Physiology Book 7 PDF

7 Introduction to the Endocrine System The separation of the endocrine system into isolated subsystems must be Colloid (red) inside...

7 Introduction to the Endocrine System The separation of the endocrine system into isolated subsystems must be Colloid (red) inside thyroid follicles recognized as an artificial one, convenient from a pedagogical point of view but not accurately reflecting the interrelated nature of all these systems. Howard Rasmussen, in Williams’ Textbook of Endocrinology, 1974 7.1 Hormones 195 7.3 Control of Hormone 7.5 Endocrine Pathologies 214 LO 7.1.1 Explain the four criteria that make a Release 205 LO 7.5.1 Name the three most common types chemical signal a hormone. LO 7.3.1 Describe the role of the nervous of endocrine pathologies. LO 7.1.2 Explain what the cellular mechanism of system in endocrine reflexes. LO 7.5.2 Explain how negative feedback can be action of a hormone is. LO 7.3.2 Compare the structure and function used to determine the location of a problem of the anterior and posterior pituitaries. with one gland in a two- or three-gland 7.2 The Classification of LO 7.3.3 List the six anterior pituitary pathway. Hormones 199 hormones, the hormones that control their release, and their primary targets. 7.6 Hormone Evolution 217 LO 7.2.1 List three chemical classes of hor- mones and give an example of each. LO 7.6.1 Explain how comparative LO 7.3.4 Compare long-loop negative feedback endocrinology is useful for understanding LO 7.2.2 Compare endocrine cells’ synthesis, for anterior pituitary hormones to the nega- human physiology. storage, and release of peptide and steroid tive feedback loops for insulin and parathy- hormones. roid hormone. LO 7.2.3 Compare the location of hormone receptors and the cellular mechanisms of 7.4 Hormone Interactions 212 action of peptide and steroid hormones. LO 7.4.1 Explain permissiveness, synergism, LO 7.2.4 Compare the three main groups of and functional antagonism as they apply to amine hormones. hormones. BACKGROUND BASICS 168 Receptors 32 Peptides and proteins 186 Comparison of endocrine and nervous systems 170 Signal transduction 30 Steroids 46 Specificity  7.1 Hormones 195 avid was seven years old when the symptoms first appeared. Hormones Have Been Known Since Ancient Times D His appetite at meals increased, and he always seemed to be hungry. Despite eating more, however, he was losing weight. When he started asking for water instead of soft drinks, David’s Although the scientific field of endocrinology is relatively young, diseases of the endocrine system have been documented for more than a thousand years. Evidence of endocrine abnormalities can mother became concerned, and when he wet the bed three nights even be seen in ancient art. For example, one pre-Colombian in a row, she knew something was wrong. The doctor listened to statue of a woman shows a mass on the front of her neck (FIG. 7.1). David’s symptoms and ordered tests to determine the glucose con- The mass is an enlarged thyroid gland, or goiter, a common condi- centrations of David’s blood and urine. The test results confirmed tion high in the Andes, where the dietary iodine needed to make CHAPTER the diagnosis: David had diabetes mellitus. In David’s case, the thyroid hormones was lacking. disease was due to lack of insulin, a hormone produced by the The first association of endocrine structure and function was pancreas. David was placed on insulin injections, a treatment he probably the link between the testes and male sexuality. Castration would continue for the rest of his life. of animals and men was a common practice in both Eastern and 7 One hundred years ago, David would have died not long after Western cultures because it decreased the sex drive and rendered the onset of symptoms. The field of endocrinology, the study of males infertile. hormones, was then in its infancy. Most hormones had not been In 1849, A. A. Berthold used this knowledge to perform the discovered, and the functions of known hormones were not well first classic experiment in endocrinology. He removed the testes understood. There was no treatment for diabetes, no birth control from roosters and observed that the castrated birds had smaller pill for contraception. Babies born with inadequate secretion of combs, less aggressiveness, and less sex drive than uncastrated thyroid hormone did not grow or develop normally. roosters. If the testes were surgically placed back into the donor Today, all that has changed. We have identified a long and rooster or into another castrated bird, normal male behavior growing list of hormones. The endocrine diseases that once killed and comb development resumed. Because the reimplanted tes- or maimed can now be controlled by synthetic hormones and tes were not connected to nerves, Berthold concluded that the sophisticated medical procedures. Although physicians do not glands must secrete something into the blood that affected the hesitate to use these treatments, we are still learning exactly how entire body. hormones act on their target cells. This chapter provides an intro- duction to the basic principles of hormone structure and function. You will learn more about individual hormones as you encounter FIG. 7.1 An endocrine disorder in ancient art them in your study of the various systems. This pre-Colombian stone carving of a woman shows a mass at her neck. This mass is an enlarged thyroid gland, a condition known as goiter. It was considered a sign of beauty among the 7.1 Hormones people who lived high in the Andes mountains. As you have learned, hormones are chemical messengers secreted into the blood by specialized epithelial cells. Hormones are respon- sible for many functions that we think of as long-term, ongoing functions of the body. Processes that fall mostly under hormonal control include metabolism, regulation of the internal environment (temperature, water balance, ions), and reproduction, growth, and development. Hormones act on their target cells in one of three basic ways: (1) by controlling the rates of enzymatic reactions, (2) by controlling the transport of ions or molecules across cell membranes, or (3) by controlling gene expression and the synthesis of proteins. RUNNING PROBLEM Graves’ Disease The ball slid by the hole and trickled off the green: another bogey. Ben Crenshaw’s golf game was falling apart. The 33-year-old professional had won the Masters Tournament only a year ago, but now something was not right. He was tired and weak, had been losing weight, and felt hot all the time. He attributed his symptoms to stress, but his family thought otherwise. At their urging, he finally saw a physician. The diagnosis? Graves’ disease, which results in an overactive thyroid gland. 195 204 212 214 216 217 219 196 CHAPTER 7 Introduction to the Endocrine System Experimental endocrinology did not receive much atten- Hormones identified by this technique are sometimes called tion, however, until 1889, when the 72-year-old French physician classic hormones. They include hormones of the pancreas, thyroid, Charles Brown-Séquard made a dramatic announcement of his adrenal glands, pituitary, and gonads, all discrete endocrine sexual rejuvenation after injecting himself with extracts made from glands that could be easily identified and surgically removed. bull testes ground up in water. An international uproar followed, Not all hormones come from identifiable glands, however, and and physicians on both sides of the Atlantic began to inject their we have been slower to discover them. For example, many hor- patients with extracts of many different endocrine organs, a prac- mones involved in digestion are secreted by endocrine cells scat- tice known as organotherapy. tered throughout the wall of the stomach or intestine, which We now know that the increased virility Brown-Séquard has made them difficult to identify and isolate. The Anatomy reported was most likely a placebo effect because testosterone is a Summary in FIGURE 7.2 lists the major hormones of the body, hydrophobic steroid that cannot be extracted by an aqueous prepa- the glands or cells that secrete them, and the major effects of ration. His research opened the door to hormone therapy, however, each hormone. and in 1891, organotherapy had its first true success: A woman was treated for low thyroid hormone levels with glycerin extracts What Makes a Chemical a Hormone? of sheep thyroid glands. As the study of “internal secretions” grew, Berthold’s experi- In 1905, the term hormone was coined from the Greek verb meaning ments became a template for endocrine research. Once a gland or “to excite or arouse.” The traditional definition of a hormone is structure was suspected of secreting hormones, the classic steps for a chemical secreted by a cell or group of cells into the blood for identifying an endocrine gland became: transport to a distant target, where it exerts its effect at very low concentrations. However, as scientists learn more about chemical 1. Remove the suspected gland. This is equivalent to induc- communication in the body, this definition is continually being ing a state of hormone deficiency. If the gland does produce challenged. hormones, the animal should start to exhibit anatomical, behavioral, or physiological abnormalities. Hormones Are Secreted by a Cell or Group of Cells Traditionally, 2. Replace the hormone. This can be done by placing the the field of endocrinology has focused on chemical messengers gland back in the animal or administering an extract of the secreted by endocrine glands, the discrete and readily identifi- gland. This replacement therapy should eliminate the symptoms able tissues derived from epithelial tissue [p. 79]. However, we of hormone deficiency. now know that molecules that act as hormones are secreted 3. Create a state of hormone excess. Take a normal ani- not only by classic endocrine glands but also by isolated endo- mal and implant an extra gland or administer extract from the crine cells (hormones of the diffuse endocrine system), by neurons gland to see if symptoms characteristic of hormone excess appear. (neurohormones), and occasionally by cells of the immune system (cytokines). Once a gland is identified as a potential source of hormones, sci- entists purify extracts of the gland to isolate the active substance. Hormones Are Secreted into the Blood Secretion is the They test for hormone activity by injecting animals with the puri- movement of a substance from inside a cell to the extracellular fied extract and monitoring for a response. fluid or directly into the external environment. According to the traditional definition of a hormone, hormones are secreted into the blood. However, the term ectohormone {ektos, outside} CLINICAL FOCUS has been given to signal molecules secreted into the external Diabetes: The Discovery of Insulin environment. Pheromones {pherein, to bring} are specialized ectohor- Type 1 diabetes mellitus, the metabolic condition associated with insulin deficiency, has been known since ancient times. mones that act on other organisms of the same species to elicit a Until the early 1900s physicians had no means of treating the physiological or behavioral response. For example, sea anemones disease, and patients invariably died. It was a series of classic secrete alarm pheromones when danger threatens, and ants release experiments that pinpointed the cause of diabetes. In 1889, trail pheromones to attract fellow workers to food sources. Phero- Oskar Minkowski at the University of Strasbourg (France) mones are also used to attract members of the opposite sex for surgically removed the pancreas from dogs and noticed that mating. Sex pheromones are found throughout the animal king- the dogs developed symptoms of diabetes. He found that dom, in animals from fruit flies to dogs. implanting pieces of pancreas under the dogs’ skin would But do humans have pheromones? This question is still a prevent development of diabetes. Then, in 1921 Frederick matter of debate. Some studies have shown that human axillary G. Banting and Charles H. Best (Toronto, Canada) isolated (armpit) sweat glands secrete volatile steroids related to sex hor- a substance from pancreatic extracts that reversed the mones that may serve as human sex pheromones. In one study, elevated blood glucose levels of diabetes. From there, it was when female students were asked to rate the odors of T-shirts a relatively short process until, in 1922, purified insulin was worn by male students, each woman preferred the odor of men used in the first clinical trials. Science had found a treatment who were genetically dissimilar from her. In another study, female for a once-fatal disease. axillary secretions rubbed on the upper lip of young women altered the timing of their menstrual cycles. Putative human  7.1 Hormones 197 pheromones are now sold as perfume advertised for attracting Hormones Act by Binding to Receptors the opposite sex, as you will see if you do a web search for human All hormones bind to target cell receptors and initiate bio- pheromone. How humans may sense pheromones is discussed later chemical responses. These responses are the cellular mecha- (see Chapter 10). nism of action of the hormone. As you can see from the table in Figure 7.2, one hormone may act on multiple tissues. Hormones Are Transported to a Distant Target By the traditional To complicate matters, the effects may vary in different tissues or definition, a hormone must be transported by the blood to a dis- at different stages of development. Or a hormone may have no tant target cell. Experimentally, this property is sometimes difficult effect at all in a particular cell. Insulin is an example of a hormone CHAPTER to demonstrate. Molecules that are suspected of being hormones with varied effects. In muscle and adipose tissues, insulin alters but not fully accepted as such are called candidate hormones. They glucose transport proteins and enzymes for glucose metabolism. are usually identified by the word factor. For example, in the early In the liver, it modulates enzyme activity but has no direct effect on 1970s, the hypothalamic regulating hormones were known as glucose transport proteins. In the brain and certain other tissues, 7 “releasing factors” and “inhibiting factors” rather than releasing glucose metabolism and inhibiting hormones. Play A&P Flix Animation is totally indepen- Currently, growth factors, a large group of substances that @Mastering Anatomy & Physiology dent of insulin. influence cell growth and division, are being studied to determine if they meet all the criteria for hormones. Although many growth factors act locally as autocrine or paracrine signals [p. 167], most Concept Check do not seem to be distributed widely in the circulation. A simi- lar situation exists with the lipid-derived signal molecules called 1. Name the membrane transport process by which glucose moves from the extracellular fluid into cells. eicosanoids [p. 178]. Complicating the classification of signal molecules is the fact that a molecule may act as a hormone when secreted from one location but as a paracrine or autocrine signal when Hormone Action Must Be Terminated secreted from a different location. For example, in the 1920s, Signal activity by hormones and other chemical signals must be of scientists discovered that cholecystokinin (CCK) in extracts of limited duration if the body is to respond to changes in its internal intestine caused contraction of the gallbladder. For many years state. For example, insulin is secreted when blood glucose con- thereafter, CCK was known only as an intestinal hormone. centrations increase following a meal. As long as insulin is pres- Then in the mid-1970s, CCK was found in neurons of the ent, glucose leaves the blood and enters cells. However, if insulin brain, where it acts as a neurotransmitter or neuromodulator. activity continues for too long, blood glucose levels can fall so low In recent years, CCK has gained attention because of its pos- that the nervous system becomes unable to function properly—a sible role in controlling hunger. potentially fatal situation. Normally, the body avoids this situation in several ways: by limiting insulin secretion, by removing or inac- Hormones Exert Their Effect at Very Low Concentrations One tivating insulin circulating in the blood, and by terminating insulin hallmark of a hormone is its ability to act at concentrations in the activity in target cells. nanomolar (10-9 M) to picomolar (10-12 M) range. Some chemical In general, hormones in the bloodstream are degraded (broken signals transported in the blood to distant targets are not consid- down) into inactive metabolites by enzymes found primarily in the ered hormones because they must be present in relatively high liver and kidneys. The metabolites are then excreted in either the concentrations before an effect is noticed. For example, histamine bile or the urine. The rate of hormone breakdown is indicated released during severe allergic reactions may act on cells through- by a hormone’s half-life in the circulation, the amount of time out the body, but its concentration exceeds the accepted range for required to reduce the concentration of hormone by one-half. Half- a hormone. life is one indicator of how long a hormone is active in the body. As researchers discover new signal molecules and new Hormones bound to target membrane receptors have their receptors, the boundary between hormones and nonhor- activity terminated in several ways. Enzymes that are always pres- monal signal molecules continues to be challenged, just as ent in the plasma can degrade peptide hormones bound to cell the distinction between the nervous and endocrine systems membrane receptors. In some cases, the receptor-hormone com- has blurred. Many cytokines (p. 167) seem to meet many of the plex is brought into the cell by endocytosis, and the hormone is criteria of a hormone. However, experts in cytokine research then digested in lysosomes [Fig. 5.19, p. 148]. Intracellular enzymes do not consider cytokines to be hormones because cytokines metabolize hormones that enter cells. are synthesized and released on demand, in contrast to clas- sic peptide hormones, which are made in advance and stored in the parent endocrine cell. A few cytokines—for example, Concept Check erythropoietin, the molecule that controls red blood cell produc- 2. What is the suffix in a chemical name that tells you a molecule tion—were classified as hormones before the term cytokine was is an enzyme? [Hint: p. 101] Use that suffix to name an enzyme coined, contributing to the overlap between the two groups of that digests peptides. signal molecules. FIG. 7.2 ANATOMY SUMMARY... Hormones Location Hormone Primary Target(s) Pineal gland Melatonin Brain, other tissues Hypothalamus Trophic hormones [P , A] (see Fig. 7.9) Anterior pituitary Oxytocin [P] Breast and uterus Posterior pituitary (N) Vasopressin (ADH) [P] Kidney Anterior pituitary Prolactin [P] Breast Growth hormone (somatotropin) [P] Liver, many tissues Corticotropin (ACTH) [P] Adrenal cortex Thyrotropin (TSH) [P] Thyroid gland Follicle-stimulating hormone [P] Gonads Lutienizing hormone [P] Gonads Thyroid gland Triiodothyronine and thyroxine [A] Many tissues Calcitonin [P] Bone Parathyroid gland Parathyroid hormone [P] Bone, kidney Thymus gland Thymosin, thymopoietin [P] Lymphocytes Heart (C) Atrial natriuretic peptide [P] Kidneys Liver (C) Angiotensinogen [P] Adrenal cortex, blood vessels Insulin-like growth factors [P] Many tissues Stomach and Gastrin, cholecystokinin, GI tract and pancreas small intestine (C) secretin, and others [P] Pancreas (G) Insulin, glucagon, somatostatin, Many tissues pancreatic polypeptide [P] Adrenal cortex (G) Aldosterone [S] Kidney Cortisol [S] Many tissues Androgens [S] Many tissues Adrenal medulla (N) Epinephrine, norepinephrine [A] Many tissues Kidney (C) Erythropoietin [P] Bone marrow 1,25 Dihydroxy-vitamin D3 Intestine (calciferol) [S] Skin (C) Vitamin D3 [S] Intermediate form of hormone Testes (male) (G) Androgens Many tissues Inhibin Anterior pituitary Ovaries (female) (G) Estrogen, progesterone [S] Many tissues Inhibin [P] Anterior pituitary Relaxin (pregnancy) [P] Uterine muscle Adipose tissue (C) Leptin, adiponectin, resistin [P] Hypothalamus, other tissues KEY Placenta (pregnant Estrogen [S] Many tissues G = gland females only) (C) C = endocrine cells Chorionic somatomammotropin [P] Many tissues N = neurons Chorionic gonadotropin [P] Corpus luteum P = peptide S = steroid A = amino acid–derived 198  7.2 The Classification of Hormones 199 Main Effects 7.2 The Classification of Hormones Circadian rhythms; immune function; antioxidant Hormones can be classified according to different schemes. The scheme used in Figure 7.2 groups them according to their source. Phosphorylates proteins. Alters channel opening A different scheme divides hormones into those whose release is Milk ejection; labor and delivery; behavior controlled by the brain and those whose release is not controlled by Water reabsorption the brain. Another scheme groups hormones according to whether they bind to G protein-coupled receptors, tyrosine kinase-linked Milk production receptors, or intracellular receptors, and so on. CHAPTER Growth factor secretion; growth and metabolism A final scheme divides hormones into three main chemical Cortisol release classes: peptide/protein hormones, steroid hormones, and amino acid–derived, or amine, hormones (TBL. 7.1). The peptide/pro- Thyroid hormone synthesis 7 tein hormones are composed of linked amino acids. The steroid Egg or sperm production; sex hormone production hormones are all derived from cholesterol [p. 30]. The amino Sex hormone production; egg or sperm production acid–derived hormones, also called amine hormones, are modifica- tions of single amino acids, either tryptophan or tyrosine. Metabolism, growth, and development Plasma calcium levels (minimal effect in humans) Regulates plasma Ca2+ and phosphate levels Concept Check Lymphocyte development 3. What is the classic definition of a hormone? 4. Based on what you know about the organelles involved in Increases Na+ excretion protein and steroid synthesis [p. 65], what would be the major differences between the organelle composition of a steroid- Aldosterone secretion; increases blood pressure producing cell and that of a protein-producing cell? Growth Assist digestion and absorption of nutrients Most Hormones Are Peptides or Proteins Metabolism of glucose and other nutrients The peptide/protein hormones range from small peptides of only three amino acids to larger proteins and glycoproteins. Despite Na+ and K+ homeostasis the size variability among hormones in this group, they are usu- ally called peptide hormones for the sake of simplicity. You can Stress response remember which hormones fall into this category by exclusion: If Sex drive in females a hormone is not a steroid hormone and not an amino acid deriva- Fight-or-flight response tive, then it must be a peptide or protein. Red blood cell production Peptide Hormone Synthesis, Storage, and Release The synthesis Increases calcium absorption and packaging of peptide hormones into membrane-bound secre- tory vesicles is similar to that of other proteins. The initial peptide that comes off the ribosome is a large inactive protein known as Precursor of 1,25-dihydroxycholecalciferol (vitamin D3) a preprohormone (FIG. 7.3 1 ). Preprohormones contain one Sperm production, secondary sex characteristics or more copies of a peptide hormone, a signal sequence that directs Inhibits FSH secretion the protein into the lumen of the rough endoplasmic reticulum, and other peptide sequences that may or may not have biological Egg production, secondary sex characteristics activity. Inhibits FSH secretion As the inactive preprohormone moves through the endoplas- Relaxes muscle mic reticulum, the signal sequence is removed, creating a smaller, still-inactive molecule called a prohormone (Fig. 7.3 4 ). In the Food intake, metabolism, reproduction Golgi complex, the prohormone is packaged into secretory vesicles Fetal, maternal development along with proteolytic {proteo-, protein + lysis, rupture} enzymes that chop the prohormone into active hormone and other fragments. Metabolism This process is called post-translational modification [p. 116]. Hormone secretion The secretory vesicles containing peptides are stored in the cytoplasm of the endocrine cell until the cell receives a signal for secretion. At that time, the vesicles move to the cell membrane and release their contents by calcium-dependent exocytosis [p. 147]. 200 CHAPTER 7 Introduction to the Endocrine System TABLE 7.1 Comparison of Peptide, Steroid, and Amino Acid–Derived Hormones Amine Hormones (Tyrosine Derivatives) Peptide Hormones Steroid Hormones Catecholamines Thyroid Hormones Synthesis and Made in advance; stored Synthesized on demand Made in advance; stored Made in advance; pre- Storage in secretory vesicles from precursors in secretory vesicles cursor stored in secre- tory vesicles Release from Parent Exocytosis Simple diffusion Exocytosis Transport protein Cell Transport in Blood Dissolved in plasma Bound to carrier proteins Dissolved in plasma Bound to carrier proteins Half-Life Short Long Short Long Location of Cell membrane Cytoplasm or nucleus; Cell membrane Nucleus Receptor some have membrane receptors also Response to Recep- Activation of second mes- Activation of genes for Activation of second Activation of genes tor-Ligand Binding senger systems; may acti- transcription and transla- messenger systems for transcription and vate genes tion; may have nonge- translation nomic actions General Target Modification of existing Induction of new protein Modification of existing Induction of new protein Response proteins and induction of synthesis proteins synthesis new protein synthesis Examples Insulin, parathyroid Estrogen, androgens, Epinephrine, norepi- Thyroxine (T4) hormone cortisol nephrine, dopamine All of the peptide fragments created from the prohormone are hormone-receptor complex initiates the cellular response by means released together into the extracellular fluid, in a process known of a signal transduction system (FIG. 7.4). Many peptide hormones as co-secretion (Fig. 7.3 5 ). work through cAMP second messenger systems [p. 173]. A few peptide hormone receptors, such as that of insulin, have tyrosine Post-Translational Modification of Prohormones Studies of pro- kinase activity [p. 175] or work through other signal transduction hormone processing have led to some interesting discoveries. Some pathways. prohormones, such as that for thyrotropin-releasing hormone (TRH), The response of cells to peptide hormones is usually rapid contain multiple copies of the hormone (Fig. 7.3a). Another because second messenger systems modify existing proteins. The interesting prohormone is pro-opiomelanocortin (Fig. 7.3b). This changes triggered by peptide hormones include opening or clos- prohormone splits into three active peptides plus an inactive frag- ing membrane channels and modulating metabolic enzymes or ment. In some instances, even the fragments are clinically useful. transport proteins. Researchers have recently discovered that some For example, proinsulin is cleaved into active insulin and an inac- peptide hormones also have longer-lasting effects when their sec- tive fragment known as C-peptide (Fig. 7.3c). Clinicians measure the ond messenger systems activate genes and direct the synthesis of levels of C-peptide in the blood of diabetics to monitor how much new proteins. insulin the patient’s pancreas is producing. Steroid Hormones Are Derived from Cholesterol Transport in the Blood and Half-Life of Peptide Hormones Peptide hormones are water soluble and therefore generally dissolve Steroid hormones have a similar chemical structure because easily in the extracellular fluid for transport throughout the they are all derived from cholesterol (FIG. 7.5a ). Unlike body. The half-life for peptide hormones is usually quite short, in peptide hormones, which are made in tissues all over the body, the range of several minutes. If the response to a peptide hormone steroid hormones are made in only a few organs. The adrenal must be sustained for an extended period of time, the hormone cortex, the outer portion of the adrenal glands {cortex, bark}, must be secreted continually. makes several types of steroid hormones. One adrenal gland sits atop each kidney {ad-, upon + renal, kidney}. The gonads produce Cellular Mechanism of Action of Peptide Hormones Because pep- sex steroids (estrogens, progesterone, and androgens), and the skin tide hormones are lipophobic, they are usually unable to enter the can make vitamin D. In pregnant women, the placenta is also a target cell. Instead, they bind to surface membrane receptors. The source of steroid hormones.  FIG. 7.3 ESSENTIALS Peptide Hormone Synthesis and Processing (a) Peptide Hormone Synthesis Peptide hormones are made as large, inactive preprohormones that include a signal sequence, one or more copies of the hormone, and additional peptide fragments. 1 Messenger RNA on the 2 Enzymes in 3 The prohormone 4 Secretory vesicles 5 The secretory 6 The hormone ribosomes binds amino the ER chop passes from the containing enzymes and vesicle moves into acids into a peptide chain off the signal ER through the prohormone bud off the releases its the circulation called a preprohormone. sequence, Golgi complex. Golgi. The enzymes chop contents by for transport The chain is directed into creating an the prohormone into one exocytosis to its target. the ER lumen by a signal inactive or more active peptides into the sequence of amino acids. prohormone. plus additional peptide extracellular fragments. space. Golgi complex Ribosome Preprohormone To target Signal sequence 1 2 mRNA Active Peptide hormone fragment 5 6 Prohormone 4 Release 3 Secretory signal vesicle Transport Capillary vesicle endothelium Endoplasmic Cytoplasm ECF Plasma reticulum (ER) (b) Preprohormones (c) Prohormones PreproTRH (thyrotropin-releasing hormone) has Prohormones, such as pro-opiomelanocortin, the prohormone for six copies of the 3-amino acid hormone TRH. ACTH, may contain several peptide sequences with biological activity. Preprohormone PreproTRH (242 amino acids) Pro-opiomelanocortin processes to processes to + + + Signal Other peptide fragments 6 TRH Peptide fragment ACTH γ lipotropin β endorphin sequence (3 amino acids each) (d) Prohormones Process to Active Hormone Plus Peptide Fragments The peptide chain of insulin's prohormone folds back on itself with the help of disulfide Proinsulin (S—S) bonds. The prohormone cleaves to processes to Insulin + C-peptide S S S insulin and C-peptide. S S S S S S S S S 201 202 CHAPTER 7 Introduction to the Endocrine System FIG. 7.4 Peptide hormone receptors and signal the adrenal cortex, has a half-life of 60–90 minutes. (Compare this transduction with epinephrine, an amino acid–derived hormone whose half-life is measured in seconds.) Peptide hormones (H) cannot enter their target Although binding steroid hormones to protein carriers extends cells and must combine with membrane receptors (R) that initiate signal transduction processes. their half-life, it also blocks their entry into target cells. The carrier- steroid complex remains outside the cell because the carrier pro- teins are lipophobic and cannot diffuse through the membrane. H H Only an unbound hormone molecule can diffuse into the target cell (Fig. 7.5b 2 ). As unbound hormone leaves the plasma, the carriers obey the law of mass action and release hormone so that R the ratio of unbound to bound hormone in the plasma remains R constant [the K d, p. 48]. Fortunately, hormones are active in minute concentrations, and only a tiny amount of unbound steroid is enough to produce G TK AE a response. As unbound hormone leaves the blood and enters cells, additional carriers release their bound steroid so that some Opens ion unbound hormone is always in the blood and ready to enter a channel cell. Second messenger systems Cellular Mechanism of Action of Steroid Hormones The best- studied steroid hormone receptors are found within cells, either in the cytoplasm or in the nucleus. The ultimate destination of steroid receptor-hormone complexes is the nucleus, where the complex phosphorylate acts as a transcription factor, binding to DNA and either activating or repressing (turning off) one or more genes (Fig. 7.5b 3 ). Activated KEY genes create new mRNA that directs the synthesis of new proteins. Proteins Any hormone that alters gene activity is said to have a genomic effect TK = Tyrosine kinase AE = Amplifier enzyme on the target cell. G = G protein When steroid hormones activate genes to direct the production Cellular response of new proteins, there is usually a lag time between hormone- receptor binding and the first measurable biological effects. This lag can be as much as 90 minutes. Consequently, steroid hormones do not mediate reflex pathways that require rapid responses. Steroid Hormone Synthesis and Release Cells that secrete steroid In recent years, researchers have discovered that several ste- hormones have unusually large amounts of smooth endoplasmic roid hormones, including estrogens and aldosterone, have cell reticulum, the organelle in which steroids are synthesized. Steroids membrane receptors linked to signal transduction pathways, are lipophilic and diffuse easily across membranes, both out of just as peptide hormones do. These receptors enable those ste- their parent cell and into their target cell. This property also means roid hormones to initiate rapid nongenomic responses in that steroid-secreting cells cannot store hormones in secretory ves- addition to their slower genomic effects. With the discovery of icles. Instead, they synthesize their hormone as it is needed. When nongenomic effects of steroid hormones, the functional differ- a stimulus activates the endocrine cell, precursors in the cytoplasm ences between steroid and peptide hormones seem almost to have are rapidly converted to active hormone. The hormone concentra- disappeared. tion in the cytoplasm rises, and the hormones move out of the cell by simple diffusion. Some Hormones Are Derived from Single Amino Transport in the Blood and Half-Life of Steroid Hormones Like Acids their parent cholesterol, steroid hormones are not very soluble in The amino acid–derived, or amine, hormones are small molecules plasma and other body fluids. For this reason, most of the steroid created from either tryptophan or tyrosine, both notable for the hormone molecules found in the blood are bound to protein car- carbon ring structures in their R-groups [p. 32]. The pineal gland rier molecules (Fig. 7.5b 1 ). Some hormones have specific car- hormone melatonin is derived from tryptophan (see Focus On: riers, such as corticosteroid-binding globulin. Others simply bind to The Pineal Gland, Fig. 7.16) but the other amino acid–derived general plasma proteins, such as albumin. hormones—the catecholamines and thyroid hormones—are made The binding of a steroid hormone to a carrier protein pro- from tyrosine (FIG. 7.6). Catecholamines are a modification of a tects the hormone from enzymatic degradation and results in an single tyrosine molecule. The thyroid hormones combine two tyro- extended half-life. For example, cortisol, a hormone produced by sine molecules with iodine atoms. FIG. 7.5 ESSENTIALS Steroid Hormones Most steroid hormones are made in the adrenal cortex or gonads (ovaries and testes). Steroid hormones are not stored in the endocrine cell because of their lipophilic nature. They are made on demand and diffuse out of the endocrine cell. (a) Cholesterol is the parent compound for all steroid hormones. OH CH3 Dihydro- KEY testosterone (DHT) Adrenal DHEA = dehydroepiandrosterone cortex HO Ovary = intermediate compounds whose names have been omitted for simplicity. aromatase Testosterone Estradiol CH2OH C O CH3 OH Andro- aromatase HO DHEA Estrone stenedione CH3 CH2OH CH3 H O C O H C CH2 CH2 O CH3 CH CH2 C CH3 HO 21-hydroxylase CH3 CH3 Cortisol CH3 HO O 21-hydroxylase Cholesterol Progesterone Corticosterone Aldosterone *Each step is catalyzed by an enzyme, but only two enzymes are shown in this figure. (b) Steroid hormones act primarily on intracellular receptors. Blood Cell surface receptor 1 Most hydrophobic steroids are bound to Steroid vessel plasma protein carriers. Only unbound hormone hormones can diffuse into the target cell. 2a Rapid responses 1 2 Steroid hormone receptors are in the 2 cytoplasm or nucleus. Protein carrier Nucleus Cytoplasmic 2a Some steroid hormones also bind Nuclear to membrane receptors that use receptor receptor second messenger systems to create rapid cellular responses. DNA Interstitial 3 The receptor-hormone complex binds to fluid DNA and activates or represses one or more genes. 3 Endoplasmic reticulum Cell Transcription Activated genes create new mRNA that 4 membrane produces mRNA moves back to the cytoplasm. 5 4 New proteins Translation Translation produces new proteins 5 for cell processes. 203 204 CHAPTER 7 Introduction to the Endocrine System FIG. 7.6 Amine hormones Most amine hormones are derived Tyrosine FIGURE QUESTION from the amino acid tyrosine. is the parent amino acid for Determine how each catecholamines and thyroid hormones. catecholamine molecule H H differs from the tyrosine H molecule. HO C C N H C H O OH Catecholamines Thyroid hormones are made by modifying are synthesized from two the side groups of tyrosine. tyrosines and iodine (I) atoms. HO H H I I H H H H HO C C N HO O C C N H H H H H C I I Dopamine O OH HO H H Thyroxine (Tetraiodothyronine, T4) H HO C C N H OH H Norepinephrine I I H H H HO H H H HO O C C N HO C C N H H C I CH3 OH H O OH Epinephrine Triiodothyronine (T3) Despite a common precursor, the two families of tyrosine- based hormones have little in common. The catecholamines RUNNING PROBLEM (epinephrine, norepinephrine, and dopamine) are neurohormones Shaped like a butterfly, the thyroid gland straddles the trachea that bind to cell membrane receptors the way peptide hormones just below the Adam’s apple. The thyroid gland concentrates do. The thyroid hormones, produced by the butterfly-shaped iodine, an element found in food (most notably as an ingredi- thyroid gland in the neck, behave more like steroid hormones, with ent added to salt), and combines it with the amino acid tyrosine intracellular receptors that activate genes. to make two thyroid hormones: thyroxine and triiodothyronine. These thyroid hormones perform many important functions in the body, including the regulation of growth and development, oxygen consumption, and the maintenance of body temperature. Concept Check Q1: To which of the three classes of hormones do the thyroid 5. What are the three chemical classes of hormones? hormones belong? 6. The steroid hormone aldosterone has a short half-life for a Q2: If a person’s diet is low in iodine, predict what happens to steroid hormone—only about 20 minutes. What would you pre- thyroxine production. dict about the degree to which aldosterone is bound to blood proteins? 195 204 212 214 216 217 219  7.3 Control of Hormone Release 205 7.3 Control of Hormone Release Concept Check Some hormones have clear stimuli that initiate their release, such as 7. In the blood glucose example, the increase in blood glucose insulin secreted in response to increasing blood glucose concentra- corresponds to which step of a reflex pathway? Insulin secretion tions. Other hormones have less obvious stimuli or are secreted con- and the decrease in blood glucose correspond to which steps? tinuously, often with a circadian rhythm [p. 17]. The sections that 8. Which insulin release pathway in Figure 7.7b is a simple endo- follow examine some of the most common control pathways for crine reflex? Which is a complex endocrine reflex? Which is a combination neural-endocrine reflex? hormones. This discussion is not all-inclusive, and you will encoun- 9. Glucagon is released from alpha cells in the pancreas when blood ter a few hormones that do not fit exactly into these patterns. CHAPTER glucose levels decrease. Glucagon acts on multiple target tissues Reflex pathways are one convenient way to classify hormones to increase blood glucose. Draw a reflex pathway to match this and simplify learning the steps that regulate their secretion. All description. reflex pathways have similar components: a stimulus, a sensor, an input signal, integration of the signal, an output signal, one 7 or more targets, and a response [Fig. 6.16, p. 184]. In endocrine Many Endocrine Reflexes Involve the Nervous and neuroendocrine reflexes, the output signal is a hormone or a System neurohormone. The nervous system and the endocrine system overlap in both struc- ture and function [see Fig. 6.19, pathways 3–5, p. 189]. Stimuli inte- The Endocrine Cell Is the Sensor in Simple grated by the central nervous system influence the release of many Endocrine Reflexes hormones through efferent neurons, as previously described for insu- lin. In addition, specialized groups of neurons secrete neurohormones, The simplest reflex control pathways in the endocrine system are those and two endocrine structures are incorporated in the anatomy of the in which an endocrine cell directly senses a stimulus and responds by brain: the pineal gland [see Fig. 7.16, p. 218] and the pituitary gland. secreting its hormone [Fig. 6.19, pathway 6, p. 189]. In this type of One of the most fascinating links between the brain and the pathway, the endocrine cell acts as both sensor and integrating center. endocrine system is the influence of emotions over hormone secre- The hormone is the output signal, and the response usually serves tion and function. Physicians for centuries have recorded instances in as a negative feedback signal that turns off the reflex [Fig. 1.12a, p. 16]. which emotional state has influenced health or normal physiological Parathyroid hormone (PTH), which controls calcium processes. Women today know that the timing of their menstrual homeostasis, is an example of a hormone that uses a simple endo- periods may be altered by stressors such as travel or final exams. The crine reflex. PTH is secreted by four small parathyroid glands in the condition known as “failure to thrive” in infants can often be linked neck. The parathyroid endocrine cells monitor plasma Ca2+ concen- to environmental or emotional stress that increases secretion of some tration with the aid of G protein-coupled Ca2+ receptors on their cell pituitary hormones and decreases production of others. The interac- membranes. When a certain number of receptors are bound to Ca2+, tions among stress, the endocrine system, and the immune system PTH secretion is inhibited. If the plasma Ca2+ concentration falls are receiving intense study by scientists (Chapter 24). below a certain level and fewer Ca2+ receptors are bound, inhibition ceases and the parathyroid cells secrete PTH (FIG. 7.7a). Parathyroid hormone travels through the blood to act on bone, kidney, and intes- Neurohormones Are Secreted into the Blood tine, initiating responses that increase the concentration of Ca2+ in by Neurons the plasma. The increase in plasma Ca2+ is a negative feedback signal As noted previously, neurohormones are chemical signals released that turns off the reflex, ending the release of parathyroid hormone. into the blood by a neuron [p. 167]. The human nervous system Other hormones that follow a simple endocrine reflex pat- produces three major groups of neurohormones: (1) catechol- tern include the classic hormones insulin and glucagon. Pancreatic amines (described earlier) made by modified neurons in the adrenal endocrine cells are sensors that monitor blood glucose concentra- medulla, (2) hypothalamic neurohormones secreted from the pos- tion [p. 158]. If blood glucose increases, the pancreatic beta cells terior pituitary, and (3) hypothalamic neurohormones that control respond by secreting insulin (Fig. 7.7b). Insulin travels through the hormone release from the anterior pituitary. Because the latter two blood to its target tissues, which increase their glucose uptake and groups of neurohormones are associated with the pituitary gland, metabolism. Glucose moving into cells decreases the blood con- we describe that important endocrine structure next. centration, which acts as a negative feedback signal that turns off the reflex, ending release of insulin. Hormones can be released by more than one pathway, how- Concept Check ever. For example, insulin secretion can also be triggered by sig- 10. Catecholamines belong to which chemical class of hormone? nals from the nervous system or by a hormone secreted from the digestive tract after a meal is eaten (Fig. 7.7b). The pancreatic beta cells—the integrating center for these reflex pathways—therefore The Pituitary Gland Is Actually Two Fused Glands must evaluate input signals from multiple sources when “deciding” The pituitary gland is a lima bean–sized structure that extends whether to secrete insulin. downward from the brain, connected to it by a thin stalk and 206 CHAPTER 7 Introduction to the Endocrine System FIG. 7.7 Simple endocrine pathways (a) A Simple Endocrine Reflex: Parathyroid Hormone (b) Multiple Pathways for Insulin Secretion Blood Glucose in Low plasma Eat a meal glucose lumen [Ca2+] Stretch receptor in digestive tract Parathyroid cell Sensory neuron Parathyroid CNS Endocrine hormone cells in small intestine Efferent neuron Negative feedback Negative feedback Pancreas GLP-1 Insulin Bone and kidney Target Bone Kidney Production of calcitriol tissues resorption reabsorption of leads to intestinal calcium absorption of Ca2+ Glucose uptake and utilization Plasma [Ca2+] Blood glucose KEY Stimulus Sensory neuron FIGURE QUESTION What shuts off the pathway that begins Receptor with the stimulus of “eat a meal”? Efferent neuron Hormone Integrating center Target Tissue response Systemic response cradled in a protective pocket of bone (FIG. 7.8a). The first accu- theorized that substances produced in the brain passed down the rate description of the function of the pituitary gland came from stalk into the gland and from there into the blood. Richard Lower (1631–1691), an experimental physiologist at Lower did not realize that the pituitary gland is actu- Oxford University. Using observations and some experiments, he ally two different tissue types that merged during embryonic  7.3 Control of Hormone Release 207 development. The anterior pituitary is a true endocrine gland The Anterior Pituitary Secretes Six Hormones of epithelial origin, derived from embryonic tissue that formed As late as 1889, it was being said in reviews of physiological the roof of the mouth [Fig. 3.11, p. 80]. It is also called the function that the pituitary was of little or no use to higher adenohypophysis {adeno-, gland + hypo-, beneath + phyein, to grow}, vertebrates! By the early 1900s, however, researchers had and its hormones are adenohypophyseal secretions. The posterior discovered that animals with their anterior pituitary glands sur- pituitary, or neurohypophysis, is an extension of the neural tis- gically removed were unable to survive more than a day or two. sue of the brain. It secretes neurohormones made in the hypo- This observation, combined with the clinical signs associated thalamus, a region of the brain that controls many homeostatic with pituitary tumors, made scientists realize that the anterior CHAPTER functions. pituitary is a major endocrine gland that secretes not one but six physiologically significant hormones: prolactin (PRL), thy- The Posterior Pituitary Stores and Releases Two rotropin (TSH), adrenocorticotropin (ACTH), growth hormone Neurohormones (GH), follicle-stimulating hormone (FSH), and luteinizing hor- 7 mone (LH) (Fig. 7.8b). The posterior pituitary is the storage and release site for two neu- Secretion of all the anterior pituitary hormones is controlled rohormones: oxytocin and vasopressin (Fig. 7.8c). The neurons by hypothalamic neurohormones. The pathways can become producing oxytocin and vasopressin are clustered together in areas quite complex because some hypothalamic neurohormones of the hypothalamus known as the paraventricular and supraoptic alter the secretion of several anterior pituitary hormones. In this nuclei. (A cluster of nerve cell bodies in the central nervous system book, we focus only on the primary targets for the hypothalamic is called a nucleus.) Each neurohormone is made in a separate cell hormones. type, and the synthesis and processing follow the standard pattern The anterior pituitary hormones, their primary hypothalamic for peptide hormones described earlier in this chapter. neurohormones, and their targets are illustrated in FIGURE 7.9. The Once the neurohormones are packaged into secretory vesicles, hypothalamic neurohormones that control release of anterior the vesicles are transported to the posterior pituitary through long pituitary hormones are usually identified as releasing hormones (e.g., extensions of the neurons called axons. After vesicles reach the axon thyrotropin-releasing hormone) or inhibiting hormones (e.g., growth terminals, they are stored there, waiting for the release signal. hormone-inhibiting hormone). For many years after they were first When a stimulus reaches the hypothalamus, an electrical sig- discovered, the hypothalamic hormones were called factors, as in nal passes from the neuron cell body in the hypothalamus to the corticotropin-releasing factor. distal (distant) end of the cell in the posterior pituitary. Depolar- Notice that of the six anterior pituitary hormones, prolactin ization of the axon terminal opens voltage-gated Ca2+ channels, acts only on a nonendocrine target (the breast). The remaining five and Ca2+ enters the cell. Calcium entry triggers exocytosis and hormones have another endocrine gland or cell as one of their tar- the vesicle contents are released into the circulation. [Compare to gets. These hormones that control the secretion of other hormones insulin release, Fig. 5.26, p. 158.] Once in the blood, the neurohor- are known as trophic hormones. mones travel to their targets. The adjective trophic comes from the Greek word trophikós, The two posterior pituitary neurohormones are composed of which means “pertaining to food or nourishment” and refers to the nine amino acids each. Vasopressin, also known as antidiuretic hor- manner in which the trophic hormone “nourishes” the target cell. mone or ADH, acts on the kidneys to regulate water balance in the Trophic hormones often have names that end with the suffix -tropin, body. In women, oxytocin released from the posterior pituitary as in gonadotropin.* The root word to which the suffix is attached is controls the ejection of milk during breast-feeding and contrac- the target tissue: The gonadotropins are hormones that are trophic tions of the uterus during labor and delivery. to the gonads. A few neurons release oxytocin as a neurotransmitter or neu- You should be aware that many of the hypothalamic romodulator onto neurons in other parts of the brain. A number and anterior pituitary hormones have multiple names as well of animal experiments plus some human experiments indicate that as standardized abbreviations. For example, hypothalamic oxytocin plays an important role in social, sexual, and maternal somatostatin (SS) is also called growth hormone-inhibiting behaviors. One recent study suggests that autism, a developmen- hormone (GHIH), or in older scientific papers, somatotropin tal disorder in which patients are unable to form normal social release-inhibiting hormone (SRIH). The table in Figure 7.9 lists the relationships, may be related to defects in the normal oxytocin- hypothalamic and anterior pituitary abbreviations and current modulated pathways of the brain. alternate names. Concept Check 11. What intracellular structure is used for transport of secretory vesicles within the cell? * 12. Name the membrane process by which the contents of secre- A few hormones whose names end in -tropin do not have endocrine cells as tory vesicles are released into the extracellular fluid. their targets. For example, melanotropin acts on pigment-containing cells in many animals. FIG. 7.8 ESSENTIALS The Pituitary Gland (a) Structure of the Pituitary Gland The pituitary is actually two glands with different embryological origins that fused during development. HYPOTHALAMUS It sits in a protected pocket of bone, connected to the brain by a thin stalk. Infundibulum is the stalk that connects the pituitary to the brain. Sphenoid bone Posterior pituitary is an extension of the neural tissue. Anterior pituitary is a ANTERIOR POSTERIOR true endocrine gland of epithelial origin. (b) The Anterior Pituitary The anterior pituitary is a true endocrine gland that secretes six classic hormones. Neurohormones from the hypothalamus control release of the anterior pituitary hormones. The hypothalamic hormones reach the anterior pituitary through a specialized region of the circulation called a portal system. 1 Neurons synthesizing HYPOTHALAMUS trophic neurohormones release them into capillaries of the portal system. Capillary bed 2 Portal veins carry the trophic neurohormones Artery directly to the anterior pituitary, where they act on the endocrine cells. Posterior pituitary 3 Endocrine cells release Capillary bed their peptide hormones into the second set of capillaries for distribution ANTERIOR PITUITARY to the rest of the body. Veins TO TARGET ORGANS Prolactin Gonadotropins (LH & FSH) GH TSH ACTH Ovary Testis Mammary glands Musculoskeletal system Thyroid gland Adrenal cortex Gonads 208  7.3 Control of Hormone Release 209 (c) The Posterior Pituitary A Portal System Connects the Hypothalamus and Anterior Pituitary The posterior pituitary is an extension of Most hormones in the body are secreted into the blood and the brain that secretes neurohormones become rapidly diluted as they distribute throughout the 5 L of made in the hypothalamus. blood volume. To avoid dilution, the hypothalamic neurohor- mones destined for the anterior pituitary enter a special modifi- HYPOTHALAMUS