Chapter 11 SECTION A FOUNDATIONS OF HORMONAL CONTROL SYS GENERAL INTRODUCTION The endocrine system, like the nervous system, adjusts and correlates the activities of various body systems, making them appropriate to the demands of the external and internal environment changes. Dif- ferent from nervous system, in which signals con- duction by action potentials along the nerve fib very rapid and precise but of short duration, the sig- nalling in the endocrine system mediated by chemi- cal messages via body fluid is relatively slow, dif- fuse but with a longer duration. The hypothalamus combines the actions of the nervous and endocrine systems, and allows the two communication systems to coordinate responses to maintain homeostasis. ‘The endocrine system consists of endocrine glands, tissues and cells that are able to produce hhormones. The endocrine glands, such as pituitary gland, thyroid gland, adrenal, and others (shown in Figurel1-1) , are all ductless glands. ‘Their prod- ucts, hormones, are chemical messengers or signal molecules, which are transported by blood to their ‘The target cells of a hormone are equipped with the receptors that specifically distant target cells recognize the particular hormone and response to it Some chemical messengers, for example Angio- tensin IT, growth hormone, prolactin and others, are also secreted by local endocrine tissues and cells into the interstitial fluid surrounding the cells, and can act either on nearby target cells or on the cells of origin. ‘These two forms of hormone regulation are termed paracrine and autocrine, respectively. It is thought to exert a huge number of regulating func- tions in the endocrine system. We now know that almost all organs contain some endocrine tissues and cells, and hormone molecules Endocrinology form a large signal family, which will be summarized in table 11-1 Pancreas Isles of [Cangerhans Figure 11-1 crine glands. Location of the major human endo- Table 11-1 provides an overview of the differen endocrine glands, the hormones they secrete, and ‘the major functions the hormones control. ‘The endo- cine system differs from most of the other organ sys- tems of the body in that the various glands are not anatomically connected; however, they do form a system in the functional sense. ‘The reader may be puzzled to see listed as endocrine glands some or gans—the heart and kidney, for instance—that clearly have other functions. ‘The explanation is that, in addition to the cells that camy out the or- gan’ other functions, the organ also contains cells This illustrates the fact that organs are made up of different types of cells. that secrete hormones. +369 +Note also in Table 11-1 that the hypothalamus, a part of the brain, is considered part of the endocrine system, too, This is because the chemical messen- gers released by certain neuron terminals in both the hypothalamus and its extension, the posterior pitui- tary, do not function as neurotransmitters affecti adjacent cells but rather enter the blood, which car- ries them to their sites of action— target cells Table 11-1 demonstrates that a single gland may secrete multiple hormones. ‘The usual pattem in such cases is that a single cell type secretes only one hormone, thus 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. ‘Another point of interest illustrated by Table 11-1 is that a particular hormone may be produced by more than one type of endocrine gland. For example, som- atostatin is secreted by endocrine cells in both the gastrointestinal tract and the pancreas and is also one of the hormones secreted by the hypothalamus. ‘As described above, this area of physiology is rapidly expanding and now it is becoming difficult to remain even reasonably up to date yet comprehensive in a textbook like this. ‘The aims of the present chapter are to present (1) the general principles of endocrinology—that is, a structural and functional analysis of hormones in general that transcends individual glands; and (2) an analysis of several of the most important hor- ‘onal systems. ‘Table 11-1 Summary of the Endocrine Glands, Hormones, and ‘Their Functions ‘Thywid-stimulatng hormone (TSH) Adrenocanticottpic hormone ( ACTH) Prolactin Foliclestimalating hormone (FSH) Luteinizing hormone (LH) GLAND) HORMONES ‘MAJOR FUNCTIONS Hypothalamas | Thyrtropin-rleasing hormone (TRH) ‘Stimulates secretion of TSH and prolactin Conictropin-zeleasing hormone (CRH) (Causes secretion of ACTH Growth hormone-elesing harmene (CHRH) | Causes secretion of growth hormone Groth hormone inhibitory honmone (CHIH) | Inhibits secretion of growth hormone (somatostatin) Causes secretion of LH and FSH Gonadotrpin-releasing hormone (GnRH) | Inhibits secretion of prolactin Dopamine or prolactn-inhibiting factor PIF Anterior pituitary | Growth hormone ‘Stimulates protein symibesis and overall growth of most cells and tesues ‘Stimulates synthesis and secretion of thyroid omones (thyroxine end triiodothyronine) ‘Stimulates synthesis and secretion of adrenal corticlhor- ‘monet (Cortisol, Androgens, and eldosterone) Promotes development and secretion af the female breasts Causes growth of follicles in ovaries and sperm matuation in Sertoli cells of testes ‘Stimulates testosterone synthesis in Leydig cell of testes; stimulates ovulation, formation of corpus lteum, estrogen ad progesterone synthesis in ovaes Posterior pituitary ‘Antdiuretc hormone (ADH) (also called vas- Tncreases water reabsorption by the kidneys and causes opessin) ‘asoconsttion and increased blood pressure Oxytocin ‘Stimulates milk ejection fom breast and uterine contrac- Thyroid ‘Thyroxine(T, and tsfodthyronine (Ty) Tnereates the rates of chemical reactions in most cells, thus increasing boay metabolic eae Calcitonin Promotes deposition of ealeium inthe bones and decreases ‘estacellular uid calcium ion concentration ‘Adrenal cortex | Conta Has multiple metabolic funetions fr contlling metabolism of protein, carbohydrate and ft, lao has ant-inflammato- 1y effects, and response to stress Aldosterone Increases renal sodium reabsorption, potassium secretion and hydrogen ion secretioncontinued) GLAND HORMONES ‘MAJOR FUNCTIONS Arenal medulla | Norepinephrine, epinephrine Same effets es sympatetic simula, and response to Pancreas Tnwlin (calls) Promos glucose en in many cl, and inthis way eon- tl erhlmte metabli lucagye (a eels) Increases synthesis and release of hit from the liver n- tothe ody fide Somatostatin Inhibits the clea of insulin, Parthtod Parathyroid mone (PTH) Conta serum caleium ion (Ca?* ) soncentration by ine creasing Cs?” abortion by the gut an kidneys and reese sing Cs¥* fom bones Ovaries Estrogens Promote guwh and develpnent of female reproductive system, female beasts, and female svondary sex char Progesterone Stimulates secretion of “ein ik” by the uterine endo- metal lands and promtesdevlopoeat of seeeory ap- part of breasts Testes Testasterone Promotes development of male reprodotve syst and rale secondary sexual charcteriton Placenta Human chorionic gymadotopin (HCG) Promotes growth of corpus Iteum and sretion of etogen nd progesterone hy comps teu Human somsiomsnmotopin or Human placen- | Probably helps promote development of some fetal tisues tal lactogen (APL) ‘swell asthe mother’s ease Earogens, Progesterone See actions ofeaogens and progesterone frm ovaia Kidney Renin Cotalyes conversion of angitesioger to angiotensin | Increases instal absopin of Ca? and bone minral- 1, 25-Dinyroxycoleaeitera sation Engthmpoietin Increates eto eyte paduton Hea Avia naartic peptide (ANP) Trcreaes sodium excretion by Kidngs, reduces bod essure Gestointetinal | Gustin Stimulates Hl secretion by pail cee wact Seeetin Stimulates pancreatic acinar ells to slate bicarbonate and water Choleystokinin (CCK) imulates gallbladder contraction and reese of pancreatic: cenaymes Mottin Induces powerful motor activity in the fndio gland area and anal pouches ofthe somach, with an incese in pepsin utp rom the forme. Somatostatin Inhibits the release of psi. Thymus ‘Toymoaiein Tapeoes Tymphocytefncton Pinal Melatonin Integrates photoperiod, and regulates cadian rhythms, sxpmiuction, slepwake oles, al wer plewmen Showing ciratian rythm. ‘ver and wher cells | Tnsln-ike pow factor (IGF and TGP | Promote al division an growth ‘Aipone tue calls | Leptin Regulates fod intakesmtablc rte epeduction ukoeyes, Macro | Cyokines (thee include teltereukins,colo- | TnereaseTnmune defenses ‘phages, Endothelial | ny-stimlatng factor, Interferon, Tumor neo- cells Fibroblasts | roi Stes) Muikiple call pes _| Growth factors (e.g. epidemal gow factor) | Promote gomth and proifetion of wea eel pesPRINCIPLES OF HORMONAL CONTROL SYSTEMS Classical and Modern Definition of Hormone (Figure 11-2) Classical Hormones Till, say the 1960s, by the term hormone, one understood only the classical hormones. They are produced by an endocrine gland or specialized cells, carried by blood to the target organ (s) where they produce messengers” effect. Example: Estrogen is produced by the ovary and carried by blood to target organs, which include uterus and breast, The target organs are situated far away from the endocrine gland, which is producing the hormone. Members of the classical hormones include: those produced by the anterior-or-posterior pituitary, thyroid, parathy- roid, pancreas, adrenal cortex, adrenal medulla and gonads (ovary and testis). Paracrines Recent research has revealed many locally acting chemical substances that have challenged the classi- cal definition of hormones. In some cases chemical jgnal producing cell produces the chemical sub- stances that diffuse into the extracellular fluid and affect target cells that are situated very close to the producer cell, which is termed paraerines. Exam- ple: insulin also acts as a paracrine hormone that diffuses to reach its target (cx cells ofthe islets) and then glucagon secretion is influenced. Autocrines ‘The producer cell produces the chemical substance that influences the function of the producer cell itself by binding to the cell surface receptors. Autocrine effects may be very important for the growth-suste- nanee of cancer cells. In some hostile envionment, normal cells die or eannat grow, but cancer cells can. This is because cancer cells produce some growth factors, which by, autocrine effects can cause protein synthesis of the cancer cell itself. Neuroendocrine Some neurons release the chemical substances (neurohormones) that reach the circulating blood and influence the function of cells at another loca- tion in the body. [Link] Autocrine Figure 11-2 Four modes of delivery for hormone. Chemical Classification of Hormones Hormones fall into three chemical classes; (1) amines, (2) polypeptides and proteins, and (3) steroids. Amine Hormones ‘Amine hormones are all derivatives of the amino acid tyrosine. They include thyroxine and triiodothy- ronine (secreted by the thyroid) , dopamine ( pro- duced by the hypothalamus) , and epinephrine and norepinephrine (released by the adrenal medulla). ‘The adrenal medulla, inner adrenal, is really modified sympathetic ganglions whose cell bodies do not have axons but instead release their secretions into the blood, thereby fulfilling a criterion for an endocrine gland. hhe adrenal medulla secretes approximately four times more epinephrine (E) than norepinephrine (NE). This is because the adrenal medulla expresses high amounts of an enzyme called phenyl-N-methyltransferase ( PN- MT), which catalyzes the step that converts norepi nephrine to epinephrine. Epinephrine and norepi nephrine exert actions similar to those of the sympa~ thetic nerves, which, because they do not express PNMT, make only norepinephrine. These effects are described in various chapters, The structure and pathways for synthesis of the catecholamines (epinephrine and norepinephrine ) were described in chapter 10, where they were dealt In humans ,with as neurotransmitters. Polypeptide and Protein Hormones Polypeptide and protein hormones range in size from small peptides having only three amino acids (thyrotropin-releasing hormone ) to proteins almost 200 amino acids long (growth hormone and prolae tin). In general, polypeptides with 100 or more amino acids are called proteins, and those with fe- wer than 100 amino acids are referred to as pep- tides. Most of the hormones in our body are either polypeptides or proteins. For convenience, we shall refer to all these hormones as peptide hormones that are stored in secretory vesicles until needed. In many cases, peptides are initially synthesized on the ribosomes of the endocrine cells as larger pro- teins known as preprohormones that are not biolog- ical active, and are then cleaved to prohormones by proteolytic enzymes in the rough endoplasmic re- ticulum (Figure 11-3). Symons | Packaging | Srge Secretion Preropomone °rohomone Harmon Homone prblmene Hertlome” {gray ror Figure 113 Typical synthesis and secretion of polypeptide and protein hormones. ‘The prohormone is then packaged into secretory vesicles by the Golgi apparatus. In this process, the prohormone is cleaved to yield the active hormone and other peptide chains found in the prohormone. ‘Therefore, when the cell is stimulated to release the contents of the secretory vesicles by exocytosis, the other peptides are secreted along with the hor- mone. In other words, instead of just one peptide hormone, the cell may be secreting multiple pep- hormones that differ in their effects on target cells. Many peptides serve as both hormones and as neurotransmitters (or neuromodulators). For exam- ple, cholecystokinin (CCK) secreted by the endo- crine glands in the gastrointestinal tract is also pro- duced by neurons in the brain, where they may fanction as neuromodulators. Steroid Hormones Steroid Hormones are the thinl family of hor- ‘mones, which are primarily produced by the adrenal cortex (cortisol and aldosterone ) and the gonads (estrogens, progesterone and testosterone ) as well as by the placenta during pregnancy. The chemical structure of steroid hormones is similar to cholester- ol. Figurel 1-4 shows some examples of the Steroid Hormones, the lipids whose ringlike structure. In addition, the hormone 1, 25-dihydroxyvitamin D, the active form of vitamin D, also is a steroid. All of the steroid hormones are derived from cho- lesterol. Cells producing steroid homones synthesize some of their own cholesterol for this purpose from molecules of acetate, but typically most of the cho- lesterol enters the cells in the form of low-density Lipoproteins (LDLs) from plasma. Steroid hormones are highly lipid soluble, Al- though there is usually very little harmone storage in stervid-producing endocrine cells, large stores of cholesterol esters in cytoplasm vacuoles can be rap- idly mobilized for steroid synthesis after the cell is stimulated by a tropic hormone (¢. g., ACTH). Once they are synthesized, they simple diffuse across the cell membrane and enter the interstitial fluid and then the blood. However, steroid hor- rmones are not greatly soluble in blood, and thus they are largely transported ound to carrier proteins (such as albumin). Transport and Clearance of Hormone. Transport of Hormone in the Blood Most peptides and all catecholamine hormones are water-soluble. Therefore, with the exception of a few peptides, these hormones are transported simplyFigure 11-4 Chemical structures of representati dissolved in plasma (‘Table 11-2). In contrast, the poorly soluble steroid hormones and thyroid hor- zones circulate in the blood largely bound to plasma proteins. Even though the steroid and thyroid hor- rmones exist in plasma mainly bound to large pro- teins, small concentrations of these hormones do ex- ist dissolved in the plasma. The dissolved, or free, hormone is in equilibrium with the bound hormone: Free hormone + Binding protein = Hormone - protein complex ‘The total hormone concentration in plasma ii the sum of the free and bound hormone. It is im= portant to realize, however, that only the free hor~ mone can diffuse across capillary walls and en- counter its target cells. Therefore, the concentra- tion of the free hormone is what is physiologically important rather than the concentration of the total hormone. Most of hormones bound to proteins serve as reservoirs replenishing the coneentr of free hormones when they are bound to target re- ceptors or lost from the circulation. Also, binding of hormones to plasma proteins greatly slows their clearance from the plasma. Metabolism and “ Clearance” of Hormone A hormone’ s concentration in the plasma depends upon (1) its rate of secretion by the endocrine cH,OH HL ¢=0 HO: SS of Aldosterone ‘Testosterone ive steroid hormones derived from cholesterol. gland, and (2) its rate of removal from the blood. Removal, or “clearance,” of the hormone occurs ei- ther by excretion or by metabolic. transformation. The liver and the kidneys are the major organs that excrete or metabolize hormones. Sometimes the hor- mone is also metabolized by the cells, upon which it acts. Very importantly, in the case of peptide hor- mones, endocytosis of hormone-receptor complexes on plasma membranes enables cells to remove the hormones rapidly from their sucfaces and eatabolize them intracellularly. ‘The receptors are then often re~ cycled to the plasma membrane, Most of the peptide hormones and catecholamines are water-soluble and circulate freely in the blood. They are usually degraded by enzymes in the blood and tissues and rapidly excreted by the kidneys and liver, thus remaining in the blood for only a short time. For example, the half-life of angiotensin Tl circulating in the blood is less than @ minute. Hormones that are bound to plasma proteins are cleared from the blood at much slower rates and may remain in the circulation for several hours or even days, The half-life of adrenal steroids in the circula- n, for example, ranges between 20 and 100 min, whereas the half-life of the protein-bound thyroid hormones may be as long as 1 to 6 days. ‘Table 11-2 Comparison of different types of hormone POLYPEPTIDES AND CATE. | STEROIDS | THYROID HORMONE, | cutoLaMmes ‘TRANSPORT FORM IN PLASMA. | Free Bound to Protein | Found to Prats SIZE lane Seal Very Sal SOLUBLE IN: Water Fat Fat LOCATION OF RECEPTORS —_| Plasmamembrane Cytoplam Nucl(continued) POLYPEPTIDES AND CAT- ECHOLAMINES ‘STEROIDS ‘THYROID HORMONE MOST COMMON SIGN- | 1, Second messenger ( &., ormone-receptors complex from | Nuclew receptors dieely ALING MECHANISMS ‘cAMP, Ca?" IP3) ‘ytoplasm to nucleus alter gene | alter gene transcription 2. aug activation by seven | transcription | (e-g sIAK Kinase ) | 2. tnminsic nay atic activity of | | receptor Cen. 5 tyne ans | | to phosphorylation) | RATE OF CLEARANCE | Fest (minutes) Slow (hours wo days) Slow (hours to days) In some cases, metabolism of the hormone acti- vates the hormone rather than inactivates it. In other words, the secreted hormone may be relatively or completely unable to act upon a target cell until me- tabolism transforms it. One example is testosterone which is converted either to estradiol or dihydrotestos- tetone in certain of its target cells. These molecules, rather than testosterone itself, then bind to receptors inside the target cell and elicit the cell’ s response. Control of Hormone Secretion In onder to fit the needs of the body, the secretion of all hormones studied thus far appears to be closely controlled mainly by three types of signals to endo- rine cells: (1) negative feedback; (2) neurotrans- mitters; and (3) another hormone or neurohormone (or, a paracrine/autocrine agent). ‘These signals are processed by cells to determine the rate of hormones, secretion. For example, insulin secretion is con- trolled by the extracellular concentrations of glucose and other nutrients, by both sympathetic and para- sympathetic neurons to the insulin-secreting endo- crine cells, and by several hormones acting on these cells. Thus, endocrine cells, like neurons, may be subject to multiple, simultaneous, often opposing sig- nals, and the resulting output—the rate of hormone se- cretion—reflects the integration of all these signals. Control by Negative Feedback An almost universal feature of hormones secretion regulation is feedback from the plasma concentra tions of specific mineral ions, organic nutrients and the hormone that are released. In most instances, the feedback is inhibitory. In other words, the ac- tion of the hormone tend to suppress its further re- lease, thus a hormone can inhibit its own produe- tions this process is called negative feedback. It is aan essential mechanism that prevents excess secre- tion of many hormones or overactivity at the target tissue, and ensures a proper level of activity of the hormone at the target tissue after a stimulus causes release of the hormone. For example, when the sig- nals, elevated plasma concentration of thyroid hor- mones, feed back to the anterior pituitary, the re- lease of TSH will be inhibited (Figure 11-5). simu ortomone reese} | cen neemenenenen a Negative feedback EE e| jo Figure 11-5 Negative feedback, Another example is the regulation of Ca** homeo- stasis by the hormone called parathyroid hormone (PTH) that is produced by cells of the parathyroid lands. When plasma Ca** concentration decreases, PTH secretion is directly stimulated. PTH exerts several actions, in coordination with other hormones that restore plasma Ca°* to normal Negative feedback regulation of hormones can oc~ cur at all levels, including gene transcription and translation steps involved in synthesis of the hormone and steps involved in processing the hormone or re= leasing the stored hormone. Control by Neurons The adrenal medulla behaves like a sympathetic ganglion and thus is stimulated by sympathetic pre= ganglionic fibers. In addition to controlling the adre~ nal medulla, the autonomic nervous system influ- ences other endocrine glands. Both parasympatheticand sympathetic inputs to these other glands may oc- cur, some inhibitory and some stimulatory. Exam- ples are the secretion of insulin and the gastrointesti- nal hormones, which are stimulated by neurons of the parasympathetic nervous system and inhibited by sympathetic neurons. ‘Thus far, our discussion of neural control of hor- mone release has been limited to the role ofthe auto- nomic nervous system. However, one large group of hhormones—those secreted by the hypothalamus and its extension, the posterior pituitary—are under the direct control not of autonomic neurons, but of neu- rons in the brain itself, Control by Other Hormones In many cases, the secretion of a particular hor- mone is directly controlled by the blood concentra- tion of another hormone. There are often complex sequences in which the only funetion of the first hor- ones in the sequence is to 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 refering to growth-promoting. actions, the term trophic is often used). Control by Positive Feedback In a few instances, positive feedback oceurs when the biological action of the hormone causes additional secretion of the hormone. One example of this is the surge of luteinizing hormone (LH) that oceurs as a result of the stimulatory effect of estrogen on the ante rior pituitary before ovulation. The secreted LH then acts on the ovaries to stimulate additional secretion of estrogen, which in tum causes more secretion of LH. Eventually, LH reaches an appropriate concentration and typical negative feedback control of hormone se cretion is then exerted. Control by Cyclical Variations Superimposed on the negative and positive feed- back control of hormone secretion are periodie varia- tions in hormone release that are influenced by sea- sonal changes, various stages of development and ag- ing, the diumal (daily) cycle, or sleep. For exam- ple, the secretion of growth hormone is markedly in- creased during the early period of sleep but is re- duced during the later stages of sleep. In many e3- ses, these cyclical variations, in hormone secretion are due to changes in activity of neural pathways in- volved in controlling hormone release. Candidate Hormones ‘A number of substances, called candidate hor- ones, are suspected of being hormones in humans but are not considered classical hormones for one of two reasons; Either (1) their functions in humans have not been conclusively documented; or (2) they have well-documented funetions as paractine/auto- czine agents, but itis not certain that they ever reach additional target cells via the blond, an essential eri- ‘This second terion for classification as @ hormone. category includes « number of so-called growth factors that are secreted by multiple cell types and that stim- ulate specific cells to undergo cell division and differ- entiation. Hormonal Receptors Hormonal receptors are large proteins, and each cell that is to be stimulated usually has some 2000 to 100,000 receptors. Also, cach receptor is usually highly specific for a single hormone; this determines the type of hormone that wil act on a particular tis- sue. ‘The target tissues are those that contain specific receptors affected by @ hormone. The first step of a hormone’ s action is to bind to specifie receptors at the target cell, ‘The receptors for some hormones are located on the lorget cell sunface, termed membrane receptors, whereas other hormone receptors are located in the cytoplasm or the nucleus, termed intracellular re- ceptors. The membrane receptors are specific mostly for the protein, peptide, and catecholamine hor- tones. The receptors in cytoplasm are specifie for the different steroid hormones. The receptors specific for the thyroid hormones are found in the nucleus and are believed to be located in diveet association with The ability of re- sponse to a hormone depends upon the presence of fone or more of the chromosomes. specific receptors for those hormenes on (or in) the target cells ‘The number of hormone receptor can be regulated. As the receptor proteins themselves are often inaetiva- ted or destroyed during the course of their function, and at other times, the number of receptors in a tar- get cell usually does not remain constant from day to day, or even from minute to minute, In the context of hormones, down-regulation is a decrease in recep-tor number, often from exposure to high concentra tions of the hormone. This decreases target cell re- sponsiveness to the hormone, thus preventing overs timulation. Up-regulation is an increase in the num- ber of a hormone” s receptors, often resulting from a prolonged exposure to a low concentration of the hor- mone. This has the effect of increasing target cell re- sponsiveness to the hormone. In some cases, hormones can down-regulate or up-regulate not only their own receptors but the re- ceptors for other hormones as well. If one hormone induces an inerease in the number of receptors for a second hormone, the effectiveness of the second hor- mone is inereased, This phenomenon underlies the important hormone-hormone interaction known as permissiveness. In general terms, permissiveness ‘means that hormone A must be present for the full strength of hormone B" s effect. A low concentration of hormone A is usually all that is needed for this permissive effect, which may be due to A” ability to up-regulate B’s receptors. For example (Figure 11-6), epinephrine causes, a large release of fatty acids from adipose tissue, but only in the presence of permissive amounts of thyroid hormone. One reason is that thyroid hormone stimu- lates the synthesis of beta-adrenergic receptors for epinephrine in adipose tissue; thus, the tissue be- comes much more sensitive to epinephrine. Epinepioe Tips shyoid ormone —/"Epinpirine sormone ‘el Sma Figure 11-6 The ability of thyroid hormone to “permit” epinephrine-induced release of fatty ‘acids from adipose tissue cells. It should be noted, however, that receptor up- regulation does not explain all cases of permissive- ness; often the explanation is not known, or is due to changes in the signalling pathway that mediates the actions of a given hormone. Receptor Activation and Intracellular Signal: ling Almost without exception, the activation of recep tors is initiated by the hormone selectively binding to them and forming hormone-receptor complex, which then triggers a cascade of intracellular signalling and clicits a cellular response, as described previously in Chapter 2. Here, we will only brefly review them at this point (Table 11-2). The Activation of the Receptors on the Mem- brane ‘As stated previously, the recepiors for the pro- tein, peptide hormones and the catecholamine hor- rmones are located on the outer surface of the target cell’ s plasma membrane. ‘This location is very im- portant for these hormones, since these hormones are very large and hydrophilic, and difficult to diffuse through the plesma membrane, although it has now been found that there is the translocalization to the nucleus for some receptors of peptides (for example: GH, IGF-1 and others) When activated by hormone binding, the recep- tors trigger one or more of the signal transduction pathways described for plasma-memprane receptors. ‘That is, the activated receptors diectly influence; (1) enzyme activity that is part of the receptors (2) activity of cytoplasmic JAK kinases associated with the receptor; or (3) G-proteins coupled in the plasma membrane to effector proteins—ion channels and enzymes—that generate second messengers such as cAMP and Ca**. The opening or closing of ion channels changes the electrical potential across the membrane. When a caleium channel is involved, the cytosolic concentration of this important ion that is second messenger will be changed. The changes in enzyme activity are usually very repid (e.g. 5 due to phosphorylation) and produce changes in the con- formation and hence the activity of various cellular proteins. ‘The reactions in the cell with each stage are becoming more powerfully setivated so that even ‘small concentrations of the hormone can have a large effect. 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 coded by these genes. ‘Thus, peptide hor- ones and catecholamines may exert both rapid and delayed (gene transcription ) actions on the same target cell. The Activation of the Receptors in Cytoplasm Structurally, the steroid hormones secreted by the adrenal cortex, ovaries, and testes are all lipophil- ic. They readily cross the cell membrane, enter the cytoplasm of the cell, and binding with their specific receptors. The combined receptor protein-hormone then diffuses into or is transported into the nucleus, where the combination binds at specific points on the DNA strands in the chromosomes, which leads to the activation (or in some cases, inhibition) of the transcription process of specific genes to form mes- senger RNA. Finally, the messenger RNA diffuses into the cytoplasm, where it promotes the translation process at the ribosomes to form new proteins, ‘The ultimate result of changes in the concentra tions of these proteins is an enhancement or inhibi- tion of particular processes the cell carries out, or a change in the cell” s rate of protein secretion. For example, aldosterone, one of the hormones secreted. by the adrenal cortex, enters the cytoplasm of renal tubular cells, which contain a specific aldosterone receptor protein. Therefore, in these cells, the se- quence of events cited earlier ensues. After about 45 minutes, proteins begin to appear in the renal tubu- lar cells and promote sodium reabsorption from the tubules and potassium secretion into the tubules. ‘Thus, there is @ characteristic delay in the initial action of the steroid hormone of at least 45. minutes and up to several hours or even days for full action This is in marked contrast to the almost instantane- us action of some of the peptide and amino acid-de- rived hormones, such as vasopressin and norepi= nephrine, Surprisingly, in addition to having cytoplasm re~ ceptors. some target cells also have membrane re- ceptors for certain of the steroid hormones, notably progesterone and estradiol. In such cases, the signal transduction pathways initiated by the membrane re- ceptors elicit rapid non-genomie cell responses while the intracellular receptors mediate a delayed re- sponse, requiring new protein synthesis. The physi- logical significance of the membrane receptors of the steroid hormones in humans is still under investi- gation, but it is clear from animal studies. The Activation of the Receptors in the Nucle- us ‘The thyroid hormones thyroxine and triiodothyro- nine cause increased transcription of specific gene, in the nucleus. To accomplish this, these hormones first bind directly with receptor in the mucleus itself these nucleus receptors are protein molecules located within the chromosomal complex, and they control the function of the genetic promoters or operators. ‘Two important features of thyroid hormone funetion in the activation of the nucleus receptors are the fol- lowing: (1) They activate the genetic mechanisms for the formation of many types of intracellular pro- teins—probably 100 or more. Many of these are en~ zymes that promote enhanced intracellular metabolic activity in virtually all cells of she body. (2) Once ound to the nucleus receptors, the thyroid hormones can continue to express their control functions for days or even weeks. Generally, hormones that act via cell-surface mem- brane receptors can respond faster than those stimula~ ting intracellular receptors because the activation of pre-existing enzymes takes less time than synthesizing new proteins. This explains why catecholamines re- leased for the ‘fight-or-flight” response use cell-sur- face receptors even though they can cross cell mem- branes. ‘The response to a hormone varies between target cells so that the same hormone can have different ac- variation is partly due also the response to tions on different tissues. Th to different receptor types by receptor stimulation. Measurement of Hormone Concentration Most hormones are present in the blood and tis- sues in extremely minute quanities, some in con- centrations as low as one billionth of a milligram (1 picogram) per milliliter. ‘Therefore, it has been very difficult to measure these concentrations by the usual chemical means. An extremely sensitive meth- od, however, was developed nearly 40 years ago by Berson and Yalow that revolutionized the measure- rent of hormones, their precursors, and their meta- bolic end products. This is the method of radioim- munoassay. The technique spread rapidly to other disciplines and is currently the most commonly usedsystem for measuring peptide, protein, steroid, and thyroid hormones concentrations, as well as numer- cous other natural and synthetic compounds Radioimmunoassay ‘The principle of radioimmunoassay is based on the competition of a labelled ligand (luoxmome) with an unlabeled ligand for a fixed number of binding sites oon a specific antibody (Figure 11-7). The quantity of radiolabelled ligand bound is inversely related to the quantity of competing non-madiolabelled hor- mone, and, following mathematical transformation of the results, unknown samples can be directly read The most commonly used label is iodine 125, though tritium 3 and carbon 14 have also been employed. The procedure of radioim- rmunoassay is as follows. off of the standard curve, Figure 11-7 The Principle of Radioimmunoassay. First ‘An antibody that is highly specific for the hor- mone to be measured is produced, Second A small quantity of this antibody is (1) mixed with a quantity of fluid from the animal containing the hormone to be measured and (2) mixed simulta- neously with an appropriate amount of purified standard hormone that has been tagged with a radio- active isotope. However, one specific condition must be met: there must be too little antibody to bind completely both the radioactively tagged hor- mone and the hormone in the fluid to be assayed. ‘Therefore, the natural hormone in the assay fluid and the radioactive standard hormone compete for the binding sites of the antibody. In the process of competing, the quantity of each of the two hor- ones, the natural and the radioactive, that binds is proportional to its concentration in the assay fluid. Third After binding has reached equilibrium, the anti- body-hormone complex is separated from the remain- der of the solution, und the quantity of radioactive hormone bound in this complex is measured by radi~ active counting techniques. If a lerge amount of ra~ dioactive hormone has bound with the antibody. it is clear that there was only @ small amount of natural hormone to compete with the radioactive hormone, and therefore the concentration of the natural hor- mone in the assayed fluid was small. Conversely, if only a small amount of radioactve hormone has bound, it is clear that there was « large amount of natural hormone to compete for the binding sites. Fourth To make the assay highly quantitative, the radio- immunoassay procedure is performed also for “stand- ard” solutions of untagged hormone at several con- centration levels. ‘Then a “standanl curve” is plot- ted. By comparing the radioactive counts recorded from the “unknown” assay procedures with the standard curve, one can determine within an error of 10 to 15 percent the concentration af the hormone in the “unknown” assayed fluid. As ‘ttle as billionths or even trillionths of a gram of hormone can often beassayed in this way. Currently, with the great interest in decreasing the use of radioisotopes, fluorescent, chemi-lumi- nescent labels and biomolecular interaction analysis (Biacore) are being rapidly developed. Biomolecular Interaction Analysis ( BlAcore) BlAcore systems (Figure 11-8), which have been leading the way in protein interaction analysis lately Oyears, provide sensitive, accurate measurements of active concentration for hormones and other biomol- ecule. This is based on the ability of the biomolecule (e.g, hormone) of interest to interact with a specif= ic binding partner (receptor) , and may therefore be ‘more informative than generic measurement tech- niques. Principle: BlAcore is an optical biosensor (a la- bel-free technology) that uses surface plasmon reso- nance (SPR) to monitor binding interactions be- tween molecular partners. The BlAcore integrates this technology with a microfluidic system to allow real-time monitoring of these binding interactions be- Light Polarised Tight — i omy Semon vih I, We ‘gold film T Flow cae tween molecules on a sensor surface. ‘The sensor surface is prepared by coupling one of the molecular partners to dextran, using standard chemistries such as amine and thiol coupling. ‘This “surface” is actu- ally a lawn of carboxymethyl dextran polymers to which the molecule of interest is attached, thus lending a certain degree of mobility to the bound molecule (ligand). The partner molecule (analyte) is then passed over this prepared surface under flow, and any interaction between partners is recorded as & funetion of time in resonance units (RU)—these are arbitrary units that reflect the changes in refrac~ tive index (a function of mass} at the sensor surface that occur as a result of the binding of solution- phase analyte to (or its release from) surface-bound ligand. ‘The concentration of a specific hormone molecule is determined by monitoring its interaction with a prepared sensor surface in the presence of a target molecule in s0- lution. Concentrations are calculated by interpolation of the binding responses on a calibation curve. opiteat deteon aly ga Sensorgram Figure 11-8 The principle of BIAcore systems. SPR (Surface plasmon resonance) is a phenome- non that occurs when light is reflected off thin metal films. A fraction of the light energy incident at a sharply defined angle can interact with the delo- calised electrons in the metal film (plasmon) thus reducing the reflected light intensity. The precise angle of incidence at which this occurs is determined by # number of factors, but in dhe BIA devices the principal determinant becomes the refractive index close to the backside of the metal film, to which target molecules are immobilised and addressed by ligands in a mobile phase running along a flow cell. If binding occurs to the immobilised target the local refractive index changes, leading to a change in SPR angle, which can be monitored in real-time by detecting changes in the intensity of the reflected light, producing a sensorgram. The rates of change of the SPR signal can be analysed to yield apparent rate constants for the association ‘and dissociation phases of the reaction. The ratio of these values gives the apparent equilibrium con- stant (affinity). ‘The size of the change in SPR signal is dircctly proportional to the mass being immobilised and ean thus be interpreted crudely in terms of the stoichiometry of the interaction. Signals are easily obtained from sub-microgram quantities of material ‘Advantages :(1) Up to date, no other techniques can provide such comprehensive information in real time, without the use of labels and in one systemexcept BlAcore systems. fine the characteristics of hormones or other proteins in terms of their specificity of interaction with other molecules, the rates at which they interact (binding. and dissociation), and their affinity (how tightly they bind to another molecule). (3) The response reflects the concentration of the molecule in relation to the amount thet can interact with the immobilized in terms of active concentra Values can therefore differ from results (2) BlAcore systems de- interaction partne tion, achieved by UV absorbance or general protein assays that measure only total amounts. (4) Concentrations in the nano-molar range can be measured In summary, the advantages for BIAcore mainly include non-label, Real-time, small amount of sam- ple required and unique, high quality data on mo- lecular interactions SECTION B THE HYPOTHALAMUS AND PITUITARY GLAND THE PITUITARY GLAND AND ITS RELATION TO THE HYPOTHALA- MUS The pituitary gland, or hypophysis, is eonnect- ed to the hypothalamus by the infundibulum, a stalk containing nerve fibers and sinall blood vessels, (Figure 11-9) gland is composed of two adjacent lobes—the ante- ior pituitary (toward the front of the head, also called the adenohypophysis) and the posterior pi- tuitary (toward the back of the head ,also called the neurohypophysis ) In human beings, the pituitary In many mammalian species a well-developed intermediate lobe is found between the anterior and posterior portions of the pituitary, Dut this is not the case in humans, ‘The posterior pituitary is actually an extension of the neural components of the hypothalamus. ‘The ax- ons of two well-defined clusters of hypothalamic rons (the supraoptie and paraventricular nuclei ) pass down the infundibulum and end within the pos- terior pituitary in close proximity to capillaries (Figure 11-9). Thus, these neurons do not form a synapse with other neurons. Instead, their terminals ‘end directly on capillaries in the posterior pituitary Anterior pituitary connects with the hypothalamas by an unusual blood vessel—Hypothalamno-Pituitary Portal System. In contrast to the neural connections between the hypothalamas and posterior pituitary, there are no important neural tissue between the hypo- thalamus and anterior pituitary, while there is an unu- sual blood vessel connection between them ( Figure 11-9). ‘The eapllaies at the lowermost portion of the hypothalamus called the median eminence coalesce to form the hypothalamo-pituitary portal vessels—the term “portal” denotes blood vessels that connect two capillary beds. ‘The portal vessels pass down the stalk ‘connecting the hypothalamus and pituitary and enter anterior pituitary, where they drain into a second cap- illary bed, the anterior pituitary capillaries. Thus, the anterior pituitary is a highly vascular gland with exten- sive capillary sinuses among the glandular cells. Al- most all the blood that enters these sinuses passes first through hypothalamic capillary beds. The blood, carry- ing hypothalamic releasing and hypothalamic inhib- itory hormones, flows through hypothalamo-pituita- ry portal vessels directly into the anterior pituitary capillary sinuses (Figure 11-9). The local route for blood flow offers the advantage of a rapid response and. rinimizes the amount of hypothelamie hormone that ust be synthesized to reach an eflective blood concen- tration (since the hormone is not diluted into the gen- ral circulation of the body). POSTERIOR PITUITARY HORM- ONES ARE PRODUCED BY THE HYPOTHALAMUS ‘The two posterior pituitary hormones are Antidi~ uretic hormone (ADH) and Oxytocin (OXT) ‘The hormones are not synthesize¢ in the posterior tuitary itself but in the hypothalamus, specificall the cell bodies of the hypothalamic neurons whose axons pass down the infundibulum and end in the posterior pituitary. Enclosed in small vesicles, the hhormone moves dovn the neural axons to accumulate at the axon terminals in the posterior pituitary When the action potentials propagate to the axon ter~ rminals they trigger the release of the hormone by ex- ocytosis. The hormone then enters the capillaries to be carried away by the blood returning to the heart and to their target cells. In this way, the brain can receive stimuli and respond as if it were an endo- crine organ,Paraventeicular aucle (to posterior pituitary) Nocle sending axons to median Median eminence Short poral vessels Posterior pituitary Aneral blood Supraoptic nuclei (o posterior pituitary) Optic eriasm Ameria blood swply Anterior pituitary Endocrine cells ssnaly ‘Sphenoid bone ASS 2: ‘To venous circulation To venous sell tien circulation 75S ease ae asfaaness See ‘Figure 11-9 Neural and vascular connections between the hypothalamus and pituitary. a, Hypothalamic neurons from ‘the paraventricular and supraoptic nuclei run down the infundibulum to end in the posterior pituitary, whereas others end in the median eminence. b. Almost the entire blood supply tothe anterior pituitary comes via the hypothalamo-pitu- itary portal vessls, which originate in the median eminence. (The short portal vessels, which originate in the posterior Pituitary, carry only a smal fraction of the blood from the posterior pituitary to the anterior pitultry, ) ADH and OXT are released by the posterior pitu- itary when the messages arriving. ADH mainly con- trols the rate of water excretion into the urine from kidney and in this way helps control the eoncentra- tion of water in the body fluids. ADH is also called vasopressin (VP) because its vasoconstrietive func~ tion, Vasopressin can act on smooth muscle cells around blood vessels to cause muscle contraction when raising its blood vessels above normal, which results in the constriction of blood vessels and increa- ses blood pressure. Oxytocin stimulates contraction of smooth muscle cells in the breasts, which hel ‘express milk from the glands of the breast to the nj ples during suckling and possibly helps in the di ery of the baby at the end of gestation. ANTERIOR PITUITARY HORMO- NES ARE CONTROLLED BY THE HYPOTHALAMUS In contrast, the secretion of all the anterior pitui- lary hormones is controlled by hormones called hy- pothalamic releasing and hypothalamic inhibito- ry hormones which are secreted by hypothalamic neurons (these neurons are different from those that produce the hormones released from the posterior pi- tuitary) and then conducted, as shown in Figurel1~ 9, to the anterior pituitary throug minute blood ves- sels called hypothalamie-hypophysial portal ves- sels, In the anterior pituitary, these releasing and inhibitory hormones act on the glandular cells to control their secretion, Anterior Pituitary Glandular Cell Types and Hormones With special stains attached tc high-affinity anti- bodies that bind with the distinctive hormones, at least five cell types ean be differentiated one from another in the anterior pituitary gland. Usually, there is one cell type for each major hormone formed, as follows: (11) Somatotropes, about 30 to 40 percent of the anterior pituitary cells are somato- tropes that secrete growth hormone (GH). (2)Corticotropes, about 20 perwent are corticotropes that produce adrenocorticotropin ( ACTH ) (3) Thyrotropes that synthesis. thyroid-stimula- ting hormone (TSH). (4) Gonadotropes which release two kinds of gonadotropic hormone- zing hormone (LH) and follicte-stimul mone (FSH). (5) Lactotropes—prolactin (PRL). The later three kinds of cell type each number only 3 to 5 percent of the total neverthe- less, they secrete powerful hormones for controlling thyroid function, tion by the breasts. Somatotropes are stained strong- ly with acid dyes and, therefore, are called acido- phils. sexual functions, and milk secre- Overview of Anterior Pituitary Hormones Anterior pituitary secretes at least eight hormones in fact; only six important peptide hormones have well-established functions up to now. As shown in Figurel 1-10, these hormones play major roles in the control of metabolic functions throughout the body. Growth hormone promotes growth of the entire body by affecting protein formation, cell multiplica- tion, and cell differentiation (as described at the end in this section). Adrenocortieotropin ( corticotro- pin) controls secretion of some of the adrenocorti~ Figure 11-10 Metabolic functions of the anterior pituitary hormones. cal hormones, which in tum affect the metabolism of slucose, proteins, and fats. ‘Thyroid-stimulating hormone (thyrotropin) controls the race of secre~ tion of thyroxine and triiodothyronine by the thyroid sland, and these hormones in tum control the rates of most intracellular chemical reactions of the entire body. Prolactin promotes mammary gland develop~ ment and milk production by direct effects upon the breasts. During lactation, prolactin exerts a second- ary action to inhibit gonadotropin secretion, thus de- creasing fertility when a woman is areast-feeding. In the male, precise roles of prolactin are uncertain. And two separate gonadotropie hermones, follicle- stimulating hormone and luteinizing hormone, control growth of the ovaries and testes as well as their hormonal and reproductive activities. ‘The functions of each of these pituitary hormones are s0 intimately concerned with the functions of the respective target glands that, except for growth hor- mone, their functions are discussed in. subsequent sections along with the target glance. What about the other two hormones, beta-lipo- tropin and beta-endorphin, secreted by the anteri- or pituitary? Their physiological roles, if any, in hu- mans are unclear. In animal studies, however, beta~ endorphin has been shown to have potent pain-kill- ing effects, and beta-lipotropin can mobilize fats in the circulation to provide extra fuel. Both of these functions may contribute to an animal's ability to cope with stressful challenges. HYPOTHALAMIC RELEASING AND INHIBITORY HORMONES Hypothalamic releasing and hypothalamic in- hibitory hormones (also called hypophysiotropic hormones) are secreted by neurons that originate in discrete areas of the hypothalamus and terminate in the median eminence around the capillaries that are the origins of the hypothalamo-pituitary portal ves- ‘The generation of action pstentials in: these neurons causes them to seciete their hoununes. sels, ‘Those hormones, however, enter tke capillaries and are carried by the hypothalamo-pitaitary portal ves- sels to the anterior pituitary. There, they act upon the various anterior pituitary cells to control their hormone secretions.Major Functions of Hypothalamic. Releasing and Inhibitory Hor- mones ‘The major hypothalamic releasing and inhibitory hormones are the following: (1) Thyrotropin-re- leasing hormone (TRH) , which causes release of thyroid-stimulating hormone; (2) Corticotropi releasing hormone (CRH) , which causes release of adrenocorticotropin; (3) Growth hormone-re- leasing hormone (GHRH) , which causes release of growth hormone, and growth hormone inhibito- ry hormone (GHTH) , also called somatostatin, which inhibits release of growth hormones (4) Gonadotropin-releasing hormone (GnRH) , which causes release of the two gonadotropie hor- mones, Iuteinizing hormone and follicle-stimula- ting hormone; (5) Prolactin inhibitory hormone (PIE) , also termed dopamine, which causes inhi- ion of prolactin secretion; (6) Prolactin relea- sing hormone (PRH) that stimulates prolactin se- cretion. For most of the anterior pituitary hormones, it is the releasing hormones that are important, but for prolactin, a hypothalamic inhibitory hormone probably exerts most control. Hypophysiotropic Hormones Control! Three-Hormone Sequence With one exception, each of the hypophysiotropic hormones is the first in a three-hormone sequence: (1) A hypophysiotropic hormone controls the secre- tion of (2) an anterior pituitary hormone, which the controls the secretion of (3) a hormone from some other endocrine gland (Table 11-3). This last hor- mone then acts on its target cells. ‘The adaptive val- ue’of such chains is that they permit a variety of i portant hormonal feedbacks. They also allow ampli- fication of a response of a smal number of hypotha- amie neurons into a large peripheral hormonal. sig- nal. Table 11-3 ‘The Hypothalamus-anterior pituitary-target glands Sequence Sarre D Meron AMUS: EFFECT ON ANTERI- (OR PITUITARY HOR- MAJOR EFFECT ON TARGET GLANDS AND ‘TISSUES | Stimulates secretion of ACTH, cri Perce enero | oman as | | TRH Stanlen socrtion of TSE. Seeretes thyroxine, biodahyronine GHRH Stimulates seretion of GH Neng oe ea Protein synthesis, carbohydrate and lipid metablism GHIM (Somatostatin (SS) ) | Inhibits secretion of GH Liver and other cells Secrete IGF-1 a Gonads Gait Stimulates secretion of LH and FSH Gem cell development rs _| Estrogen, Progesterone, in Female; Testosterone in Male Pint Inhibits seraton of priaatin | Breasts | (Dopamine (DA) } Biresst development and milk production (in male may faci PRU Stimulates scretion of prolactin | tte reproductive function) Neural Control of Hypothalamic Releasing and Inhibitory Horm- ‘ones Essential Secretion in a Pulsatile Manner from Neurons All of these hypothalamic hormones are secreted at nerve endings in the median eminence. Electrical stimulation of this region excites these nerve endings and, therefore, causes release of essentially all the hypothalamic hormones. However, the neuronal cell bodies that give rise to these median eminence nerve endings excite often in a pulsatile manner, so that the hypothalamic hormones are often released in a pulsatile manner. ‘The pulses vary in amplitude and rate, often with a circadian rhythm,Central Nervous System Influence the Hor- mones Secretion Neurons of the hypothalamus receive signals from ‘many sources including stimulatory and inhibitory synaptic input, from virtually all areas of the central nervous system, and specific neural pathways influ- ence the secretion of the individual hypophysiotropic hormones. A large number of neurotransmitters (e. , the catecholamines and serotonin) are released at the synapses on the hormone-secreting hypotha- lamic neurons. In tum, much of this information is used to control secretions of the many globelly im- portant pituitary hormones, 4 es ent etn + Plasma cortisol i Target eels for cortisol, t Respond to increased cortisol Figure 11-11 ony ‘ypothalannus CRH secretion | 1 Plasma CRH (in bypothalamo-pituitary poral vessels) Anterior pituitary {ACTH secretion Figure 11-11 illustrates one example of the role of neural input to the hypothalamus. Corticotropin-re~ leasing hormone (CRH) from the hypothalamus stimulates the anterior pituitary to secrete ACTH, which in turn stimulates the adrenal cortex to secrete cortisol. A wide variety of sensory stimuli resulting from physical or emotional stress act via neural path ways to the hypothalamus to inerease CRH secre~ tion, and, therefore, ACTH and cortisol secretion. Even in the absence of stressful stimuli, however, cortisol secretion varies in a regular manner during a 24-hour period because neural shythms within the central nervous system also impinge upon the hypo- thalamic neurons that secrete CRH. sh CRH-ACTH-cortisol sequence. Neural inputs include those related to stressful stimuli and nonstress inputs like circadian rhythms. Cortisol exerts a negative feedback control over the system by act ing on (1) the hypothalamus to inhibit CRH synthesis and secretion and (2) the anterior pituitary to inhib- ACTH production,Negative Feedback Control from Target Glands Hormones ‘A prominent feature of each of the hormonal se~ quences initiated by a hypophysiotropi¢ hormone is negative feedback exerted upon the hypothalamo-pi- tuitary system by one or more of the hormones in its sequence. For example, in the CRH-ACTH-cortisol sequence (Figure 11-11) , the final hormone, corti- sol, acts upon the hypothalamus to reduce synthesis and secretion of CRH. In addition, cortisol acts di rectly on the anterior pituitary to reduce the response of the ACTH-secreting cells to CRH. Thus, by a double-barreled action, cortisol exerts a negative feedback control over its own secretion. Such a system is effective in dampening hormonal responses—that is, in limiting the extremes of hor- mone secretory rates. For example, when a painful stimulus elicits increased secretion, in tum, of CRH, ACTH, and cortisol, the resulting elevation in plasma cortisol concentration feeds back to inhibit the hypothalamus and anterior pituitary. Therefore, cortisol secretion does not rise as much as it would without these negative feedbacks. ‘The control model described for cortisol in which the hormone secreted by the third endocrine gland in a se- quence exerts a negative feedback effect over the ante- rior pituitary and/or hypothalamus, is known as a long-loop negative feedback (Figure 11-12). This type of feedback exists for each of the three-hormone sequences initiated by a hypophysio-tropie hormone. Long-loop feedback does not exist for prolactin since this is one anterior pituitary hormone that does not have major control over another endocrine gland—that is, it does not participate in a three~ hhormone sequence. Nonetheless, there is negative feedback in the prolactin system, for this hormone itself acts upon the hypothalamus to stimulate the se- cretion of dopamine, which then inhibits the secre- tion of prolactin. The influence of an anterior pitui- tary hormone on the hypothalamus is known as a short-loop negative feedback (Figure 11-12). Like prolactin, several other anterior pituitary hor rmones, including growth hormone, also exert such feedback on the hypothalamus. Tt must be noted that there are many stimulatory and inhibitory hormonal influences on the hypothala- rus and/or anterior pituitary other than those that fit the feedback pattems just described. For example, estrogen markedly enhances the secretion of prolac- Hypothalamus {Hormone | secretion =: Gn byporhalame-pituitary portal vessels) iy “Plasma hommone 1 LLong-loop feedback 3 “Plasma hormone 3 é Tare eels for hormone 3 ‘Respond t hormene 3 Figure 11-12 Hormonal Feedback Control of the Hypothalamus and Anterior Pituitary. Long-loop feedback is exerted on the hypothalamus and/or anterior pituitary by the third hormone in the se- quence. Short-loop feedback is exerted on the hy- pothalamus by the anterior pituitary hormone, tin by the anterior pituitary, even though estrogen secretion is not normally controlled by prolactin. ‘Thus, the sequences we have been describing should not be viewed as isolated units and there also are the controls of “Nonsequence” hormones. DISORDERS OF THE HYPOTHAL- AMUS Primary diseases of the hypothalamus are very rare, but they tend to cause deficiency of hypotha- lamic hormones and the corresponding pituitary hor- rmones. Dopamine deficiency has the opposite effect, resulting in excessive prolactin secretion from the an- terior pituitary. The main causes of hypothalamic hhormone deficiency are: (1) Trauma /surgerys (2) Radiotherapy; (3) Congenital gonadotrophin re-leasing hormone (GnRH) deficiency ( Kallmann’s syndrome) causing infertility; (4) Congenital GHRH deficiency causing dwarfism; (5) Primary glial cell tumors of the hypothalamus. Lesions in the hypothalamus can cause many other abnormalities, including disorders of consciousness, behavior, thirst, satiety, and temperature regula- tion, These disorders usually occur together with hy- popituitarism and diabetes insipidus. DISORDERS OF THE ANTERIOR PITUITARY Aetiology ‘The five P's of pituitary pathology are: (1) Tatro- genic (e.g. , surgery or radiotherapy) ; (2) Invac sion (i, e., tumours); (3) Infarction (e.g. , Sheehan's syndrome); (4) Idiopathic (i. €. , no underlying cause known) ; (5) Injury (e.g. , se- vere head trauma). Tumours The majority of pituitary gland disorders are ised by benign tumours of the secretory cells called adenomas. Disease occurs as a result of three processes: (1) Hyperpituitarism excess pituitary hormonesecretion; (2) Hypopituitarism insufficient Pituitary hormoneseeretions (3) Compression of sur- rounding structures caused by space-oceupying le- ‘These tumours are classified into two groups: fanctioning and non-functioning adenomas. Functio- ning adenomas present early whilst still very small. ‘These microadenomas cause disease by excess hor mone release, which can be fatal if untreated. ‘They also cause compression, so other pituitary hormones may be deficient, Non-functioning adeno- ‘mas usually present at a Inter stage as larger mac- roadenomas. ‘These cause disease indirectly by eom= pressing surrounding structures, often causing insu ficient pituitary hormone release when they compress the portal vessels or secretory cells. Hyperpituitarism Prolactinomas All the anterior pituitary secretory cells can form tumours, however, the vast majority are prolactino- mas i. e. tumours of the prolactin secreting cells ‘They are more common in women in whom they tend to present earlier, before visual disturbance occurs. Excess prolactin secretion—hyperprolactinaemia— causes galactorrhoea and hypogonadism. Hypopituitarism Pituitary insufficiency ( hypopituitarism) often presents with insidious onset depression, tiredness, and hypogonadism as most hormene levels fall and prolactin levels rise. When there is a deficiency of more than one pituitary hormone it is called panhy- popituitarism. The causes of pituitary insufficiency are more varied than those of hyperpituitarism. However, the most common cause is the treatment of hyperpituitarism, ‘Non-Funetioning Adenomas About 20% of pituitary tumoxs do not produce hormones so they are called non-functioning adeno- mas (sometimes called chromophobe adenomas ) They are almost always non-active prolactinomas Since there is no excess hormone production they present late with symptoms caused by compression of surrounding structures, which become progressively severe: (1) Headaches; (2) Pituitary hormone de- ficiencies; (3) Hypogonadism due to hyperprolacti- naemia; (4) Loss of peripheral vision due to com- pression of the optic nerve (bitemporal hemi- anopia) ; (5) Cranial nerve palses (starting with nerve IV) ; (6) Raised intracranial pressure. ‘The tumor can cause hormone deficiencies by di- rect compression of the secretory cells or by com- pressing the portal veins that bring the hypothalamic releasing factors. Secretion of anterior pituitary hor- mones is inhibited in a characteristic order: GH, LH and FSH, ACTH, TSH. Unless the compression is very severe prolactin secretion often increases ini- tially since dopamine inhibition is lost. This excess prolactin secretion is not from the cells of the adeno- ‘ma but it causes the symptoms, GROWTH HORMONE All the major anterior pituitary hormones besides growth hormone exert their principel effects by stim- ulating target glands, including the thyroid gland, the adrenal cortex, the ovaries, the testicles, and the mammary glands (Figure 11-10). The functionsof each of these pituitary hormones are so intimately concemed with the functions of the respective target glands that, except for growth hormone, their fune- tions are discussed in subsequent chapters along, with the target glands. Growth hormone, in contrast to other hormones, does not function through a target gland but exerts its effects directly on all or almost all tissues of the body(1,2). Physiologic Functions of Growth Hormone Growth hormone (GH), also called soma- totvopin., is a small protein molecule. Human growth hormone (hGH) contains 191 amino acids in a sin- gle chain and has a molecular weight of 22,000. HGH has two nonidentical sites, called site 1 and site 2. These bind two receptors in an ordered fash- jon first through site 1 and then through site 2. Re- ceptor dimerization initiates phosphorylation of the Janus tyrosine kinase, JAK2. Activated JAK2 then phosphorylates STAT3 among other proteins and stimulates transcription of new gene products leading, to cell proliferation and other effects. Tt causes growth of almost all tissues of the body that are capable of growing. It promotes increased sites of the cells and increased mitosis, with devel- ‘opment of increased numbers of cells and specific differentiation of certain types of cells such as bone growth cells and early muscle cells. Specific Metabolic Effects of Growth Hor- mone Aside from its general effect in causing growth, GH has multiple specific metabolic effects, inclu- ding (1) increased rate of protein synthesis in most cells of the body; (2) increased mobilization of fat- ty acids from adipose tissue, increased free fatty acids in the blood, and increased use of the fatty acids for energy; and (3) decreased rate of glucose utilization throughout the body. ‘Thus, in effect, GH enhances ody protein, uses up the fat stores, and ‘conserves carbohydrates. Growth Hormone Promotes Protein Deposition in Tis- sues Although the precise mechanisms by which GH increases protein deposition are not known, a series of different effects are known, all of which could lead to enhanced protein deposition. Enhancement of Amino Acid Transport ‘Through the Cell Membranes. GH directly en- hances transport of at least some and perhaps most amino acids through the cell membranes to the inte- rior of the cells. This increases the concentrations of the amino acids in the cells and is presumed to be at least partly responsible for the increased protein syn thesis to the effect of insulin in controlling glucose trans- port through the membrane, Enhancement of RNA Translation to Cause Protein Synthesis by the Ribosomes. Even when concentrations are not increased in This control of amino acid transport is similar the amino aci the cells, GH still increases RNA translation, cau- sing protein to be synthesized in increased amounts by the ribosomes in the cytoplasm. Increased Nuclear Transcription of DNA to Form RNA. Over more prolonged periods (24 to 48 hours) , GH also stimulates the transcription of DNA in the nucleus, causing formation of increased quan- tities of RNA. This in turn promotes more protein synthesis and promotes growth if sufficient energy, amino acid, vitamins, and other necessities for growth are available. In the long run, this perhaps is the most important of all the functions of GH, Decreased Catabolism of Protein and Amino ‘Acids. In addition to the increase in protein synthe- sis, there is decrease in the breakdown of cell pro- tein, A probable reason for this is that GH also mo- bilizes large quantities of free fatty acids from the adipose tissue, and these in turn are used to supply most of the energy for the body cells, thus acting as 4 potent “protein sparer. " Summary; GH enhances almost all facets of amino acid uptake and protein synthesis by cells, while at the same time reducing the breakdown of prote Growth Hormone Enhances Fat Liization for Energy GH has a specific effect in causing release of fatty acids from adipose tissue and, therefore, increasing the concentration of fatty acids in the body fluids. Tn addition, in tissues throughout the body, it en= hances the conversion of fatty acids to acetyl coen- ayme A (acetyl-CoA) and subsequent utilization of this for energy. ‘Therefore, under the influence of GH, fat is used for energy in preference to use of both carbohydrates and proteins. Growth Hormone’s effect to promote fat utiliza tion, together with its protein anabolie effect, causes an increase in lean body mass. However, GH mobi-lization of fat requires several hours to occur, where- as enhancement of protein synthesis ean begin in n nutes under the influence of GH. “Ketogenie” Effect of Growth Hormone. Un- der the influence of excessive amounts of GH, fat ‘mobilization from adipose tissue sometimes becomes so great that large quantities of acetoacetic acid are formed by the liver and released into the body flux ids, thus causing ketosis. This excessive mobili tion of fat from the adipose tissue also frequently causes a fatty liver. Growth Hormone Decreases Carbohydrate Ultlization GH causes multiple effects that influence carbohy- rate metabolism, inclnding (1) decreased glucose uptake in tissues such as skeletal muscle and fat, (2) increased glucose production by the liver, and (3) increased insulin secretion. Each of these changes results from GH-induced “insulin resist- which attenuates insulin’s actions to stimu- ance, late uptake and utilization of glucose in skeletal muscle and fat and to inhibit glucose output by the liver; this leads to increased blood glucose concen- tration and a compensatory increase in insulin secre- tion. For these reasons, GH's effects are called dia- betogenic, and excess secretion of GH ean produce metabolic disturbances very similar to those found in patients with type IT diabetes (non-insulin-depend- ent diabetes), who are also very resistant to the metabolic effects of insulin, We do not know the precise mechanism by which GH causes insulin resistance and decreased glucose utilization by the cells creases in blood concentrations of fatty acids may impair insulin’s actions on tissue glucose utilization. Experimental studies indicate that raising blood lev- els of fatty acids above normal rapidly decreases the sensitivity of the liver and skeletal muscle to insulin’s effects on carbohydrate metabolism. However, GH-induced in- Growth Hormone Stimulates Cartilage and Bone Growth Although GH stimulates increased deposition of protein and increased growth in almost all tissues of the body, its most obvious effect is to increase growth of the skeletal frame. ‘This results from multi= ple effects of GH on bone, including (1) increased deposition of protein by the chondrocytic and osteo- genie cells that cause bone growth, (2) increased rate of reproduction of these cells as well, and (3) a specific effect of converting chondrocytes into os- teogenic cells, thus causing specific deposition of new bone. ‘There are two principal mechanisms of bone growth; For one of these, in response to GH stimu- lation, the Jong bones grow in length at the epiphys- eal cartilages, where the epiphyses at the ends of the bone are separated from the shaft. ‘This growth first cause deposition of new cartilage, followed by con- version of this into new bone, thus elongating the shaft and pushing the epiphyses farther and farther apart. At the same time, the epiphyseal cartilage it- self is progressively used up, so thet by late adoles- no additional epiphyseal cartilage remains to provide for further long bone growth. At this time, bony fusion occurs between the shafi and the epiphy- sis at each end, so that no further lengthening of the long bone can occur. For the second mechanism of bore growth, osteo- blasts in the bone periosteum and in some bone eavi- ties, deposit new bone on the surfaces of older bone. Simultaneously, osteoclasts in the bone re- move old bone. When the rate of deposition is grea- ter than that of resorption, the thickness of the bone increases. GH strongly stimulates the osteoblasts. ‘Therefore, the bones can continue to enlarge in thickness throughout life under the influence of GH; this is especially true for the membranous bones. For instance, the jawbones can be stimulated to grow even after adolescence, causing forward protru- + the € rise to sion of the chin and lower teeth. Likes bones of the skull grow in thickness and gi bony protrusions over the eyes. GH Exerts Much of Its Effect through Soma- tomedin, IGFs In brief, it has heen found that GH causes the liver (and to a much less extent ather tissues) to that in tur exert direct effects on metabalism and the po- tent effect of inoreasing all aepects of bone growth Many of the somatomedin effects on growth are sitni- lar to the effects of insulin on growth, Therefore, the somatomedins are also called insulin-like growth factors (IGF). ‘At least four somatomedins have been isolated , but by far the most important of these is somatome- din C (also called insulin-like growth factor 1 [IGF-1}). The molecular weight of IGF-1 is about form several small proteins called scmatomed7500, and its concentration in the plasma normally follows closely the rate of secretion of GH. The pyg- ries of Aftiea have a congenital inability to synthe- size significant amounts of IGF-1. ‘Therefore, even though their plasma concentration of GH is either normal or high, they have diminished amounts of IGF-I in the plasma; this apparently accounts for the small stature of these people. Some other dwarfs (the Levi-Lorain dwarf) also have this problem. It has been postulated that most, if not nearly all, of the growth effects of GH result from IGF-1 ( Figure 11-13) and other somatomedin, rather than Hypothalamus OO) Anterior Ds Pituitary @ Time hes Liver Muscle Adipose Bone 4 1aF-1 Figure 11-13 Modes of GH Action and Regulation ‘of GH secretion. (a) Modes of GH Action: Serum GH can then bind to eell surface receptors ( G Rs) on target tissues such as liver, muscle, pose, and bone. This eauses an increase in the ser- lum concentration of insulin-like growth factor 1 (IGF-1). IGP-1 has growth-promoting effects and ‘an feedback to the tissues to trigger responses. In addition, high serum IGF-1 levels inhibit GHRH and GH release. () Regulation of GH secretion; 1. GH secretion is controlled by GH-releasing hor- ‘mone and GH inhibitory hormone produced in the hypothalamus. 2. Stress, sleep, and exercise can enhance the production of GHRH, increasing ser- tum levels of GH. 3. GH seeretion is also subject to typical negative feedback control. from direct effects of GH on the bones and other periph- ral tissues. Even so, experiments have demonstrated that injection of GH directly into the epiphyseal carila- 4 of bones of living animals causes specific growth of these cartilage areas and that the amount of GH required for this is minute. Therefore, some aspects of the soms- tomedin hypothesis are sill questionable. One possibility is that GH can also cause formation of enough IGF-I in the local tissue to cause the local growth. It is also pos- sible that GH itself is directly responsible for increased govt in some tissues and that the somatomedin mecha- nism is an altemative means of increasing growth but not always a necessary one. IGF-1 Prolongs the Growth-Promoting Effects of GH. Growth hormone attaches only weakly to the plas- ‘ma proteins in the blood. Therefore, it is released from the blood into the tissues rapidly, having a half time in the blood of less than 20 minutes. By con- trast, IGF-I attaches strongly to a carrier protein in the blood that, like IGF-I, is itself produced in re- sponse to GH. As a result, IGF-I is released only slowly from the blood to the tissues, with a half-time of about 20 hours. This greatly prolongs the growth- promoting effects of that we see in Figure 11-13. Effects of GH on Immunology System and Myocardium GH plays an integral ole in the maintenance of the immune system, It is important for lymphocyte funetion and required for a critical period of fetal bovine immune system development. GH can alter the expression of pro- tooncogenes and eytokines in lymphocytes. Lymphocytes also have been shown to secrete GH in a manner regula- ted differently from that of the endocrine system. Recent studies have shown that through direct ac~ tions on the brain, GH may modulate emotion, stress response, and behavior. GH has also been shown to be important for cardiac function. ‘There is growing evidence that GH and IGF-I are involved in heart development and hypertrophy. In fact, recom- binant CH (xCH) has been shown to increase myo- cardial mass and improve myocardial energy metabo- lism and hemodynamics. Regulation of Growth Hormone Secretion For many years it was believed that GH was secre-ted primarily during the period of growth but then disappeared from the blood at adolescence. This has proved not to be true. After adolescence, secretion decreases only slowly with aging, finally falling to about 25 percent of the adolescent level in very old age. Role of Metabolic Factors in the Control of GH Secretion GH is secreted in a pulsatile pattem (figure 11- 13), increasing and decreasing, which are more pronounced in males than females. The precise ‘mechanisms that control secretion of GH are not fully understood, but several factors related to a person's state of nutrition or stress are known to stimulate se- cretion: (1) starvation, especially with severe pro- tein deficiency; (2) hypoglycemia or low concentra- tion of fatty acids in the blood; (3) exercises and (4) excitement, And it is demonstrated the espe- cially powerful effect of strenuous exercise and also the high rate of GH secretion that occurs during the first 2 hours of deep sleep. Table 11-4 summarizes some of the factors that are known to influence GH secretion. Table 11-4 Factors That Stimulate or inhibit Secre- tion of GH. STIMULATE GH SE- CRETION Deereated blood glucose Decreased blood fee fty INHIBIT GH SECRETION Tnoreated blood glucose Increased Blood fee fatty acide acide Starvation o fasting, protein Aefcieney ieee ‘Trauma, stress, excitement | Obesity ae GH inhibitory hormone (som- reise tostatin) Testosterone, estrogen Growth hormone (exogenous) jy | Samamedine (inant Deep slap (stags Ian IV) | Somuonndine, Growth humone-eleasing hor ‘The normal concentration of GH in the plasma of an adult is between 1.6 and 3ng/mL and in a child or adolescent is about 6ng/mL.. These values often inerease to as high as SOng/mL after depletion of the body stores of proteins or carbohydrates during. prolonged starvation, Under acute conditions, hypoglycemia is a far more potent stimulator of GH secretion than is an acute decrease in protein intake. Conversely, in chronic conditions, GH secretion seems to correlate more with the degree of cellular protein depletion than with the degree of glucose insufficiency. Tt has been found that the extremely high levels of GH that occur during starvation are closely related to the amount of protein depletion. Role of GHRH and Somatostatin in the Con- trol of GH Secretion It is known that GH secretion is controlled by two factors, GH-releasing hormone and CH inhibitory hhormone (also called somatostatin), produced in the hypothalamus and then transported to the anteri~ or pituitary gland through the hypothalamic-hypoph- ysial portal vessels. GH inhibitory hormone inhibits GH release from the anterior pituitary, while GHRH stimulates release. Stress, sleep, and exercise can enhance the production of GHRH (Figure 11-13), increasing serum levels of GH. The hypothalamic nucleus that causes secretion of GH-releasing hor mone is the ventromedial nucleus, the same area of the hypothalamus that is known io be sensitive to blood glucose concentration to cause satiety in hy- perglycemic states and hunger in hypoglycemic states. ‘The secretion of somatostatin is controlled by other nearby areas of the hypothalamus. ‘Therefore, it is reasonable to believe that some of the same sig- nals that modify a person's behavioral feeding in- stincts also alter the rate of GH secretion. GH-releasing hormone stimulates GH secretion by attaching to specific cell membrane receptors on the outer surfaces of the Somatotropes in the pituitary gland. The receptors in tum activate the adenylyl cyclase system inside the cell membrane, increasing the intracellular level of eyelic adenosine monophos- phate (cAMP). ‘This in tum has both a short-term effect and a long-term effect. The short-term effect is to inetease calcium ion transport into the cell, which within minutes causes fusion of the GH secre- tory vesicles with the cell membrane and release of the hormone into the blood. ‘The long-term effect is to increase transcription in the mucleus by the genes to cause new GH synthesis. ‘Negative Feedback Control of GH Secretion ‘When GH is administered directly into the blood of an animal over a period of hours, the rate of en- dogenous GH secretion decreases. This demonstratesthat GH secretion, as is true for essentially all other hormones, is subject to typical negative feedback control (As shown in figure 11-13). However, the nature of this feedback mechanism and whether itis mediated mainly through inhibition of GH-releasing hhormone or through enhancement of somatostatin which in turn inhibits GH secretion, are uncertain. Abnormalities of GH Secretion Panhypopituitarism ‘This term means decreased secretion of all the an- terior pituitary hormones including GH. The decrease in seeretion may be congenital (present from bitth) , or it may occur suddenly or slowly at any time during the life of the individual , most often resulting from a Pituitary tumor that destroys the pituitary gland. Dwartism Most instances of dwarfism result from generalized deficiency of anterior pituitary secretion (panhypopi- tuitarism) during childhood. In general, all the physical parts of the body develop in appropriate pro- portion to one another, but the rate of development is greatly decreased. A child who has reached the age of 9 years may have the bodily development of a child of 4105 years, and the same person on reaching the age of 19 years may have the bodily development of child of 7 to 10 years (Figure 11-14). Figure 11-14 A 9-year-old pituitary dwarf com- pared with a 9-year-old control. ‘The panhypopituitary dwarf does not pass through puberty and never secretes sufficient quantities of gonadotropic hormones to develep adult sexual fune- tions. In one third of such dwaris, however, the de- ficiency is of GH alone; these persons do mature sexually and occasionally reproduce In other type of dvvorfiom (the African Pygmy and the Levi-Lorain dwarf) , the rate of GH secretion is normal or high, but there is a hereditary inability to form IGF-I, which is a key step for promotion of growth by GH. Treatment with Human GH. Human and monkey growth hormone receptors (GHR) are unresponsive to GHs from non-primate mammal because the Arg43 in GHRs is unique to primate (9) and Asp!71 is also present in only primate GH sequence (10). At the hGH; hGHR site 1 interface, GHITIAsp and GHR43Arg are known to form a strong, salt bridge and are, therefore, assumed to be important for the for- mation of the hormone-receptor complex and activa- tion of hGHR (11). For this wason, GH prepared from lower animals is not effeetive in human beings. In the past, as human GH (hGH) had to be pre- pared from human pituitary glands, it was difficult to obtain sufficient quantities of hGH to treat patients with GH deficiency. However, hGH can now be synthesized by Escherichia coli bacteria as a result of successful application of recombinant DNA tech~ nology. Therefore, hGH becomes available in sulfi- cient quantities for treatment purposes. Dwarfs who have pure GH deficiency can be completely cured if treated early in life. Also, hGH has proved to be beneficial in other metabolic disorders because of its widespread metabolie functions. Gigantism Occasionally, the acidophilic, GH-producing cells of the anterior pituitary gland becone excessively active, and sometimes even acidophilic tumors occur in the gland. As a result, large quantities of GH are produced. All body tissues grow rapidly, including the bones. If the condition occurs before addlescence, before the cepiphyses of the long bones have become fuser with the shafts, height increases so that the person becomes a gi- ant as tall as 8 feet as shown in Figure 11-15. Acromegaly Ian acidophilic tumor occurs after adolescence— that is, after the epiphyses of the long bones have fused with the shafts—the person cannot grow taller, but the soft tissues can continue to grow and thebones ean grow in thickness. This condition, also shown in Figurel 1-15, is known as acromegaly. En- largement is especially marked in the bones of the hands and feet and in the membranous bones, such as the cranium, nose, bosses on the forehead, lower jawbone, and portions of the vertebrae, because Uneir growth does not cease at adolescence, Conse- quently, the lower jaw protrudes forward, the nose increases to as much as twice normal size, and the fingers become extremely thickened so that the Tn addi- tion to these effects, changes in the vertebrae ordi- hands develop a size almost twice normal, narily cause a hunched back, which is known clini- cally as kyphosis. Finally, many soft tissue organs, sich as the tongue, liver, and especially the kid- neys, become greatly enlarged. Figure 11-15 Gigantism and acromegaly in one individual of 17-year-old. Note the increased hheight and the bones thickening especially marked in the bones of the face, shoulders, elbows and knees, as well as the fingers( upper let). Role of Decreased GH Secretion in Causing Aging In people who have lost their ability to secrete growth hormone, the aging process accelerates. For ance, a person at age 50 who has been without CH for many years will probably have the appear ance of a person aged 65. The aging seems to result mainly from decreased protein depesition in most tis- sues of the body and in its place increased deposi- tion of fat. The physical and physiologic effects are increased wrinkling of the skin, diminished rates of funetion of some of the organs, and diminished mus- cle mass and strength. As one ages, the average plasma concentration of GH in an otherwise normal person changes approxi- mately as follows ae ay me 5 1020 years 6 20/10 40 years 3 40 10 70 year L6 ‘Thus, it is highly possible that some of the aging effects in normal older life result from diminished GH secretion. In fact, multiple tests of GH therapy in older people have demonstrated three important effects that suggest antiaging actions; (1) increased protein deposition in the body, especially in the muscles; (2) decreased fat deposits and (3) a feel- ing of increased energy Balin) dsse) 2g). SECTION C ONE ‘The thyroid gland (from Greek, thyroid = shield) located immediately below the larynx on each side of and anterior to the trachea, is one of the largest endo- crine glands, normally weighing between 15 to 20 gms in adult. "The thyroid secretes two significant hor- tones, thyroxine and triiodothyronine, commonly called T4 and T3, respectively. Both of these hor- ‘mones exert widespread and diverse effects throughout the body. In China, however, thyroid homnone defi ciency is a very common disorder in lands far away from the sea in the past. Thyroid secretion is controlled primarily by thyroid-stimulating hormone (TSH) secre- ted by the anterior pituitary gland. ‘The purpose of this section is to discuss the for- mation and secretion of the thyroid hormones, their functions in the metabolic scheme o the body, and regulation of their secretion.SYNTHESIS AND SECRETION OF THE THYROID HORMONE ‘The thyroid gland is composed, as shown in Fig ure 11-16, of about 3 million closed follicles (100 erms Blood vessel gland. Showing the gland contains large numbers of closed follicles. Each follicle is lined by a single row of cuboidal epithelial cells and the follicle is filled up by a structureless material called colloid. aed > docs of tyroelobuln eect teas to 300 micrometers in diameter) filled with a secre- tory substance called colloid that made up of thyro- globulin, and lined with cubsidal epithelial cells (also called follicular cells). ‘The follicular cells participete in almost all pha- ses of thyroid hormone synthesis and secretion. "The principal steps are as follows: Iodide Trapping. (Step 1) Figure 11-17 shows the transport of iodides from the blood into the thy- roid glandular cells. Synthesis begins when circulat- ing iodides are actively cotrarsported with sodium ions across tile follicular cell plasma membrane. ‘There are a few other cell types in the body capable of transporting iodide, but transport into the thyroid gland accounts for the vast majority of iodide trans- port. Once inside the follicular cell, the bulky io- dide molecule cannot diffuse back into the intersti- tial fluid, this process known as iodide trapping is completed. The sodium is eventually pumped back out of the cell hy Na’ /K*-ATPases, meanwhile, 2, © lose is oxidized and attached to rings of Iyrosines in thyroglobulin 1 oncom, ‘on (Marr) ai | © The iodinated ring of one MIT or DIT is added to @ DIT at another spot Figure 11-17 Steps involved in the Synthesis and Secretion of 3 and 14.‘The negatively charged iodide ions diffuse down their electrical and concentration gradients to the I~ ‘menal border of the follicular cells ( Step 2 in Figure 1117) Todide Oxidation (Step 3). The iodide that dif- fuses to the colloid is rapidly oxidized at the lumenal surface of the follicular cells to iodine free radicals, either nascent iodine (1°) or I~, that is then capa- ble of combining directly with the phenolic rings of tyrosine molecules within the amino acid structure of thyroglobulin. This oxidation of iodine is promoted by the enzyme peroxidase and its accompanying hy- drogen peroxide, which provide a potent system ca- pable of oxidizing iodides. ‘The peroxidase is synthe- sized by follicular cells and is attached to the apical membrane of the cell, thus providing the oxidized iodine at exactly the point in the cell where the thy- roglobulin molecule issues forth from the Golgi appa- ratus and through the cell membrane into the stored thyroid gland colloid. When the peroxidase system is blocked or when it is hereditarily absent from the cells, the rate of formation of thyroid hormones falls to zero, Thyroglobulin itself is also synthesized by the follicular cells and secreted by exocytosis into the follicle lumen. Organification of Thyroglobulin (Step 4). The binding of iodine with tyrosine molecules within the thyroglobulin and the coupling reaction of iodoty- rosine residues are called organification of the thy globulin. In the follicular cells the oxidized iodine is associated with an iodinase enzyme that causes the process to occur within seconds or minutes. There- fore, almost as rapidly as the thyroglobulin molecule is secreted through the apical cell membrane into the follicle, iodine binds to either of two positions on sven tyrosine within thyroglobulin. A tyrosine atta- ched one iodine is called monoiodotyrosine (MIT) ; if two iodines are attached, the product is Gijodotyrosine (DIT). Then, during the next few minutes, hours, and even days, more and more of the iodotyrosine residues become coupled with one another. ‘The phenolic ring of « molecule of MIT or DIT is removed from the remainder of its tyrosine and coupled to another DIT on the thyroglobulin molecule. This reaction is also mediated by thyroid peroxidase. If two DIT molecules are coupled, the result is thyroxine(T4). If one MIT and one DIT are coupled, the result is triiodothyronine (T3). Figure 11-18 shows the chemistry of thyroxine, triio- dothyronine and reverse triiodothyronine (rT3) for mation, T4 and T3 are two important thyroid hor- ‘mones, and 173 is an important metabolite of T'. iti} ° oO ‘etraiodathyronine (iyroxine-T4 ) Triidtyronine (T3) -@- @~y cn bon Reverse T3 Figure 11-18 Chemistry of Thyrosine(T4) , Trii- odothyronine(‘T3) and Reverse ‘T3 Formation, Storage of Thyroglobulin. ‘The thyroid gland is unique among the endocrine glands in its ability to store large amounts of hormone. As Figure 11-16 shows, in the follicular space of the thyroid foli cles, large amount of thyroglobulin is present. This represents storage of thyroid hormores after synthe has run its course. Normally, the stored amount of thyroid hormones in the follicles is enough to meet the requirements of the body for 2 10 3. months. Release of thyroid hormone (Step 5 and 6) ‘When thyroid hormone is needed in the blood, ex- tensions of the colloid-facing memb-anes of follicular cells engulf portions of the iodinated thyroglobulin from colloid by endocytosis. The thyroglobulin, with its coupled MITs and DITs, is brought into contact with lysosomes in the cell interior. Proteolysis of thyroglobulin releases 13 and 14, vhich then diffuse out of the follicular cell into the interstitial fluid and from there to the blood (Step 7). CARRIAGE OF THYROID HOR- MONES About 99% of the iodothyronines (‘T4 and T3) are bound with protein; only about 1% is free in blood. Nevertheless, only the free 74 (or T3) is ‘active, rather than the bound ones. ‘The proteinswhich bind with the T4 (or T3) are thyroxine binding globulin (TBG) accounting for nearly 75% of all the thyroid binding proteins in blood, thyroxine binding prealbumin (TBPA, also called transthyretin) and albumin, Note: (1) The protein ound T4 (or T3) acts as a reservoir, When tissues take up free hormone the lost amount of the free hor- mone is made good by the reservoir. (2) The pro- tein bound thyroid hormones, being large mole- cules, are not renal filter passing; hence wastage via urine is prevented. FUNCTIONS OF THYROID HORMONES ‘The general effect of 13 and TS is to activate nu- clear transcription of large numbers of genes by acti- vating the thyroid hormone receptors (‘TH re tor). TH receptors are present in the nuclei of most of the cells. Therefore, great numbers of protein en~ zymes, structural proteins, transport proteins, and other substances are synthesized and the functional activities are increased in many organs and tissues of the body ‘As most of the T4 that enters cells is defodinated to T3 and intracellular TH receptors have a very high affinity for T3. Consequently, about 90 percent of the TH receptors are generally occupied by T3 and only 10 percent by T4. Thyroid Hormones Increase Metabolic Actions ‘The thyroid hormones increase the metabolic ac- tivities of almost all the tissues of the body because ‘T3 and T4 stimulate earbohydrate absorption from the small intestine, enhance synthesis of body pro- teins under physiological condition and increase fat- ty acid release from adipocytes. These actions pro- vide energy to maintain metabolic rate at a high lev- el, and are consistent with one of the major actions of TH, which is to stimulate the activity of Na*/ K"-ATPases throughout the body. ‘Thus, as ATP is consumed by Na‘ /K*-ATPases at a high rate due to ‘TH activation, the cellular stores of ATP must be maintained by increased activity of mitochondria with metabolism of fuels. This ealorigenic action of ‘TH represents a very significant fraction of the total heat produced each day in a typical person. Clinically, excess thyroid secretion (hyperthy- roidism) causes elevation of BMR (basal meta- bolic rate) and blood sugar levels, and hyposecre- tion of thyroid causes fall of BMR. But, accor to some recent findings, in hyperthyroidism resist- ance of the cells which are targets of insulin, rises due to excess '3; this can be a major factor contrib- tting to the hyperglycemia of hyperthyroidism. On the other hand, although TH enhances anabolism under physiological condition excess T3 enhances catabolism (break down of endogenous protein ). ‘Thus, breakdown of endogenous muscle, leading to muscle wasting, reduction of body weight and in- creasing gluconeogenesis (because large amount of amino acids are available) are common features of hyperthyroidism. Thyroid Hormones Improve Growth and Development Physical Growth ( Skeletal, Muscular and Visceral Growth) In humans, the effect of chyroid hormone on growth is manifest mainly in gowing children. In those who are hypothyroid, the rate of growth is greatly retarded. In those who are hyperthyroid, ex- cessive skeletal growth often occurs, causing the child to become considerably taller at an earlier age. However, the bones also mature more rapidly and the epiphyses close at an early age, so that the dura- tion of growth and the eventual height of the adult ‘may actually be shortened. ‘That is because TH is needed for normal production of growth hormone. Bat the visceral growth is less restricted. ‘The re~ sult shows weak abdominal muscles but abdominal viscera of near normal volume ( pot belly); or, small mouth cavity but nearly nermal sized tongue— protruding tongue and dribbling of saliva. Mental Growth An important effect of thyroid hormone is to pro- mote growth and development of the brain during fe- tal life: and for the first few yesrs of postnatal life During fetal life, TH exerts many effects on central nervous system development, including the forma- tion of nerve terminals and the production of synap- ses, the growth of dendrites and dendritic exten- sions, and the formation of myelin, Absence of TH during fetal life results in a poorly developed nervous system and a form of mental reterdation called eret- nism, ‘The most common cause of cretinism aroundthe world is dietary iodine deficiency in the mother. ‘Thus, even though the fetal thyroid may be normal , it cannot manufacture sufficient TH. If the condition is discovered and corrected with iodine and TH ad- ministration shorily after birth, mental and physical retardation can be prevented. Some evidence sug- gests, however, that cretinism cannot be reversed if the treatment is not initiated in the early neonatal period. Despite the availability of iodized salt prod- ucts in many countries, cretinism is still a common disorder in some parts of the world, particularly in mountainous regions where snow and rainwater leach iodine out of the soil. However, The effects of TH fon nervous system function are not limited to fetal ‘and neonatal life. Figure 11-19 Neonatal hypothyroidism with men- tal retardation. Sexual Growth In the abss development in children are decreased, which also includes the characteristics of small penis, small testis, no pubic hair, no axillary/chest hair and no libido; similarly, this infantile sex is also seen in girls (no axillary pubic hair, no breast develop- ment, no growth of vulva-vagina-uterus and no men- struation) of thyroid hormones, growth and Permissive Actions of Thyroid Hor- mones Many of the actions of TH are attributable to its permissive effects on catecholamines. TH up regu lates beta-adrenergic reveplors in many tissues, no= tably the heart and nervous system, Thus, it should not be surprising that the symptoms of excess thyroid hormone concentration closely resemble some of the symptoms of excess epinephrine and norepinephrine (sympathetic nervous system activity). It is because the inereased thyroid hormone potentiates the actions of the catecholamines, even though the latter are within normal levels. Because of this potentiating effect, people with hyperthyroidism are often treated with drugs that block beta-adrenergic receptors to al leviate the anxiety, nervousness, and “ racing heart” associated with excessive sympathetic stimu lati Effects of Thyroid Hormones on Specific Systems On the Cardiovascular System ‘TH can increase heart rate and heart strength, as well as cardiac output and blood ‘low, all of which are because the thyroid hormone potentiates the ac- tions of the catecholamines and increases metabolism in the tissues. However, the heart rate increases considerably more under the influence of thyroid hhormone than would be expected from the increase in cardiac output. Therefore, thyroid hormone seems to have a direct effect on the excitability of the heart, which in tum increases the heart rate. On the Central Nervous System in Adult In general, thyroid hormone increases the rapidi ty of cerebration but also often dissociates this in adult; conversely, lack of thyroid hormone decres- ses this funetion. The hyperthyroid individual is likely to have extreme nervousness and many psy- choneurotic tendencies, such as anxiety comple- xes, extreme worry, and paranoia— Excitatory Effects. In addition, TH is also needed for proper nerve/muscle reflexes and for narmal cognition in adults.On the Function of the Muscles—Weak- ened, Sluggish and Tremor When the quantity of TH becomes excessive, the muscles become weakened because of excess protein catabolism. Conversely, lack of thyroid hormone causes the muscles to become sluggish, and they re- lax slowly after a contraction, Fine muscle tremor is one of the most characteris- tic signs of hyperthyroidism. ‘This is not the coarse tremor that occurs in Parkinson’s shive- ring, because it occurs at the rapid frequency of 10, to 15 times per second. The tremor can be observed easily by placing a sheet of paper on the extended fingers and noting the degree of vibration of the pa- per. This tremor is believed to be caused by increased reactivity of the neuronal synapses in the areas of the spinal cord that control muscle tone. The tremor is ‘an important means for assessing the degree of thy- roid hormone effect on the central nervous system. ‘On Other Endocrine Glands Increased thyroid hormone increases the rates of secretion of most other endocrine glands, but it also increases the need of the tissues for the hormones. For instance, increased thyroxine secretion increases the rate of glucose metabolism everywhere in the body and therefore causes @ corresponding need for increased insulin secretion by the pancreas. Also, thyroid hormone increases many metabolic activities related to bone formation and, as a consequence, increases the need for parathyroid hormone. In addition, thyroid hormone increases the rate at which adrenal glucocorticoids are inactivated by the liver. This leads to feedback increase in adrenocor- ticotropic hormone production by the anterior pitu- itary and, therefore, increased rate of glucocorticoid secretion by the adrenal glands. Finally, although the action of thyroid hormone on the gonads cannot be pinpointed to a specific function but probably re- sults from a combination of direct metabolic effects on the gonads az well ae excitatory and inhibitory feedback effects operating through the anterior pitui- tary hormones that control the sexual functions. It is observed that lack of thyroid hormone in men is like~ ly to cause loss of libido and sometimes cause impo- tence; in women often causes menorthagia and poly- menomhea. Yet, strangely enough, in other women thyroid lack may cause irregular periods. nase 0% Newoseeretory Cells Releasing TRH TSHis A Released J into Bioos Figure 11-20 TRH-TSH-TH sequence. The re- lease of TH from thyroid gland is the end result of ‘a long series of events mediated by TRH, then ‘ISH. TRH stimulates the secretion of TSH ( th rotropin) that stimulates the thyroid gland to ‘crease production of T4 and T3, and release them. ‘The control mechanism of TRH and TSH produc- tion is the negative feedback action of TSH and TH. CONTROL OF THYROID HORMONE SECRETION. To maintain normal levels of metabolic activity, and velocity of growth and development in the body, the right amount of thyroid hormone secretion is con- trolled at all times by a specific feedback mecha- nisms as described in section B, which operates through the hypothalamos and anterior pituitary gland (TRH-TSH-TH sequence / Short-loop and Tong-loop feedbacks) as showed in Figure 11-20.TSH, an anterior pituitary hormone, also known as thyrotropin stimulates all of the actions of the thyroid follicular cells. Its specific effects on the thyroid gland include: (1) Increased activity of the iodide pump, which increases the rate of “ iodide trapping” in the glandular cells; (2) Increased io- ination of tyrosine to form the thyroid hormones; (3) Increased proteolysis of the thyroglobulin that has already been stored in the follicles, with resu ant release of the thyroid hormones into the circulat- ing blood; (4) Increased size and increased secre- tory activity of the thyroid cells; (5) Increased number of thyroid cells plus a change from cuboidal to columnar cells and much infolding of the thyroid epithelium into the follicles. In summary, TSH not only stimulates T3/T4 production, it also increases protein synthesis in foliar cells and other cellular machinery needed for protein synthesis, and the thy- roid glandular cells division. Thus, if a thyroid cell is exposed to higher TSH levels than normal it will undergo hypertrophy (increase in size, called a goi- ter). As stated earlier, the synthesis and release of ‘TSH is stimulated by TRH. The basic control mech- anism of TSH production is the negative feedback action of TH on the anterior pituitary and, to a less extent, the hypothalamus. Autoregulation of thyroid. Daily iodine require- ‘ment is 200,1¢/day in adult. If the food contains ex- cess iodine, the “iodide trapping mechanism” be- comes inefficient so that not much iodine is trapped. If the food iodine uptake is very low, the iodide trapping mechanism becomes super efficient so that the entire amount of available iodine is trapped by the follicular cells of the thyroid. ‘The whole phe- nomenon is called “ autoregulation” of thyroid. However, if the food iodine intake is less than Sy. /Aay, then despite the autoregulation , iodine defi- ciency (hypothyroidism) develops. SUMMARY 1, Hormones have evolved as the mediators of communication between cells located at great dis- tances in the body. They are identical to or derived from chemicals that are used for local cell communi- cation. 2. Hormones function in groups, affecting the major physiologic processes necessary for the life of the organism, including growth, metabolism, repro- duction, and adaptation to the extemal environment. 3. Hormones’ action is initiated by binding to spe- cific cellular receptors that are coupled to second- messenger effector mechanisms, which amplify im- portant cellular eytoplasmic processes, or to nuclear receptors that interact with specific DNA regulatory elements to initiate RNA transcription. 4, Numerous sensitive techniques have been de~ veloped for hormone measurement that allows assess- ‘ment of their storage, secretion, and metabolism. 5. The CNS regulates the endocrine system through specific neuroanatomic pathways that involve the hypothalamus, and a series of specific releasing, and inhibiting hormones that control the secretion of the anterior pituitary. 6. The feedback systems also are influenced by signals derived from perturbations of the external en- vironment, inherent biologic rhythms, and circulat- ing nutrients. "The most important of endocrine func- tions—growth, reproduction, and the response to stress—all require the integrative functions of this system. 7. The anterior pituitary, once called the “master gland,” is the primary target through which the cen- tral nervous system controls endocrine function. 8. The secretion of each of the pituitary hormones is regulated by hypothalamic—relecsing or hypotha- lamic-inhibiting hormones, or both, and by feed- back signals derived from the target glands or organs affected by the pituitary hormone. 9. The pituitary gland also includes, except the anterior pituitary, the posterior pituitary. Specific axons, whose cell bodies are in the hypothalamus, terminate in the posterior pituitary and release oxyto- cin and vasopressin. 10. TH is synthesized by thyroid follicular cells in a series of steps that include I upiake, oxidation, and organification, 11. TH secretion involves the reuplake of stored hormones into the apex of follicular cells and their transport to the base, where they are secreted and discharged into the plasma 12, TH secretion is controlled by TSH produced in pituitary thyrotrophs. All of the synthetic steps involved in T3/T4 synthesis are stimulated by TSH. It also causes growth (hypertrophy) of thyroid tis- 13, Excessive exposure of the thyroid to TSH can ‘cause goiter. The secretion of TSH, in turn, de- pends on the amount of eirculating free TH. This in-volves a classic feedback-inkibition loop and the stimulatory influence of hypothalamic TRH. 14. The interaction of thyroid hormones with cells is predominantly mediated by their binding to specif- ic nuclear receptors. 15. TH increases the metabolie rate, and thus promotes consumption of calories ( calorigenic effect). 16. Thyroid hormones are necessary for integra- ting normal development and proper bodily function throughout life. REVIEW QUESTIONS 1. Which classes of hormones are carried in the blood mainly as unbound, dissolved hormone? Mainly bound to plasma proteins? 2. Do protein-bound hormones cross capillary walls? 3. Which organs are the major sites of hormone excretion and metabolic transformation? 4, How do hormones influence the concentrations of their own receptors and those of other hormones? 5. Deseribe the sequence of events when peptide or catecholamine hormones bind to their receptors. 6. Describe the sequence of events when steroid or thyroid hormones bind to their receptors. "7. What are the direct inputs to endocrine glands controlling hormone secretion? 8, What roles does the autonomic nervous system play in controlling hormone secretion? 9. What groups of hormone-secreting, cells receive input from neurons located in the brain rather than in the autonomic nervous system? 10. Where do the neurons whose axons comprise the substance of the posterior pituitary originate? 11, Name the two posterior pituitary hormones and describe their site of synthesis, mechanism of release and physiological effects. 12, List the major releasing and inhibiting, hor- mones from the hypothalamus and the hormone ‘whose release each controls. 13. What kinds of inputs control secretion uf the releasing and inhibiting hormones from the hypothal- amus? 14, What is the difference between long-loop and short-loop negative feedback in the hypothalamo-an- terior pituitary system? 15. What can occur when GH levels are increased and somatomedin levels are depressed? 16. Describe the steps leading to T3 and T4 pro- duction, beginning with the transport of iodide into the thyroid follicular cell. 17. What are the plasma proteins that determine the free concentration of thyroid hormone? 18, What are the major actions uf TSH on thyroid function and growth? 19. What is the major way in which the TRH/ ‘TSH/TH pathway is regulated? 20. What is the effect of thyroid hormone excess on the brain and the skeletal system in adults? THOUGHT QUESTIONS 1, Explain what is meant by down-regulation de~ sensitization of receptors, and how too much of a medicine can paradoxically make the medicine lose its effectiveness. 2. What are some roles of hormone binding to proteins in the bloodstream in Formone physiology? 3. What are some differences between the mecha- nisms of steroid and polypeptide hormone action? 4. Why it is important to know what kind of assay is used when you request determination of a hormone level in a patient's bloodstream? 5S. What is the role of the hypothalamic-pituitary unit in the overall scheme of bedy physiology? 6. Why was the defect in the adrenal axis only picked up by provocative testing and not by simply measuring blood levels of ACTH? 7. What is the rationale for treatment with a do- pamine agonist? 8. What is @ common complication involving the hypothalamic-pituitary unit thet can occur either transiently (as an indirect result of edema postoper- atively) or permanently (as a result of direct trau- ma)? 9. In what ways would transection of the hypotha- lamic stalk be functionally similar to or different from complete destruction of the pituitary gland?” 10. How would you distinguish between hypose- taetion and. hyporesponsiveness? 11. Explain why the symptoms of hyperthyroidism may be confused with a disorcer of the autonomic nervous system. (Wan Yu)