/lib/twc-ebooks/detail.action?docID=6861910. Created from twc-ebooks on 2024-10-03 14:33:47.  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: Copyright © 2022. McGraw-Hill US Higher Ed ISE. All rights reserved. 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 Widmaier, Eric, et al. Vander's Human Physiology, McGraw-Hill US Higher Ed ISE, 2022. ProQuest Ebook Central, http://ebookcentral.proquest.com/lib/twc-ebooks/detail.action?docID=6861910. Created from twc-ebooks on 2024-10-03 14:33:47.  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. Copyright © 2022. McGraw-Hill US Higher Ed ISE. All rights reserved. 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: Widmaier, Eric, et al. Vander's Human Physiology, McGraw-Hill US Higher Ed ISE, 2022. ProQuest Ebook Central, http://ebookcentral.proquest.com/lib/twc-ebooks/detail.action?docID=6861910. Created from twc-ebooks on 2024-10-03 14:33:47.  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 Copyright © 2022. McGraw-Hill US Higher Ed ISE. All rights reserved. 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. Widmaier, Eric, et al. Vander's Human Physiology, McGraw-Hill US Higher Ed ISE, 2022. ProQuest Ebook Central, http://ebookcentral.proquest.com/lib/twc-ebooks/detail.action?docID=6861910. Created from twc-ebooks on 2024-10-03 14:33:47.  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 Copyright © 2022. McGraw-Hill US Higher Ed ISE. All rights reserved. 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 Widmaier, Eric, et al. Vander's Human Physiology, McGraw-Hill US Higher Ed ISE, 2022. ProQuest Ebook Central, http://ebookcentral.proquest.com/lib/twc-ebooks/detail.action?docID=6861910. Created from twc-ebooks on 2024-10-03 14:33:47.  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? Copyright © 2022. McGraw-Hill US Higher Ed ISE. All rights reserved. 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). Widmaier, Eric, et al. Vander's Human Physiology, McGraw-Hill US Higher Ed ISE, 2022. ProQuest Ebook Central, http://ebookcentral.proquest.com/lib/twc-ebooks/detail.action?docID=6861910. Created from twc-ebooks on 2024-10-03 14:33:47.  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 Copyright © 2022. McGraw-Hill US Higher Ed ISE. All rights reserved. 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 Widmaier, Eric, et al. Vander's Human Physiology, McGraw-Hill US Higher Ed ISE, 2022. ProQuest Ebook Central, http://ebookcentral.proquest.com/lib/twc-ebooks/detail.action?docID=6861910. Created from twc-ebooks on 2024-10-03 14:33:47.  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. Copyright © 2022. McGraw-Hill US Higher Ed ISE. All rights reserved. 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 Widmaier, Eric, et al. Vander's Human Physiology, McGraw-Hill US Higher Ed ISE, 2022. ProQuest Ebook Central, http://ebookcentral.proquest.com/lib/twc-ebooks/detail.action?docID=6861910. Created from twc-ebooks on 2024-10-03 14:33:47.  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. Copyright © 2022. McGraw-Hill US Higher Ed ISE. All rights reserved. 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 Widmaier, Eric, et al. Vander's Human Physiology, McGraw-Hill US Higher Ed ISE, 2022. ProQuest Ebook Central, http://ebookcentral.proquest.com/lib/twc-ebooks/detail.action?docID=6861910. Created from twc-ebooks on 2024-10-03 14:33:47.  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 Copyright © 2022. McGraw-Hill US Higher Ed ISE. All rights reserved. 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 Widmaier, Eric, et al. Vander's Human Physiology, McGraw-Hill US Higher Ed ISE, 2022. ProQuest Ebook Central, http://ebookcentral.proquest.com/lib/twc-ebooks/detail.action?docID=6861910. Created from twc-ebooks on 2024-10-03 14:33:47.  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) Copyright © 2022. McGraw-Hill US Higher Ed ISE. All rights reserved. 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