578 PART IX ENDOCRINE PHYSIOLOGY being equal to the total receptor number (R 0 ). Other mone increases, the affinity (slope) steadily decreases. equally valid mathematical and graphic methods can be Whether curvilinear Scatchard plots in fact result from used to analyze hormone-receptor interactions, but the two-site receptor systems or from negative cooperativity Scatchard plot is probably the most widely used. between receptors is unknown. In practice, Scatchard plots are not always straight lines but instead can be curvilinear (Fig. 31.9B). Insulin is a clas- sic example of a hormone that gives curved Scatchard plots. Dose-Response Curves Are Useful in Determining One interpretation of this result is that cells contain two Whether There Has Been a Change in separate and distinct classes of receptors, each with a dif- Responsiveness or Sensitivity ferent binding affinity. Typically, one receptor population Hormone effects are generally not all-or-none phenom- has a higher affinity but is fewer in number compared to the ena—that is, they generally do not switch from totally off second population. Therefore, as indicated in Figure 31.9B, to totally on, and then back again. Instead, target cells ex- Ka 1 Ka 2 , but R0 2 R0 1 . Computer analysis is often re- hibit graded responses proportional to the concentration of quired to fit curvilinear Scatchard plots accurately to a two- free hormone present. site model. The dose-response relationship for a hormone generally Another explanation for curvilinear Scatchard plots is exhibits a sigmoid shape when plotted as the biological re- that occupied receptors influence the affinity of adjacent, sponse on the y-axis versus the log of the hormone con- unoccupied receptors by negative cooperativity. Accord- centration on the x-axis (Fig. 31.10). Regardless of the bio- ing to this theory, when one hormone molecule binds to its logical pathway or process being considered, cells typically receptor, it causes a decrease in the affinity of nearby un- exhibit an intrinsic basal level of activity in the absence of occupied receptors, making it more difficult for additional added hormone, even well after any previous exposure to hormone molecules to bind. The greater the amount of hormone. As the hormone concentration surrounding the hormone bound, the lower the affinity of unoccupied re- cells increases, a minimal threshold concentration must be ceptors. Therefore, as shown in Figure 31.9B, as bound hor- present before any measurable increase in the cellular re- sponse can be produced. At higher hormone concentra- tions, a maximal response by the target cell is produced, and no greater response can be elicited by increasing the A hormone concentration. The concentration of hormone re- quired to produce a response half-way between the maxi- mal and basal responses, the median effective dose or ED 50 , is a useful index of the sensitivity of the target cell Slope = -K a Bound hormone for that particular hormone (see Fig. 31.10). For some peptide hormones, the maximal response may Free hormone occur when only a small percentage (5 to 10%) of the total X-intercept = receptor population is occupied by hormone. The remain- receptor ing 90 to 95% of the receptors are called spare receptors number (R ) 0 Bound hormone Maximal response 100 B Bound hormone Biological response (percentage of maximum) -K a 1 Free hormone -K 50 a 2 R 0 1 R 0 2 Bound hormone Threshold Basal Scatchard plots of hormone-receptor bind- 0 FIGURE 31.9 ED ing data. A, A straight-line plot typical of hor- 50 mone binding to a single class of receptors. B, A curvilinear Log hormone concentration Scatchard plot typical of some hormones. Several models have been proposed to account for nonlinearity of Scatchard plots. FIGURE 31.10 A normal dose-response curve of hormone (See text for details). activity.
CHAPTER 31 Endocrine Control Mechanisms 579 because on initial inspection they do not appear necessary AB to produce a maximal response. This term is unfortunate, because the receptors are not “spare” in the sense of being unused. While at any one point in time only 5 to 10% of the receptors may be occupied, hormone-receptor interactions are an equilibrium process, and hormones continually dis- Biological response (percentage of maximum) sociate and reassociate with their receptors. Therefore, from one point in time to the next, different subsets of the total population of receptors may be occupied, but presum- ably all receptors participate equally in producing the bio- logical response. Physiological or pathophysiological alterations in target Log hormone concentration Log hormone concentration tissue responses to hormones can take one of two general FIGURE 31.11 Altered target tissue responses reflected by forms, as indicated by changes in their dose-response curves dose-response curves. A, Decreased target (Fig. 31.11). Although changes in dose-response curves are tissue responsiveness. B, Decreased target tissue sensitivity. not routinely assessed in the clinical setting, they can serve to distinguish between a receptor abnormality and a postre- ceptor abnormality in hormone action, providing useful in- formation regarding the underlying cause of a particular dis- sustained period of time typically results in a decreased num- ease state. A change in responsiveness is indicated by an ber of receptors for that hormone per cell. This phenomenon increase or decrease in the maximal response of the target is referred to as down-regulation. In the case of peptide hor- tissue and may be the result of one or more factors (Fig. mones, which have receptors on cell surfaces, a redistribution 31.11A). Altered responsiveness can be caused by a change of receptors from the cell surface to intracellular sites usually in the number of functional target cells in a tissue, by a occurs as part of the process of down-regulation. Therefore, change in the number of receptors per cell for the hormone there may be fewer total receptors per cell, and a smaller per- in question or, if receptor function itself is not rate-limiting centage may be available for hormone binding on the cell sur- for hormone action, by a change in the specific rate-limiting face. Although somewhat less prevalent than down-regula- postreceptor step in the hormone action pathway. tion, up-regulation may occur when certain conditions or A change in sensitivity is reflected as a right or left shift treatments cause an increase in receptor number compared to in the dose-response curve and, thus, a change in the ED 50; normal. Changes in rates of receptor synthesis may also con- a right shift indicates decreased sensitivity and a left shift tribute to long-term down- or up-regulation. indicates increased sensitivity for that hormone (Fig. In addition to changing receptor number, many target 31.11B). Changes in sensitivity reflect (1) an alteration in cells can regulate receptor function. Chronic exposure of receptor affinity or, if submaximal concentrations of hor- cells to a hormone may cause the cells to become less re- mone are present, (2) a change in receptor number. Dose- sponsive to subsequent exposure to the hormone by a response curves may also reflect combinations of changes process termed desensitization. If the exposure of cells to in responsiveness and sensitivity in which there is both a a hormone has a desensitizing effect on further action by right or left shift of the curve (a sensitivity change) and a that same hormone, the effect is termed homologous de- change in maximal biological response to a lower or higher sensitization. If the exposure of cells to one hormone has level (a change in responsiveness). a desensitizing effect with regard to the action of a dif- Cells can regulate their receptor number and/or function ferent hormone, the effect is termed heterologous de- in several ways. Exposing cells to an excess of hormone for a sensitization.
580 PART IX ENDOCRINE PHYSIOLOGY REVIEW QUESTIONS DIRECTIONS: Each of the numbered (E) The affinity of binding between the (D) (D Bound to cortisol receptors items or incomplete statements in this hormone and its receptor (E) Bound to corticosteroid-binding section is followed by answers or by 3. The principal mineralocorticoid in the globulin (CBG) completions of the statement. Select the body is 7. The ability of hormones to be effective ONE lettered answer or completion that is Aldosterone regulators of biological function BEST in each case. (A) Testosterone despite circulating at very low (B) Progesterone concentrations results from (A) The multiplicity of their effects (C) Prostaglandin E 2 1. A shift to the right in the biological (D) Cortisol Transport proteins activity dose-response curve for a 4. An index of the binding affinity of a (B) Pleiotropic effects hormone with no accompanying hormone for its receptor can be (C) Signal amplification change in the maximal response obtained by examining the (D) Competitive binding indicates (A) Y-intercept of a Scatchard plot (A) Decreased responsiveness and (B) Slope of a Scatchard plot SUGGESTED READING decreased sensitivity (C) Maximum point on a biological Goodman HM. Basic Medical Endocrinol- (B) Increased responsiveness dose-response curve ogy. 2nd Ed. New York: Raven, 1994. (C) Decreased sensitivity (D) X-intercept of a Scatchard plot Griffin JE, Ojeda SR, eds. Textbook of En- (D) Increased sensitivity and decreased (E) The threshold point of a biological docrine Physiology. 4th Ed. New York: responsiveness dose-response curve Oxford University Press, 2000. (E) Increased sensitivity 5. Most peptide and protein hormones Hedge GA, Colby HD, Goodman RL. 2. Within the endocrine system, are synthesized as Clinical Endocrine Physiology. specificity of communication is (A) A secretagogue Philadelphia: WB Saunders, 1987. determined by (B) A pleiotropic hormone Norman AW, Litwack G. Hormones. 2nd (A) The chemical nature of the (C) Proopiomelanocortin (POMC) Ed. San Diego: Academic Press, 1997. hormone (D) A preprohormone Scott JD, Pawson T. Cell communication: (B) The distance between the (E) Propressophysin The inside story. Sci Am endocrine cell and its target cell(s) 6. The primary form of cortisol in the 2000;282(6):72–79. (C) The presence of specific receptors plasma is that which is Wilson JD, Foster DW, Kronenberg HM, on target cells (A) Bound to albumin Larsen PR, eds. Williams Textbook of (D) Anatomical connections between (B) Bound to transthyretin Endocrinology. 9th Ed. Philadelphia: the endocrine and target cells (C) Free in solution WB Saunders, 1998.
CHAPTER The Hypothalamus 32 32 and the Pituitary Gland Robert V. Considine, Ph.D. CHAPTER OUTLINE ■ HYPOTHALAMIC-PITUITARY AXIS ■ HORMONES OF THE ANTERIOR PITUITARY ■ HORMONES OF THE POSTERIOR PITUITARY KEY CONCEPTS 1. The hypothalamic-pituitary axis is composed of the hypo- from the adrenal cortex, to comprise the hypothalamic-pi- thalamus, infundibular stalk, posterior pituitary, and ante- tuitary-adrenal axis. rior pituitary 7. ACTH secretion is regulated by glucocorticoids, physical 2. Arginine vasopressin (AVP) and oxytocin are synthesized and emotional stress, AVP, and the sleep-wake cycle. in hypothalamic neurons whose axons terminate in the 8. Hypothalamic TRH stimulates TSH release from thy- posterior pituitary. rotrophs, which, in turn, stimulates T 3 and T 4 release from 3. AVP increases water reabsorption by the kidneys in re- the thyroid follicles, to comprise the hypothalamic-pitu- sponse to a rise in blood osmolality or a fall in blood vol- itary-thyroid axis. ume. 9. TSH secretion is regulated by the thyroid hormones, cold 4. Oxytocin stimulates milk letdown in the breast in response temperatures, and the sleep-wake cycle. to suckling and muscle contraction in the uterus in re- 10. Hypothalamic GHRH increases and hypothalamic SRIF de- sponse to cervical dilation during labor. creases GH secretion from somatotrophs. 5. The hormones ACTH, TSH, GH, FSH, LH, and PRL are syn- 11. GH secretion is regulated by the GH, IGF-I, aging, deep thesized in the anterior pituitary and secreted in response sleep, stress, exercise, and hypoglycemia. to hypothalamic releasing hormones carried in the hy- 12. LHRH stimulates the secretion of FSH and LH from the an- pophyseal portal circulation. terior pituitary. These hormones, in turn, affect functions of 6. Hypothalamic CRH stimulates ACTH release from corti- the ovaries and testes. cotrophs, which, in turn, stimulates glucocorticoid release 13. Dopamine inhibits the secretion of prolactin. he pituitary gland is a complex endocrine organ that which call for changes in pituitary hormone secretion. This Tsecretes an array of peptide hormones that have im- important functional connection between the brain and the portant actions on almost every aspect of body function. pituitary, in which the hypothalamus plays a central role, is Some pituitary hormones influence key cellular processes called the hypothalamic-pituitary axis. involved in preserving the volume and composition of body fluids. Others bring about changes in body function, which enable the individual to grow, reproduce, and re- HYPOTHALAMIC-PITUITARY AXIS spond appropriately to stress and trauma. The pituitary hormones produce these physiological effects by either The human pituitary is composed of two morphologically acting directly on their target cells or stimulating other en- and functionally distinct glands connected to the hypo- docrine glands to secrete hormones, which, in turn, bring thalamus. The pituitary gland or hypophysis is located at about changes in body function. the base of the brain and is connected to the hypothalamus Stimuli that affect the secretion of pituitary hormones by a stalk. It sits in a depression in the sphenoid bone of may originate within or outside the body. These stimuli are the skull called the sella turcica. The two morphologically perceived and processed by the brain, which signals the pi- and functionally distinct glands comprising the human pi- tuitary gland to increase or decrease the rate of secretion of tuitary are the adenohypophysis and the neurohypophysis a particular hormone. Thus, the brain links the pituitary (Fig. 32.1). The adenohypophysis consists of the pars tu- gland to events occurring within or outside the body, beralis, which forms the outer covering of the pituitary 581
582 PART IX ENDOCRINE PHYSIOLOGY Neurohypophysis Adenohypophysis mone are then released into the nearby capillary circulation, from which they are carried into the systemic circulation. Median eminence Pars Pars tuberalis distalis (anterior lobe) Anterior Pituitary Hormones Are Synthesized Infundibular and Secreted in Response to Hypothalamic stem Releasing Hormones Carried in the Hypophyseal Portal Circulation Infundibular The anterior lobe contains clusters of histologically distinct process (posterior lobe) types of cells closely associated with blood sinusoids that drain into the venous circulation. These cells produce ante- rior pituitary hormones and secrete them into the blood si- Pars nusoids. The six well-known anterior pituitary hormones intermedia are produced by separate kinds of cells. Adrenocorti- A midsagittal section of the human pituitary cotropic hormone (ACTH), also known as corticotropin, FIGURE 32.1 gland. is secreted by corticotrophs, thyroid-stimulating hormone (TSH) by thyrotrophs, growth hormone (GH) by soma- totrophs, prolactin (PRL) by lactotrophs, and follicle- stalk, and the pars distalis or anterior lobe. The neurohy- stimulating hormone (FSH) and luteinizing hormone (LH) pophysis is composed of the median eminence of the hy- by gonadotrophs. pothalamus, the infundibular stem, which forms the inner The cells that produce anterior pituitary hormones are part of the stalk, and the infundibular process or posterior not innervated and, therefore, are not under direct neural lobe. In most vertebrates, the pituitary contains a third control. Rather, their secretory activity is regulated by re- anatomically distinct lobe, the pars intermedia or interme- leasing hormones, also called hypophysiotropic hor- diate lobe. In adult humans, only a vestige of the interme- mones, synthesized by neural cell bodies in the hypothal- diate lobe is found as a thin diffuse region of cells between amus. Granules containing releasing hormones are stored the anterior and posterior lobes. in the axon terminals of these neurons, located in capillary The adenohypophysis and neurohypophysis have dif- networks in the median eminence of the hypothalamus ferent embryological origins. The adenohypophysis is and lower infundibular stem. These capillary networks formed from an evagination of the oral ectoderm called give rise to the principal blood supply to the anterior lobe Rathke’s pouch. The neurohypophysis forms as an exten- of the pituitary. sion of the developing hypothalamus, which fuses with The blood supply to the anterior pituitary is shown in Rathke’s pouch as development proceeds. The posterior Figure 32.2. Arterial blood is brought to the hypothalamic- lobe is, therefore, composed of neural tissue and is a func- pituitary region by the superior and inferior hypophyseal tional part of the hypothalamus. arteries. The superior hypophyseal arteries give rise to a rich capillary network in the median eminence. The capil- laries converge into long veins that run down the pituitary Posterior Pituitary Hormones Are Synthesized stalk and empty into the blood sinusoids in the anterior by Hypothalamic Neurons Whose Axons lobe. They are considered to be portal veins because they Terminate in the Posterior Lobe deliver blood to the anterior pituitary rather than joining the venous circulation that carries blood back to the heart; The infundibular stem of the pituitary gland contains bun- therefore, they are called long hypophyseal portal vessels. dles of nonmyelinated nerve fibers, which terminate on the The inferior hypophyseal arteries provide arterial blood to capillary bed in the posterior lobe. These fibers are the axons the posterior lobe. They also penetrate into the lower in- of neurons that originate in the supraoptic nuclei and par- fundibular stem, where they form another important capil- aventricular nuclei of the hypothalamus. The cell bodies of lary network. The capillaries of this network converge into these neurons are large compared to those of other hypo- short hypophyseal portal vessels, which also deliver blood thalamic neurons; hence, they are called magnocellular neu- into the sinusoids of the anterior pituitary. The special rons. The hormones arginine vasopressin (AVP) and oxy- blood supply to the anterior lobe of the pituitary gland is tocin are synthesized as parts of larger precursor proteins known as the hypophyseal portal circulation. (prohormones) in the cell bodies of these neurons. Prohor- When a neurosecretory neuron is stimulated to secrete, mones are then packaged into granules and enzymatically the releasing hormone is discharged into the hypophyseal processed to produce AVP and oxytocin. The granules are portal circulation (see Fig. 32.2). Releasing hormones travel transported down the axons by axoplasmic flow; they accu- only a short distance before they come in contact with their mulate at the axon terminals in the posterior lobe. target cells in the anterior lobe. Only the amount of releas- Stimuli for the secretion of posterior lobe hormones may ing hormone needed to control anterior pituitary hormone be generated by events occurring within or outside the secretion is delivered to the hypophyseal portal circulation body. These stimuli are processed by the central nervous by neurosecretory neurons. Consequently, releasing hor- system (CNS), and the signal for the secretion of AVP or mones are almost undetectable in systemic blood. oxytocin is then transmitted to neurosecretory neurons in A releasing hormone either stimulates or inhibits the the hypothalamus. Secretory granules containing the hor- synthesis and secretion of a particular anterior pituitary
CHAPTER 32 The Hypothalamus and the Pituitary Gland 583 M hormone. Corticotropin-releasing hormone (CRH), thy- rotropin-releasing hormone (TRH), and growth hor- 2 Hypothalamus mone-releasing hormone (GHRH) stimulate the secretion Third and synthesis of ACTH, TSH, and GH, respectively ventricle (Table 32.1). Luteinizing hormone-releasing hormone 1 (LHRH), also known as gonadotropin-releasing hormone Superior (GnRH), stimulates the synthesis and release of FSH and hypophyseal LH. In contrast, somatostatin, also called somatotropin artery release inhibiting factor (SRIF), inhibits GH secretion. All Median of the releasing hormones are peptides, with the exception eminence of dopamine, which is a catecholamine that inhibits the Long portal synthesis and secretion of PRL. Releasing hormones can be Stalk vessels produced synthetically, and several are currently under Anterior study for use in the diagnosis and treatment of diseases of lobe the endocrine system. For example, synthetic GnRH is Posterior Hormone- now used for treating infertility in women. lobe secreting cell Releasing hormones are secreted in response to neural inputs from other areas of the CNS. These signals are gen- Hormone Hormone erated by external events that affect the body or by changes occurring within the body itself. For example, sensory nerve excitation, emotional or physical stress, biological rhythms, changes in sleep patterns or in the sleep-wake cy- cle, and changes in circulating levels of certain hormones or metabolites all affect the secretion of particular anterior pi- Vein Short portal Vein tuitary hormones. Signals generated in the CNS by such vessels events are transmitted to the neurosecretory neurons in the Inferior hypothalamus. Depending on the nature of the event and hypophyseal the signal generated, the secretion of a particular releasing artery hormone may be either stimulated or inhibited. In turn, this response affects the rate of secretion of the appropriate an- terior pituitary hormone. The neural pathways involved in The blood supply to the anterior pituitary. FIGURE 32.2 transmitting these signals to the neurosecretory neurons in This illustration shows the relationship of the hypothalamic magnocellular neurons and hypothalamic neurose- the hypothalamus are not well defined. cretory cells that produce releasing hormones to the pituitary blood vessels. M represents a magnocellular neuron releasing AVP or oxytocin at its axon terminals into capillaries that give HORMONES OF THE POSTERIOR PITUITARY rise to the venous drainage of the posterior lobe. Neurons 1 and 2 are secreting releasing factors into capillary networks that give Arginine vasopressin (AVP), also known as ADH, antidi- rise to the long and short hypophyseal portal vessels, respec- uretic hormone, and oxytocin are produced by magnocel- tively. Releasing hormones are shown reaching the hormone-se- lular neurons in the supraoptic and paraventricular nuclei of creting cells of the anterior lobe via the portal vessels. the hypothalamus. Individual neurons make either AVP or TABLE 32.1 Hypothalamic Releasing Hormones Hormone Chemistry Actions on Anterior Pituitary Corticotropin-releasing hormone (CRH) Single chain of 41 amino acids Stimulates ACTH secretion by corticotrophs; stimulates expression of POMC gene in corticotrophs Thyrotropin-releasing hormone (TRH) Peptide of 3 amino acids Stimulates TSH secretion by thyrotrophs; stimulates expression of genes for and subunits of TSH in thyrotrophs; stimulates PRL synthesis by lactotrophs Growth hormone-releasing hormone (GHRH) Two forms in human: Stimulates GH secretion by somatotrophs; single chain of 44 amino acids, stimulates expression of GH gene in single chain of 40 amino acids somatotrophs Luteinizing hormone-releasing hormone (LHRH), Single chain of 10 amino acids Stimulates FSH and LH secretion by gonadotropin-releasing hormone (GnRH) gonadotrophs Somatostatin, somatotropin release inhibiting Single chain of 14 amino acids Inhibits GH secretion by somatotrophs; factor (SRIF) inhibits TSH secretion by thyrotrophs Dopamine Catecholamine Inhibits PRL synthesis and secretion by lactotrophs
584 PART IX ENDOCRINE PHYSIOLOGY AVP NP-II GP tion and the formation of osmotically concentrated urine (see Chapter 23). This action of AVP works to counteract the conditions that stimulate its secretion. For example, re- Proteolytic cleavage ducing water loss in the urine limits a further rise in the os- molality of the blood and conserves blood volume. Low blood AVP levels lead to diabetes insipidus and the exces- AVP + NP-II + GP sive production of dilute urine (see Chapter 24). The structural organization and proteolytic FIGURE 32.3 processing of AVP from its prohormone. Oxytocin Stimulates the Contraction of Smooth AVP, arginine vasopressin; NP-II, neurophysin II; GP, glycoprotein. Muscle in the Mammary Glands and Uterus Two physiological signals stimulate the secretion of oxy- tocin by hypothalamic magnocellular neurons. Breast-feed- oxytocin, but not both. The axons of these neurons form ing stimulates sensory nerves in the nipple. Afferent nerve the infundibular stem and terminate on the capillary net- impulses enter the CNS and eventually stimulate oxytocin- work in the posterior lobe, where they discharge AVP and secreting magnocellular neurons. These neurons fire in oxytocin into the systemic circulation. synchrony and release a bolus of oxytocin into the blood- AVP and oxytocin are closely related small peptides, stream. Oxytocin stimulates the contraction of myoepithe- each consisting of nine amino acid residues. Two forms of lial cells, which surround the milk-laden alveoli in the lac- vasopressin, one containing arginine and the other con- tating mammary gland, aiding in milk ejection. taining lysine, are made by different mammals. Arginine va- Oxytocin secretion is also stimulated by neural input sopressin is made in humans. Although AVP and oxytocin from the female reproductive tract during childbirth. Cer- differ by only two amino acid residues, the structural dif- vical dilation before the beginning of labor stimulates ferences are sufficient to give these two molecules very dif- stretch receptors in the cervix. Afferent nerve impulses pass ferent hormonal activities. They are similar enough, how- through the CNS to oxytocin-secreting neurons. Oxytocin ever, for AVP to have slight oxytocic activity and for release stimulates the contraction of smooth muscle cells in oxytocin to have slight antidiuretic activity. the uterus during labor, aiding in the delivery of the new- The genes for AVP and oxytocin are located near one born and placenta. The actions of oxytocin on the mam- another on chromosome 20. They code for much larger mary glands and the female reproductive tract are discussed prohormones that contain the amino acid sequences for further in Chapter 39. AVP or oxytocin and for a 93-amino acid peptide called neurophysin (Fig. 32.3). The neurophysin coded by the AVP gene has a slightly different structure than that coded by the oxytocin gene. Neurophysin is important in the pro- HORMONES OF THE ANTERIOR PITUITARY cessing and secretion of AVP, and mutations in the neuro- The anterior pituitary secretes six protein hormones, all of physin portion of the AVP gene are associated with central which are small, ranging in molecular size from 4.5 to 29 diabetes insipidus, a condition in which AVP secretion is kDa. Their chemical and physiological features are given in impaired. Prohormones for AVP and oxytocin are synthe- Table 32.2. sized in the cell bodies of magnocellular neurons and trans- Four of the anterior pituitary hormones have effects on ported in secretory granules to axon terminals in the poste- the morphology and secretory activity of other endocrine rior lobe, as described earlier. During the passage of the glands; they are called tropic (Greek meaning “to turn to”) or granules from the Golgi apparatus to axon terminals, pro- trophic (“to nourish”) hormones. For example, ACTH main- hormones are cleaved by proteolytic enzymes to produce tains the size of certain cells in the adrenal cortex and stim- AVP or oxytocin and their associated neurophysins. ulates these cells to synthesize and secrete glucocorticoids, When magnocellular neurons receive neural signals for the hormones cortisol and corticosterone. Similarly, TSH AVP or oxytocin secretion, action potentials are gener- maintains the size of the cells of the thyroid follicles and ated in these cells, triggering the release of AVP or oxy- stimulates these cells to produce and secrete the thyroid tocin and neurophysin from the axon terminals. These hormones thyroxine (T 4 ) and triiodothyronine (T 3 ). The substances diffuse into nearby capillaries and then enter two other tropic hormones, FSH and LH, are called go- the systemic circulation. nadotropins because both act on the ovaries and testes. FSH stimulates the development of follicles in the ovaries and regulates the process of spermatogenesis in the testes. AVP Increases the Reabsorption of LH causes ovulation and luteinization of the ovulated Water by the Kidneys graafian follicle in the ovary of the human female and stim- Two physiological signals, a rise in the osmolality of the ulates the production of the female sex hormones estrogen blood and a decrease in blood volume, generate the CNS and progesterone by the ovary. In the male, LH stimulates stimulus for AVP secretion. Chemical mediators of AVP re- the Leydig cells of the testis to produce and secrete the lease include catecholamines, angiotensin II, and atrial na- male sex hormone, testosterone. triuretic peptide (ANP). The main physiological action of The two remaining anterior pituitary hormones, GH AVP is to increase water reabsorption by the collecting and PRL, are not usually thought of as tropic hormones be- ducts of the kidneys. The result is decreased water excre- cause their main target organs are not human endocrine
CHAPTER 32 The Hypothalamus and the Pituitary Gland 585 TABLE 32.2 Hormones of the Anterior Pituitary Hormone Chemistry Physiological Actions Adrenocorticotropic hormone (ACTH, Single chain of 39 amino acids 4.5 kDa Stimulates production of glucocorticoids and corticotropin) androgens by adrenal cortex; maintains size of zona fasciculata and zona reticularis of cortex Thyroid-stimulating hormone Glycoprotein having two subunits, Stimulates production of thyroid hormones, (TSH, thyrotropin) and ; 28 kDa T 4 and T 3, by thyroid follicular cells; maintains size of follicular cells Growth hormone (GH, somatotropin) Single chain of 191 amino acids; Stimulates postnatal body growth; stimulates 22 kDa triglyceride lipolysis; inhibits insulin action on carbohydrate and lipid metabolism Follicle-stimulating hormone (FSH) Glycoprotein having two subunits, Stimulates development of ovarian follicles; and ; 28–29 kDa regulates spermatogenesis in testes Luteinizing hormone (LH) Glycoprotein having two subunits, Causes ovulation and formation of corpus and ; 28–29 kDa luteum in ovaries; stimulates production of estrogen and progesterone by ovaries; stimulates testosterone production by testes Prolactin (PRL) Single chain of 199 amino acids Essential for milk production by lactating mammary glands glands. As discussed later, however, these two hormones zymes involved in steroidogenesis. It also maintains the have certain effects that can be regarded as “tropic.” The size and functional integrity of the cells of the zona fascic- main physiological action of GH is its stimulatory effect on ulata and zona reticularis. ACTH is not an important regu- the growth of the body during childhood. In humans, PRL lator of aldosterone synthesis and secretion. is essential for the synthesis of milk by the mammary glands The actions of ACTH on glucocorticoid synthesis and during lactation. secretion and details about the physiological effects of glu- The following discussion focuses on ACTH, TSH, and cocorticoids are described in Chapter 34. GH. Regulation of the secretion of the gonadotropins and PRL, and descriptions of their actions, are given in greater The Structure and Synthesis of ACTH. ACTH, the small- detail in Chapters 37 to 39. est of the six anterior pituitary hormones, consists of a single chain of 39 amino acids and has a molecular size of 4.5 kDa. ACTH is synthesized in corticotrophs as part of a larger 30- ACTH Regulates the Function of the kDa prohormone called proopiomelanocortin (POMC). Adrenal Cortex Enzymatic cleavage of POMC in the anterior pituitary re- The adrenal cortex produces the glucocorticoid hormones, sults in ACTH, an amino terminal protein, and -lipotropin cortisol and corticosterone, in the cells of its two inner (Fig. 32.4). -Lipotropin has effects on lipid metabolism, but zones, the zona fasciculata and the zona reticularis. These its physiological function in humans has not been estab- cells also synthesize androgens or male sex hormones, with the main androgen being dehydroepiandrosterone. Glucocorticoids act on many processes, mainly by alter- ing gene transcription and, thereby, changing the protein composition of their target cells. Glucocorticoids permit metabolic adaptations during fasting, which prevent the development of hypoglycemia or low blood glucose level. They also play an essential role in the body’s response to physical and emotional stress. Other actions of glucocorti- coids include their inhibitory effect on inflammation, their ability to suppress the immune system, and their regulation of vascular responsiveness to norepinephrine. Aldosterone, the other physiologically important hor- mone made by the adrenal cortex, is produced by the cells of the outer zone of the cortex, the zona glomerulosa. It acts to stimulate sodium reabsorption by the kidneys. Adrenocorticotropic hormone (ACTH) is the physio- logical regulator of the synthesis and secretion of gluco- corticoids by the zona fasciculata and zona reticularis. The proteolytic processing of proopiome- ACTH stimulates the synthesis of these steroid hormones FIGURE 32.4 lanocortin (POMC) by the human corti- and promotes the expression of the genes for various en- cotroph. -LPH, -lipotropin.
586 PART IX ENDOCRINE PHYSIOLOGY lished. Although POMC can be cleaved into other peptides, Corticotroph such as -endorphin, only ACTH and -lipotropin are pro- duced from POMC in the human corticotroph. Proteolytic processing of POMC occurs after it is packaged into secre- tory granules. Therefore, when the corticotroph receives a signal to secrete, ACTH and -lipotropin are released into the bloodstream in a 1:1 molar ratio. POMC is also synthesized by cells of the intermediate lobe of the pituitary gland and neurons in the hypothala- mus. In the intermediate lobe, the ACTH sequence of POMC mRNA POMC is cleaved to release a small peptide, -melanocyte- cAMP PKA P proteins stimulating hormone (-MSH), and, therefore, very little ATP ACTH is produced. -MSH acts in lower vertebrates to AC produce temporary changes in skin color by causing the dispersion of melanin granules in pigment cells. As noted G s earlier, the adult human has only a vestigial intermediate lobe and does not produce and secrete significant amounts CRH POMC of -MSH or other hormones derived from POMC. How- ever, because ACTH contains the -MSH amino acid se- quence at its N-terminal end, it has melanocyte-stimulating Secretory activity when present in the blood at high concentrations. granules Humans who have high blood levels of ACTH, as a result of Addison’s disease or an ACTH-secreting tumor are of- ten hyperpigmented. In the hypothalamus, -MSH is im- portant in the regulation of feeding behavior. ACTH β-LPH CRH and ACTH Synthesis and Secretion. Corticotropin- FIGURE 32.5 The main actions of corticotropin-releasing releasing hormone is the main physiological regulator of hormone (CRH) on a corticotroph. CRH ACTH secretion and synthesis. In humans, CRH consists binds to membrane receptors that are coupled to adenylyl cyclase of 41 amino acid residues in a single peptide chain. (AC) by stimulatory G proteins (G s ). Adenylyl cyclase is stimulated, CRH is synthesized in the paraventricular nuclei of the hy- and cAMP rises in the cell. cAMP activates protein kinase A (PKA), which then phosphorylates proteins (P proteins) involved in stimu- pothalamus by a group of neurons with small cell bodies, lating ACTH secretion and the expression of the POMC gene. called parvicellular neurons. The axons of parvicellular neu- rons terminate on capillary networks that give rise to hy- pophyseal portal vessels. Secretory granules containing CRH duces the rate of secretion of glucocorticoids by the adre- are stored in the axon terminals of these cells. Upon receiving nal cortex. If the blood glucocorticoid level begins to fall the appropriate stimulus, these cells secrete CRH into the for some reason, this negative-feedback effect is reduced, capillary network; CRH enters the hypophyseal portal circu- stimulating ACTH secretion and restoring the blood glu- lation and is delivered to the anterior pituitary gland. cocorticoid level. This interactive relationship is called the CRH binds to receptors on the plasma membranes of hypothalamic-pituitary-adrenal axis (Fig. 32.6). This con- corticotrophs. These receptors are coupled to adenylyl cy- trol loop ensures that the level of glucocorticoids in the clase by stimulatory G proteins. The binding of CRH to its blood remains relatively stable in the resting state, although receptor increases the activity of adenylyl cyclase, which there is a diurnal variation in glucocorticoid secretion. As catalyzes the formation of cAMP from ATP (Fig. 32.5). The discussed later, physical and emotional stress can alter the rise in cAMP concentration in the corticotroph activates mechanism regulating glucocorticoid secretion. protein kinase A (PKA), which then phosphorylates cell The negative-feedback effect of glucocorticoids on proteins. PKA-mediated protein phosphorylation stimu- ACTH secretion results from actions on both the hypo- lates the corticotroph to secrete ACTH and -lipotropin thalamus and the corticotroph (see Fig. 32.6). When the by unknown mechanisms. concentration of glucocorticoids rises in the blood, CRH Increased cAMP production in the corticotroph by secretion from the hypothalamus is inhibited. As a result, CRH also stimulates expression of the gene for POMC, in- the stimulatory effect of CRH on the corticotroph is re- creasing the level of POMC mRNA in these cells (see duced and the rate of ACTH secretion falls. Glucocorti- Fig. 32.5). Thus, CRH not only stimulates ACTH secretion coids act directly on parvicellular neurons to inhibit CRH but also maintains the capacity of the corticotroph to syn- release, and indirectly through neurons in the hippocampus thesize the precursor for ACTH. that project to the hypothalamus, to affect the activity of parvicellular neurons. At the corticotroph, glucocorticoids Glucocorticoids and ACTH Synthesis and Secretion. A inhibit the actions of CRH to stimulate ACTH secretion. rise in glucocorticoid concentration in the blood resulting If the blood concentration of glucocorticoids remains from the action of ACTH on the adrenal cortex inhibits the high for a long period of time, expression of the gene for secretion of ACTH. Thus, glucocorticoids have a negative- POMC is inhibited. As a result, the amount of POMC feedback effect on ACTH secretion, which, in turn, re- mRNA falls in the corticotroph, and gradually the produc-
CHAPTER 32 The Hypothalamus and the Pituitary Gland 587 secretion is increased. As a result, the blood level of gluco- corticoids rises rapidly. Regardless of the blood glucocorti- coid concentration, stress stimulates the hypothalamic-pi- tuitary-adrenal axis because stress-induced neural activity generated at higher CNS levels stimulates parvicellular neurons in the paraventricular nuclei to secrete CRH at a greater rate. Thus, stress can override the normal operation of the hypothalamic-pituitary-adrenal axis. If the stress per- sists, the blood glucocorticoid level remains high because the glucocorticoid negative-feedback mechanism functions at a higher set point. AVP and ACTH Secretion. Glucocorticoid deficiency and certain types of stress also increase the concentration of arginine vasopressin (AVP) in hypophyseal portal blood. The physiological significance is that AVP, like CRH, can stimulate corticotrophs to secrete ACTH. Acting along with CRH, AVP amplifies the stimulatory effect of CRH on ACTH secretion. AVP interacts with a specific receptor on the plasma membrane of the corticotroph. These receptors are cou- The hypothalamic-pituitary-adrenal axis. FIGURE 32.6 pled to the enzyme phospholipase C (PLC) by G pro- The negative-feedback actions of glucocorti- teins. The interaction of AVP with its receptor activates coids on the corticotroph and the hypothalamus are indicated by PLC, which, in turn, hydrolyzes phosphatidylinositol 4,5- dashed lines. bisphosphate (PIP 2 ) present in the plasma membrane. This generates the intracellular second messengers inosi- tol trisphosphate (IP 3 ) and diacylglycerol (DAG). IP 3 tion of ACTH and the other POMC peptides declines as mobilizes intracellular calcium stores and DAG activates well. Since CRH stimulates POMC gene expression and the phospholipid- and calcium-dependent protein kinase glucocorticoids inhibit CRH secretion, glucocorticoids in- C (PKC) to mediate the stimulatory effect of AVP on hibit POMC gene expression, in part, by suppressing CRH ACTH secretion. secretion. Glucocorticoids also act directly in the corti- As noted earlier, AVP and oxytocin are produced by cotroph itself to suppress POMC gene expression. magnocellular neurons of the supraoptic and paraventricu- The negative-feedback actions of glucocorticoids are es- lar nuclei of the hypothalamus. These neurons terminate in sential for the normal operation of the hypothalamic-pitu- the posterior lobe, where they secrete AVP and oxytocin itary-adrenal axis. This relationship is vividly illustrated by into capillaries that feed into the systemic circulation. the disturbances that occur when blood glucocorticoid lev- However, parvicellular neurons in the paraventricular nu- els are changed drastically by disease or glucocorticoid ad- clei also produce AVP, which they secrete into hypophy- ministration. For example, if an individual’s adrenal glands seal portal blood. It appears that much of the AVP secreted have been surgically removed or damaged by disease (e.g., by parvicellular neurons is made in the same cells that pro- Addison’s disease), the resulting lack of glucocorticoids al- duce CRH. It is assumed that the AVP in hypophyseal por- lows corticotrophs to secrete large amounts of ACTH. As tal blood comes from these cells and from a small number noted earlier, this response may result in hyperpigmenta- of AVP-producing magnocellular neurons whose axons tion as a result of the melanocyte-stimulating activity of pass through the median eminence of the hypothalamus on ACTH. Individuals with glucocorticoid deficiency caused their way to the posterior lobe. by inherited genetic defects affecting enzymes involved in steroid hormone synthesis by the adrenal cortex have high The Sleep-Wake Cycle and ACTH Secretion. Under nor- blood ACTH levels from the absence of the lack of the mal circumstances, the hypothalamic-pituitary-adrenal axis negative-feedback effects of glucocorticoids on ACTH se- in humans functions in a pulsatile manner, resulting in sev- cretion. Because a high blood concentration of ACTH eral bursts of secretory activity over a 24-hour period. This causes hypertrophy of the adrenal glands, these genetic dis- pattern appears to be due to rhythmic activity in the CNS, eases are collectively called congenital adrenal hyperplasia which causes bursts of CRH secretion and, in turn, bursts of (see Chapter 34). By contrast, in individuals treated chron- ACTH and glucocorticoid secretion (Fig. 32.7). A diurnal ically with large doses of glucocorticoids, the adrenal cor- oscillation in secretory activity of the axis is thought to be tex atrophies because the high level of glucocorticoids in due to changes in the sensitivity of CRH-producing neu- the blood inhibits ACTH secretion, resulting in the loss of rons to the negative-feedback action of glucocorticoids, al- its trophic influence on the adrenal cortex. tering their rate of CRH secretion. As a result, there is a di- urnal oscillation in the rate of ACTH and glucocorticoid Stress and ACTH Secretion. The hypothalamic-pitu- secretion. This circadian rhythm is reflected in the daily itary-adrenal axis is greatly influenced by stress. When an pattern of glucocorticoid secretion. In individuals who are individual experiences physical or emotional stress, ACTH awake during the day and sleep at night, the blood gluco-
588 PART IX ENDOCRINE PHYSIOLOGY 200 40 180 35 160 30 Plasma ACTH ( ) (pg/mL) 120 25 Plasma glucocorticoids( ) (µg/100mL) FIGURE 32.7 ACTH secretion and the sleep-wake cy- 140 100 20 80 15 cle. Pulsatile changes in the concentrations 60 over a 24-hour period. Note that the amplitude of the pulses in 40 10 of ACTH and glucocorticoids in the blood of a young woman ACTH and glucocorticoids is lower during the evening hours 20 5 and increases greatly during the early morning hours. This pat- Sleep tern is due to the diurnal oscillation of the hypothalamic-pitu- 0 0 itary-adrenal axis. (Modified from Krieger DT. Rhythms in Noon 4 PM 8 PM Mid- 4 AM 8 AM Noon CRF, ACTH and corticosteroids. In: Krieger DT, ed. En- night docrine Rhythms. New York: Raven, 1979.) corticoid level begins to rise during the early morning Neither subunit has significant TSH activity by itself. The hours, reaches a peak sometime before noon, and then falls two subunits must be combined in a 1:1 ratio to form an ac- gradually to a low level around midnight (see Fig. 32.7). tive hormone. The gonadotropins FSH and LH are also This pattern is reversed in individuals who sleep during the composed of two noncovalently combined subunits. The day and are awake at night. This inherent biological subunits of TSH, FSH, and LH are derived from the same rhythm is superimposed on the normal operation of the hy- gene and are identical, but the subunit gives each hor- pothalamic-pituitary-adrenal axis. mone its particular set of physiological activities. Thyrotrophs synthesize the peptide chains of the and subunits of TSH from separate mRNA molecules, which TSH Regulates the Function of the Thyroid Gland are transcribed from two different genes. The peptide The thyroid gland is composed of aggregates of follicles, chains of the and subunits are combined and undergo which are formed from a single layer of cells. The follicular glycosylation in the rough ER. These processes are com- cells produce and secrete thyroxine (T 4 ) and triiodothyro- pleted as TSH molecules pass through the Golgi apparatus nine (T 3 ), thyroid hormones that are iodinated derivatives and are packaged into secretory granules. Normally, thy- of the amino acid tyrosine. The thyroid hormones act on rotrophs make more subunits than subunits. As a result, many cells by changing the expression of certain genes, secretory granules contain excess subunits. When a thy- changing the capacity of their target cells to produce par- rotroph is stimulated to secrete TSH, it releases both TSH ticular proteins. These changes are thought to bring about and free subunits into the bloodstream. In contrast, very the important actions of the thyroid hormones on the dif- little free TSH subunit is in the blood. ferentiation of the CNS, on body growth, and on the path- ways of energy and intermediary metabolism. TRH and TSH Synthesis and Secretion. Thyrotropin-re- Thyroid-stimulating hormone (TSH) is the physiologi- leasing hormone (TRH) is the main physiological stimula- cal regulator of T 4 and T 3 synthesis and secretion by the tor of TSH secretion and synthesis by thyrotrophs. TRH is thyroid gland. It also promotes nucleic acid and protein a small peptide consisting of three amino acid residues pro- synthesis in the cells of the thyroid follicles, maintaining duced by neurons in the hypothalamus. These neurons ter- their size and functional integrity. The actions of TSH on minate on the capillary networks that give rise to the hy- thyroid hormone synthesis and secretion, and the physio- pophyseal portal vessels. Normally, these neurons secrete logical effects of the thyroid hormones, are described in de- TRH into the hypophyseal portal circulation at a constant tail in Chapter 33. or tonic rate. It is assumed that the TRH concentration in the blood that perfuses the thyrotrophs does not change The Structure and Synthesis of TSH. TSH is a glyco- greatly; therefore, the thyrotrophs are continuously ex- protein consisting of two structurally different subunits. posed to TRH. The subunit of human TSH is a single peptide chain of TRH binds to receptors on the plasma membranes of thy- 92 amino acid residues with two carbohydrate chains rotrophs. These receptors are coupled to PLC by G proteins linked to its structure. The subunit is a single peptide (Fig. 32.8). The interaction of TRH with its receptor acti- chain of 112 amino acid residues, to which a single carbo- vates PLC, causing the hydrolysis of PIP 2 in the membrane. hydrate chain is linked. The and subunits are held to- This action releases the intracellular messengers IP 3 and gether by noncovalent bonds. The two subunits combined DAG. IP 3 causes the concentration of Ca 2 in the cytosol to give the TSH molecule a molecular weight of about 28,000. rise, which stimulates the secretion of TSH into the blood.
CHAPTER 32 The Hypothalamus and the Pituitary Gland 589 Thyrotroph Hypothalamus - + TRH (+) SRIF (-) 2+ Nucleus Ca Thyrotroph Ca 2+ Ca 2+ Ca 2+ TSHα,β mRNA TRH TSH (+) Gq IP Ca 2+ TSHα,β Thyroid 3 - PLC follicles PIP TSH 2 Thyroid hormones DAG PKC P proteins The hypothalamic-pituitary-thyroid axis. FIGURE 32.9 Secretory TRH stimulates and somatostatin (SRIF) in- granules hibits TSH release by acting directly on the thyrotroph. The neg- ative-feedback loops (-), shown in red, inhibit TRH secretion and action on the thyrotroph, causing a decrease in TSH secretion. The feedback loops (), shown in gray, stimulate somatostatin TSH secretion, causing a decrease in TRH secretion. SRIF, somato- statin, or somatotropin release inhibiting factor. The actions of TRH on a thyrotroph. TRH FIGURE 32.8 binds to membrane receptors, which are cou- pled to phospholipase C (PLC) by G proteins (G q ). PLC hy- drolyzes phosphatidylinositol 4,5-bisphosphate (PIP 2) in the lease. The thyroid hormones also increase the release of so- plasma membrane, generating inositol trisphosphate (IP 3) and di- matostatin from the hypothalamus. Somatostatin (SRIF) in- 2 acylglycerol (DAG). IP 3 mobilizes intracellular stores of Ca . hibits the release of TSH from the thyrotroph (see Fig. The rise in Ca 2 stimulates TSH secretion. Ca 2 and DAG acti- 32.9). In the pituitary, thyroid hormones reduce the sensi- vate protein kinase C (PKC), which phosphorylates proteins (P tivity of the thyrotroph to TRH and inhibit TSH synthesis. proteins) involved in stimulating TSH secretion and the expres- The negative-feedback effects of the thyroid hormones sion of the genes for the and subunits of TSH. on thyrotrophs are produced primarily through the actions of T 3 . Both T 4 and T 3 circulate in the blood bound to plasma proteins, with only a small percentage (less than The rise in cytosolic Ca 2 and the increase in DAG activate 1%) unbound or free (see Chapter 33). The free T 4 and T 3 PKC in thyrotrophs. PKC phosphorylates proteins that are molecules are taken up by thyrotrophs, and T 4 is converted in some way involved in stimulating TSH secretion. to T 3 by the enzymatic removal of one iodine atom. The TRH also stimulates the expression of the genes for the newly formed T 3 molecules and those taken up directly and subunits of TSH (see Fig. 32.8). As a result, the amount from the blood enter the nucleus, where they bind to thy- of mRNA for the and subunits is maintained in the thy- roid hormone receptors in the chromatin. The interaction rotroph and the production of TSH is fairly constant. of T 3 with its receptors changes the expression of specific genes in the thyrotroph, which decreases the cell’s ability Thyroid Hormones and TSH Synthesis and Secretion. to produce and secrete TSH. For example, T 3 inhibits the The thyroid hormones exert a direct negative-feedback ef- expression of the genes for the and subunits of TSH, fect on TSH secretion. For example, when the blood con- directly decreasing the synthesis of TSH. Also, T 3 influ- centration of thyroid hormones is high, the rate of TSH se- ences the expression of other unidentified genes that code cretion falls. In turn, the stimulatory effect of TSH on the for proteins that decrease thyrotroph sensitivity to TRH. follicular cells of the thyroid is reduced, resulting in a de- The loss in sensitivity is thought to be partly due to a re- crease in T 4 and T 3 secretion. However, when the circulat- duction in the number of TRH receptors in thyrotroph ing levels of T 4 and T 3 are low, their negative-feedback ef- plasma membranes. fect on TSH release is reduced and more TSH is secreted from thyrotrophs, increasing the rate of thyroid hormone Other Factors Affecting TSH Secretion. The exposure of secretion. This control system is part of the hypothalamic- certain animals to a cold environment stimulates TSH se- pituitary-thyroid axis (Fig. 32.9). cretion. This makes sense from a physiological perspective The thyroid hormones exert negative-feedback effects because the thyroid hormones are important in regulating on both the hypothalamus and the pituitary. In the hypo- body heat production (see Chapter 33). Brief exposure of thalamic TRH-secreting neurons, thyroid hormones reduce experimental animals to a cold environment stimulates the TRH mRNA and TRH prohormone to decrease TRH re- secretion of TSH, presumably a result of enhanced TRH se-
590 PART IX ENDOCRINE PHYSIOLOGY cretion. Newborn humans behave much the same way, in Human GHRH is a peptide composed of a single chain that they respond to brief cold exposure with an increase in of 44 amino acid residues. A slightly smaller version of TSH secretion. This response to cold does not occur in GHRH consisting of 40 amino acid residues is also present adult humans. in humans. GHRH is synthesized in the cell bodies of neu- The hypothalamic-pituitary-thyroid axis, like the hypo- rons in the arcuate nuclei and ventromedial nuclei of the thalamic-pituitary-adrenal axis, follows a diurnal circadian hypothalamus. The axons of these cells project to the cap- rhythm in humans. Peak TSH secretion occurs in the early illary networks giving rise to the portal vessels. When these morning and a low point is reached in the evening. Physi- neurons receive a stimulus for GHRH secretion, they dis- cal and emotional stress can alter TSH secretion but the ef- charge GHRH from their axon terminals into the hy- fects of stress on the hypothalamic-pituitary-thyroid axis pophyseal portal circulation. are not as pronounced as on the hypothalamic-pituitary- GHRH binds to receptors in the plasma membranes of adrenal axis. somatotrophs (Fig. 32.10). These receptors are coupled to adenylyl cyclase by a stimulatory G protein, G s . The inter- action of GHRH with its receptors activates adenylyl cy- GH Regulates Growth During Childhood clase, increasing the concentration of cyclic AMP (cAMP) and Remains Important Throughout Life in the somatotroph. The rise in cAMP activates protein ki- As its name implies, growth hormone (GH) promotes the nase A (PKA), which, in turn, phosphorylates proteins that growth of the human body. It does not appear to stimu- stimulate GH secretion and GH gene expression. GHRH 2 late fetal growth, nor is it an important growth factor dur- binding to its receptor also increases intracellular Ca , ing the first few months after birth. Thereafter, it is es- which stimulates GH secretion. In addition, some evidence sential for the normal rate of body growth during suggests that GHRH may stimulate PLC, causing the hy- childhood and adolescence. Growth hormone (also called somatotropin) is se- creted by the anterior pituitary throughout life and re- Somatotroph mains physiologically important even after growth has stopped. In addition to its growth-promoting action, GH has effects on many aspects of carbohydrate, lipid, and protein metabolism. For example, GH is thought to be one of the physiological factors that counteract and, thus, modulate some of the actions of insulin on the liver and peripheral tissues. SRIF The Structure and Synthesis of Human GH. Human GH GH mRNA is a globular 22 kDa protein consisting of a single chain of G i 191 amino acid residues with two intrachain disulfide cAMP PKA P proteins bridges. Human GH has considerable structural similarity AC to human PRL and placental lactogen. Growth hormone is produced in somatotrophs of the an- G s ATP terior pituitary. It is synthesized in the rough ER as a larger prohormone consisting of an N-terminal signal peptide and GHRH Ca 2 GH the 191-amino acid hormone. The signal peptide is then cleaved from the prohormone, and the hormone traverses Secretory the Golgi apparatus and is packaged in secretory granules. granules Hypothalamic growth hormone-releasing hormone (GHRH) regulates the production of GH by stimulating the expression of the GH gene in somatotrophs. Expression of the GH gene is also stimulated by thyroid hormones. As a result, the normal rate of GH production depends on these hormones. For example, a thyroid hormone deficient GH individual is also GH-deficient. This important action of The actions of GHRH and somatostatin on thyroid hormones is discussed further in Chapter 33. FIGURE 32.10 a somatotroph. GHRH binds to membrane receptors that are coupled to adenylyl cyclase (AC) by stimula- Regulation of GH Secretion by GHRH and Somatostatin. tory G proteins (G s ). Cyclic AMP (cAMP) rises in the cell and ac- The secretion of GH is regulated by two opposing hypo- tivates protein kinase A (PKA), which then phosphorylates pro- thalamic releasing hormones. GHRH stimulates GH secre- teins (P proteins) involved in stimulating GH secretion and the 2 tion and somatostatin inhibits GH secretion by inhibiting expression of the gene for GH. Ca is also involved in the ac- tion of GHRH on GH secretion. The possible involvement of the the action of GHRH. The rate of GH secretion is deter- phosphatidylinositol pathway in GHRH action is not shown. So- mined by the net effect of these counteracting hormones matostatin (SRIF) binds to membrane receptors that are coupled on somatotrophs. When GHRH predominates, GH secre- to adenylyl cyclase by inhibitory G proteins (G i). This action in- tion is stimulated. When somatostatin predominates, GH hibits the ability of GHRH to stimulate adenylyl cyclase, block- secretion is inhibited. ing its action on GH secretion.
CHAPTER 32 The Hypothalamus and the Pituitary Gland 591 drolysis of membrane PIP 2 in the somatotroph. The impor- tance of this phospholipid pathway for the stimulation of Hypothalamus GH secretion by GHRH is not established. Somatostatin is a small peptide consisting of 14 amino acid residues. Although made by neurosecretory neurons in GHRH SRIF various parts of the hypothalamus, somatostatin neurons are especially abundant in the anterior periventricular re- gion (i.e., close to the third ventricle). The axons of these cells terminate on the capillary networks giving rise to the Somatotroph hypophyseal portal circulation, where they release somato- statin into the blood. Somatostatin binds to receptors in the plasma mem- GH branes of somatotrophs. These receptors, like those for GHRH, are also coupled to adenylyl cyclase, but they are coupled by an inhibitory G protein (see Fig. 32.10). The GH target binding of somatostatin to its receptor decreases adenylyl cells cyclase activity, reducing intracellular cAMP. Somatostatin 2 binding to its receptor also lowers intracellular Ca , re- ducing GH secretion. When the somatroph is exposed to both somatostatin and GHRH, the effects of somatostatin IGF-I are dominant and intracellular cAMP and Ca 2 are re- duced. Thus, somatostatin has a negative modulating influ- FIGURE 32.11 The hypothalamic-pituitary-GH axis. ence on the action of GHRH. Growth hormone-releasing hormone (GHRH) stimulates, and somatostatin inhibits, GH secretion by acting di- rectly on the somatotroph. The negative-feedback loops (), GH and Insulin-Like Growth Factor I. GH is not consid- shown in red, inhibit GHRH secretion and action on the soma- ered a traditional trophic hormone; however, it does stim- totroph, causing a decrease in GH secretion. The feedback loops ulate the production of a trophic hormone called insulin- (), shown in gray, stimulate somatostatin secretion, causing a like growth factor I (IGF-I). IGF-I is a potent mitogenic decrease in GH secretion. IGF-I, insulin-like growth factor I. agent that mediates the growth-promoting action of GH. IGF-I was originally called somatomedin C or soma- totropin-mediating hormone because of its role in promot- fect of these actions is the inhibition of GH secretion. By ing growth. Somatomedin C was renamed IGF-I because of stimulating IGF-I production, GH inhibits its own secre- its structural similarity to proinsulin. tion. This mechanism is analogous to the way ACTH and Insulin-like growth factor II (IGF-II), an additional TSH regulate their own secretion through the respective growth factor induced by GH, is structurally similar to IGF- negative-feedback effects of the glucocorticoid and thyroid I and has many of the same metabolic and mitogenic ac- hormones. This interactive relationship involving GHRH, tions. However, IGF-I appears to be the more important somatostatin, GH, and IGF-I comprises the hypothalamic- mediator of GH action. pituitary-GH axis. IGF-I is a 7.5 kDa protein consisting of a single chain of 70 amino acids. Because of its structural similarity to Feedback Effects of GH on Its Own Secretion. An in- proinsulin, IGF-I can produce some of the effects of in- crease in the blood concentration of GH has direct feed- sulin. IGF-I is produced by many cells of the body; how- back effects on its own secretion, independent of the pro- ever, the liver is the main source of IGF-I in the blood. duction of IGF-I. These effects of GH are due to the Most IGF-I in the blood is bound to specific IGF-I-bind- inhibition of GHRH secretion and the stimulation of so- ing proteins; only a small amount circulates in the free matostatin secretion by hypothalamic neurons (see Fig. form. The bound form of circulating IGF-I has little in- 32.11). GH circulating in the blood can enter the intersti- sulin-like activity, so it does not play a physiological role tial spaces of the median eminence of the hypothalamus in the regulation of blood glucose level. because there is no blood-brain barrier in this area. GH increases the expression of the genes for IGF-I in various tissues and organs, such as the liver, and stimulates Pulsatile Secretion of GH. In humans, GH is secreted in the production and release of IGF-I. Excessive secretion of periodic bursts, which produce large but short-lived peaks GH results in a greater than normal amount of IGF-I in the in GH concentration in the blood. Between these episodes blood. Individuals with GH deficiency have lower than of high GH secretion, somatotrophs release little GH; as a normal levels of IGF-I, but there is still some present, since result, the blood concentration of GH falls to very low lev- the production of IGF-I by cells is regulated by a variety of els. It is believed that these periodic bursts of GH secretion hormones and factors in addition to GH. are caused by an increase in the rate of GHRH secretion IGF-I has a negative-feedback effect on the secretion of and a fall in the rate of somatostatin secretion. The intervals GH (Fig. 32.11). It acts directly on somatotrophs to inhibit between bursts, when GH secretion is suppressed, are the stimulatory action of GHRH on GH secretion. It also thought to be caused by increased somatostatin secretion. inhibits GHRH secretion and stimulates the secretion of These changes in GHRH and somatostatin secretion result somatostatin by neurons in the hypothalamus. The net ef- from neural activity generated in higher levels of the CNS,
592 PART IX ENDOCRINE PHYSIOLOGY which affects the secretory activity of GHRH and somato- increase in the blood concentration of the amino acids argi- statin producing neurons in the hypothalamus. nine and leucine. Bursts of GH secretion occur during both awake and sleep periods of the day; however, GH secretion is maximal The Actions of GH. The cells of many tissues and organs at night. The bursts of GH secretion during sleep usually of the body have receptors for GH in their plasma mem- occur within the first hour after the onset of deep sleep branes. The interaction of GH with these receptors pro- (stages 3 and 4 of slow-wave sleep). Mean GH levels in the duces its growth-promoting and other metabolic effects, blood are highest during adolescence (peaking in late pu- but the mechanisms that produce these effects are not fully berty) and decline in adults. The reduction in blood GH understood. The binding of GH to its receptor activates a with aging is mainly due to decrease in the size of the GH tyrosine kinase (JAK2), which initiates changes in the secretory burst but not the number of pulses (Fig 32.12). phosphorylation pattern of cytoplasmic and nuclear pro- A variety of factors affect the rate of GH secretion in hu- teins. These phosphorylated proteins ultimately stimulate mans. These factors are thought to work by changing the the transcription of specific genes, such as that for IGF-I. secretion of GHRH and somatostatin by neurons in the Many of the mitogenic effects of GH are mediated by hypothalamus. For example, emotional or physical stress IGF-I; however, evidence indicates that GH has direct causes a great increase in the rate of GH secretion. Vigor- growth-promoting actions on progenitor cells or stem cells, ous exercise also stimulates GH secretion. Obesity results such as prechondrocytes in the growth plates of bone and in reduced GH secretion. satellite cells of skeletal muscle. GH stimulates such pro- Changes in the circulating levels of metabolites also af- genitor cells to differentiate into cells with the capacity to fect GH secretion. A decrease in blood glucose concentra- undergo cell division. An important action of GH on the tion stimulates GH secretion, whereas hyperglycemia in- differentiation of progenitor cells is stimulation of the ex- hibits it. Growth hormone secretion is also stimulated by an pression of the IGF-I gene; IGF-I is produced and released by these cells. IGF-I exerts an autocrine mitogenic action on the cells that produced it or a paracrine action on neighbor- ing cells. In response to IGF-I, these cells undergo division, 20 causing the tissue to grow mainly through cell replication. As mentioned earlier, GH deficiency in childhood causes GH in blood (ng/mL) 15 deficiency results in pituitary dwarfism. Individuals with this a decrease in the rate of body growth. If left untreated, the 14-year-old boy condition may be deficient in GH only, or they may have multiple anterior pituitary hormone deficiencies. GH defi- 10 ciency can be caused by a defect in the mechanisms that con- totrophs. In some individuals, the target cells for GH fail to respond normally to the hormone because of several differ- 5 trol GH secretion or the production of GH by soma- ent mutations in the GH receptor. See Clinical Focus Box 32.1 and the Case Study for further discussion of growth hormone deficiency, its detection and treatment. 8 AM Noon 4 PM 8 PM Mid- 4 AM 8 AM The excessive secretion of GH during childhood, caused night by a defect in the mechanisms regulating GH secretion or a GH-secreting tumor, results in gigantism. Affected individu- als may grow to a height of 7 to 8 feet (2.1 to 2.4 m). When 20 excessive GH secretion occurs in an adult, further linear growth does not occur because the growth plates of the long GH in blood (ng/mL) 10 hands, and feet to become thicker and certain organs, such as bones have calcified. Instead, it causes the bones of the face, 25-year-old man 15 the liver, to undergo hypertrophy. This condition, known as acromegaly, can also be caused by the chronic administration of excessive amounts of GH to adults. Although the main physiological action of GH is on body growth, it also has important effects on certain as- 5 pects of fat and carbohydrate metabolism. Its main action on fat metabolism is to stimulate the mobilization of triglycerides from the fat depots of the body. This process, known as lipolysis, involves the hydrolysis of triglycerides 8 AM Noon 4 PM 8 AM Mid- 4 AM 8 AM to fatty acids and glycerol by the enzyme hormone-sensi- night tive lipase. The fatty acids and glycerol are released from adipocytes and enter the bloodstream. How GH stimulates Pulsatile GH secretion in an adolescent boy FIGURE 32.12 and in an adult. In the adult, GH levels are re- lipolysis is not understood, but most evidence suggests that duced as a result of smaller pulse width and amplitude rather than it causes adipocytes to be more responsive to other lipoly- a decrease in the number of pulses. tic stimuli, such as fasting and catecholamines.
CHAPTER 32 The Hypothalamus and the Pituitary Gland 593 CLINICAL FOCUS BOX 32.1 Recombinant Human Growth Hormone and GH Deficiency the blood is not useful for diagnosing GH deficiency. How- Growth hormone (GH) is species-specific, and humans do ever, a random blood sample may be useful to detect GH not respond to GH derived from animals. In the past, the resistance, a syndrome in which the patient exhibits symp- only human GH available for treating children who were toms of GH deficiency but presents with high GH levels in GH-deficient was a very limited amount made from human the blood. pituitaries obtained at autopsy, but there was never An alternative means of diagnosing GH deficiency is to enough to meet the need. This problem was solved when measure the levels of IGF-I, IGF-II, and the IGF-binding pro- the gene for human GH was cloned in 1979 and then ex- tein 3 (IGFBP3) in the blood. The IGFs mediate many of the pressed in bacteria. The production of large amounts of re- mitogenic effects of GH on tissues in the body. IGF-I and combinant human GH, with all the activities of the natural IGF-II bind to IGFBP3 in the blood. IGFBP3 extends the half- substance, was now possible. During the 1980s, careful life of the IGFs, transports them to target cells, and facili- clinical trials established that recombinant human GH was tates their interaction with IGF receptors. GH stimulates safe to use in GH-deficient children to promote growth. the production of all three molecules, which are present in The hormone was approved for clinical use and is now the blood at fairly constant, readily detectable levels in nor- produced and sold worldwide. mal individuals. In children with GH deficiency, the con- Despite the availability of recombinant GH, the diagno- centration of IGFs and IGFBP3 are low. Treatment with re- sis of GH deficiency has remained controversial. GH is combinant GH will increase IGF-I, IGF-II, and IGFBP3 in the released in periodic bursts, the greatest of which occur in blood, which will result in increased long bone growth. the early morning hours. Between pulses of secretion, the The epiphyseal growth plate in the bone becomes less re- blood concentration of GH is nearly undetectable by most sponsive to GH and IGF-I several years after puberty, and techniques. For these reasons, a random measure of GH in long bone growth stops in adulthood (see Chapter 36). GH is also thought to function as one of the counter- Gonadotropins Regulate Reproduction regulatory hormones that limit the actions of insulin on The testes and ovaries have two essential functions in hu- muscle, adipose tissue, and the liver. For example, GH in- man reproduction. The first is to produce sperm cells and hibits glucose use by muscle and adipose tissue and in- ova (egg cells), respectively. The second is to produce an creases glucose production by the liver. These effects are array of steroid and peptide hormones, which influence vir- opposite those of insulin. Also, GH makes muscle and fat tually every aspect of the reproductive process. The go- cells resistant to the action of insulin itself. Thus, GH nor- nadotropic hormones FSH and LH regulate both of these mally has a tonic inhibitory effect on the actions of insulin, functions. The production and secretion of the go- much like the glucocorticoid hormones (see Chapter 34). nadotropins by the anterior pituitary is, in turn, regulated The insulin-opposing actions of GH can produce serious by the hypothalamic releasing hormone LHRH and the metabolic disturbances in individuals who secrete excessive hormones produced by the testes and ovaries in response to amounts of GH (people with acromegaly) or are given gonadotropic stimulation. The regulation of human repro- large amounts of GH for an extended time. They may de- duction by this hypothalamic-pituitary-gonad axis is dis- velop insulin resistance and an elevated insulin level in the blood. They may also have hyperglycemia caused by the underutilization and overproduction of glucose. These dis- turbances are much like those in individuals with non-in- TABLE 32.3 The Actions of Growth Hormone sulin-dependent (type 2) diabetes mellitus. For this reason, this metabolic response to excess GH is called its diabeto- Growth-promoting Stimulates IGF-I gene expression by target genic action. cells; IGF-I produced by these cells has In GH-deficient individuals, GH has a transitory in- autocrine or paracrine stimulatory effect sulin-like action. For example, intravenous injection of GH on cell division, resulting in growth in a person who is GH-deficient produces hypoglycemia. Lipolytic Stimulates mobilization of triglycerides The hypoglycemia is caused by the ability of GH to stimu- from fat deposits late the uptake and use of glucose by muscle and adipose Diabetogenic Inhibits glucose use by muscle and adipose tissue and increases glucose production by tissue and to inhibit glucose production by the liver. After the liver about 1 hour, the blood glucose level returns to normal. If Inhibits the action of insulin on glucose this person is given a second injection of GH, hypo- and lipid metabolism by muscle and glycemia does not occur because the person has become in- adipose tissue sensitive or refractory to the insulin-like action of GH and Insulin-like Transitory stimulatory effect on uptake remains so for some hours. Normal individuals do not re- and use of glucose by muscle and adipose spond to the insulin-like action of GH, presumably because tissue in GH-deficient individuals they are always refractory from being exposed to their own Transitory inhibitory effect on glucose endogenous GH. The actions of GH in humans are sum- production by liver of GH-deficient marized in Table 32.3. individuals
594 PART IX ENDOCRINE PHYSIOLOGY cussed in Chapters 37 and 38. Here, we describe the chem- Prolactin Regulates the Synthesis of Milk istry and formation of the gonadotropins. Like TSH, human FSH and LH are composed of two Lactation is the final phase of the process of human re- structurally different glycoprotein subunits, called and production. During pregnancy, alveolar cells of the , which are held together by noncovalent bonds. The mammary glands develop the capacity to synthesize milk subunit of human FSH consists of a peptide chain of 111 in response to stimulation by a variety of steroid and pep- amino acid residues, to which two chains of carbohydrate tide hormones. Milk synthesis by these cells begins are attached. The subunit of human LH is a peptide of shortly after childbirth. To continue to synthesize milk, 121 amino acid residues. It is also glycosylated with two these cells must be stimulated periodically by prolactin carbohydrate chains. The combined and subunits of (PRL), and this is thought to be the main physiological FSH and LH give these hormones a molecular size of function of PRL in the human female. What role, if any, about 28 to 29 kDa. PRL has in the human male is unclear. It is known to have As with TSH, the individual subunits of the go- some supportive effect on the action of androgenic hor- nadotropins have no hormonal activity. They must be mones on the male reproductive tract, but whether this is combined with each other in a 1:1 ratio in order to have an important physiological function of PRL is not estab- activity. Again, it is the subunit that gives the go- lished. nadotropin molecule either FSH or LH activity because Human PRL is a globular protein consisting of a single the subunits are identical. peptide chain of 199 amino acid residues with three intra- FSH and LH are produced by the same gonadotrophs chain disulfide bridges. Its molecular size is about 23 kDa. in the anterior pituitary. There are separate genes for the Human PRL has considerable structural similarity to human and subunits in the gonadotroph; hence, the peptide GH and to a PRL-like hormone produced by the human chains of these subunits are translated from separate placenta called placental lactogen (hPL). It is thought that mRNA molecules. Glycosylation of these chains begins as these hormones are structurally related because their genes they are synthesized and before they are released from the evolved from a common ancestral gene during the course of ribosome. The folding of the subunit peptides into their vertebrate evolution. Because of its structural similarity to final three-dimensional structure, the combination of an human PRL, human GH has substantial PRL-like or lacto- subunit and a subunit, and the completion of glycosyla- genic activity. However, PRL and hPL have little GH-like tion all occur as these molecules pass through the Golgi activity. Human placental lactogen is discussed further in apparatus and are packaged into secretory granules. As Chapter 39. with the thyrotroph, the gonadotroph produces an excess Prolactin is synthesized and secreted by lactotrophs in of subunits over FSH and LH subunits. Therefore, the the anterior pituitary. PRL is synthesized in the rough ER rate of subunit production is considered to be the rate- as a larger peptide. Its N-terminal signal peptide sequence limiting step in gonadotropin synthesis. is then removed and the 199-amino acid protein passes The synthesis of FSH and LH is regulated by the hor- through the Golgi apparatus and is packaged into secre- mones of the hypothalamic-pituitary-gonad axis. For ex- tory granules. ample, gonadotropin production is stimulated by LHRH. The synthesis and secretion of PRL is stimulated by es- It is also affected by the steroid and peptide hormones trogens and other hormones, such as TRH, which increase produced by the gonads in response to stimulation by the the expression of the PRL gene. However, dopamine in- gonadotropins. Such hormonally regulated changes in go- hibits the synthesis of PRL. Dopamine produced by hypo- nadotropin production are caused mainly by changes in thalamic neurons plays a major role in the regulation of PRL the expression of the genes for the gonadotropin subunits. synthesis and secretion by the hypothalamic-pituitary axis. More information about the regulation of gonadotropin The regulation of the synthesis and secretion of PRL and its synthesis and secretion is found in Chapters 37 and 38. physiological actions are discussed in Chapter 39. REVIEW QUESTIONS DIRECTIONS: Each of the numbered (E) Stress as a result of emotional (D) They stimulate the expression of items or incomplete statements in this trauma the GH gene in somatotrophs section is followed by answers or by (F) Increased PKA activity in (E) They increase IP 3 in thyrotrophs completions of the statement. Select the corticotrophs (F) They increase ACTH release ONE lettered answer or completion that is 2. Which of the following statements 3. A 30-year-old woman completed a the BEST in each case. most accurately describes the feedback routine pregnancy with the effects of thyroid hormones? uncomplicated delivery of a normal- 1. Which of the following conditions is (A) They increase the sensitivity of sized baby girl 6 months ago. The consistent with a decreased rate of thyrotrophs to TRH woman is currently experiencing ACTH secretion? (B) They stimulate transcription of the galactorrhea (persistent discharge of (A) Hyperosmolality of the blood and subunits of TSH in milk-like secretions from the breast) (B) Low serum glucocorticoid thyrotrophs and has not yet resumed regular (C) Loss of hypothalamic neurons (C) They increase the secretion of menstrual periods. The baby had been (D) Primary adrenal insufficiency TSH by thyrotrophs bottle-fed since birth. What is the (continued)
CHAPTER 32 The Hypothalamus and the Pituitary Gland 595 most likely explanation of the adrenocortical dysfunction in a middle- (C) Stimulation of TSH secretion by galactorrhea? aged man, ACTH and cortisol were TRH (A) Normal postpartum response measured in blood samples taken at 8 (D) Inhibition of TSH and subunit (B) Excess PRL secretion AM, 8:30 AM, 8 PM, and 8:30 PM. The gene expression by TRH (C) Insufficient TSH secretion values obtained for ACTH were 110, (E) Release of AVP (D) Reduced GH secretion 90, 120, and 200 pg/mL, respectively. (F) Inhibition of ACTH synthesis in (E) Increased dopamine synthesis in The values obtained for cortisol were corticotrophs the hypothalamus 10, 15, 25, and 20 g/dL. These 4. A decrease in blood volume would concentrations of ACTH demonstrate SUGGESTED READING result in an increase in the secretion of (A) Normal circadian pulsatile release Cuttler L. The regulation of growth hor- (A) Neurophysin (B) Primary adrenal insufficiency mone secretion. Endocrinol Metab Clin (B) Oxytocin (C) Inverted circadian pulsatile release North Am 1996;3:541–571. (C) -Lipotropin (D) Secondary adrenal insufficiency Fliers E, Wiersinga WM, Swaab DF. Physi- (D) Domatostatin (E) Normal circadian nonpulsatile ological and pathophysiological aspects (E) ACTH release of thryotropin-releasing hormone gene (F) POMC (F) ACTH-secreting tumor expression in the human hypothalamus. 5. A 50-year-old man complains of 7. Which treatment would provide the Thyroid 1998;8:921–928. decreased muscle strength, libido, and greatest therapeutic benefit in patients Itoi K, Seasholtz AF, Watson SJ. Cellular exercise intolerance. Examination with acromegaly? and extracellular regulatory mecha- reveals a 10% reduction in lean body (A) Glucocorticoid nisms of hypothalamic corticotropin- mass and an increase in body fat, (B) Somatostatin releasing hormone neurons. Endocr J primarily localized to the abdominal (C) Growth hormone 1998;45:13–33. region. Thyroid hormone levels are (D) Insulin Reichlin S. Neuroendocrinology, In: Wil- normal. Which diagnosis is most (E) GHRH son JD, Foster DW, Kronenberg HM, consistent with these symptoms? (F) Thyroid hormone Larsen PR, eds. Williams Textbook of (A) Glucocorticoid deficiency 8. Which of the following is mediated by Endocrinology. 9th Ed. Philadelphia: (B) Addison’s disease a rise in cAMP? WB Saunders, 1998. (C) GH deficiency (A) Inhibition of GH secretion by Zingg HH, Bourque CH, Bichet DG, eds. (D) PRL deficiency somatostatin Vasopressin and oxytocin. Molecular, (E) Acromegaly (B) Stimulation of GH gene expression cellular and clinical advances. Adv Exp 6. For evaluation of possible by GHRH Med Biol 1998;449:000–000.
CHAPTER The Thyroid Gland 33 33 Robert V. Considine, Ph.D. CHAPTER OUTLINE ■ FUNCTIONAL ANATOMY OF THE THYROID GLAND ■ ROLE OF THE THYROID HORMONES IN ■ SYNTHESIS, SECRETION, AND METABOLISM OF DEVELOPMENT, GROWTH, AND METABOLISM THE THYROID HORMONES ■ THYROID HORMONE DEFICIENCY AND EXCESS IN ■ THE MECHANISM OF THYROID HORMONE ACTION ADULTS KEY CONCEPTS 1. The thyroid gland consists of two lobes attached to either 8. In target tissues, T 3 binds to the thyroid hormone receptor side of the trachea. Within the lobes of the thyroid gland (TR), which then associates with a second TR or other nu- are spherical follicles surrounded by a single layer of ep- clear receptor to regulate transcription. ithelial cells. Parafollicular cells that secrete calcitonin are 9. TR regulates transcription by binding to specific thyroid also present within the walls of the follicles. hormone response elements (TRE) in target genes. 2. The major thyroid hormones are thyroxine (T 4 ) and tri- 10. Thyroid hormones are important regulators of central iodothyronine (T 3 ), both of which contain iodine. nervous system development. 3. Thyroid hormones are synthesized by iodination and the 11. Thyroid hormones stimulate growth by regulating growth coupling of tyrosines in reactions catalyzed by the enzyme hormone release from the pituitary and by direct actions thyroid peroxidase. on target tissues, such as bone. 4. Thyroid hormones are released from the thyroid gland by 12. Thyroid hormones regulate the basal metabolic rate and the degradation of thyroglobulin within the follicular cells. intermediary metabolism through effects on mitochondrial 5. The synthesis and release of thyroid hormones is regu- ATP synthesis and the expression of genes encoding meta- lated by thyroid-stimulating hormone (TSH), mainly via bolic enzymes. cAMP. 13. An excess of thyroid hormone (hyperthyroidism) is charac- 6. TSH release from the anterior pituitary is regulated by the terized by nervousness and increased metabolic rate, re- concentration of thyroid hormones in the circulation. sulting in weight loss. 7. In peripheral tissues, T 4 is deiodinated to the physiologi- 14. A deficiency of thyroid hormone (hypothyroidism) is charac- cally active hormone T 3 by 5- deiodinase. terized by decreased metabolic rate, resulting in weight gain. he development of the human body, from embryo to metabolic “housekeeping” needs but also remains poised to Tadult, is an orderly, programmed process. The timing of do its own special work in the body, such as conducting developmental events is remarkably constant from one indi- nerve impulses and contracting, absorbing, and secreting. vidual to the next, with developmental milestones reached at During its life span, the cell continues to make the enzy- about the same time in all of us. For example, the early devel- matic and structural proteins that ensure the maintenance opment of motor skills, body growth, the start of puberty, and of an appropriate rate of metabolism. final sexual and physical maturation occur within rather nar- The thyroid hormones, thyroxine and triiodothyronine, row timeframes during the human life span. play key roles in the regulation of body development and At the level of the individual cell, the timing or rate of govern the rate at which metabolism occurs in individual metabolic processes is also tightly regulated. For example, cells. Although these hormones are not essential for life, energy metabolism occurs at a rate needed to make the without them, life would lose its orderly nature. Without amount of ATP required for activities such as excitability, adequate levels of thyroid hormones, the body fails to de- secretion, maintaining osmotic integrity, and countless velop on time. Cellular housekeeping moves at a slower biosynthetic processes. The cell not only meets its basic pace, eventually influencing the ability of individual cells to 596
CHAPTER 33 The Thyroid Gland 597 carry out their physiological functions. The thyroid hor- cells, which face the lumen, are covered with microvilli. mones exert their regulatory functions by influencing gene Pseudopods formed from the apical membrane extend into expression, affecting the developmental program and the the lumen. The lateral membranes of the follicular cells are amount of cellular constituents needed for the normal rate connected by tight junctions, which provide a seal for the of metabolism. contents of the lumen. The basal membranes of the follicu- lar cells are close to the rich capillary network that pene- trates the stroma between the follicles. FUNCTIONAL ANATOMY OF THE The lumen of the follicle contains a thick, gel-like sub- stance called colloid (see Fig. 33.1). The colloid is a solu- THYROID GLAND tion composed primarily of thyroglobulin, a large protein The human thyroid gland consists of two lobes attached to that is a storage form of the thyroid hormones. The high either side of the trachea by connective tissue. The two viscosity of the colloid is due to the high concentration (10 lobes are connected by a band of thyroid tissue or isthmus, to 25%) of thyroglobulin. which lies just below the cricoid cartilage. A normal thy- The thyroid follicle produces and secretes two thyroid roid gland in a healthy adult weighs about 20 g. hormones, thyroxine (T 4 ) and triiodothyronine (T 3 ). Each lobe of the thyroid receives its arterial blood sup- Their molecular structures are shown in Figure 33.2. Thy- ply from a superior and an inferior thyroid artery, which roxine and triiodothyronine are iodinated derivatives of arise from the external carotid and subclavian artery, re- the amino acid tyrosine. They are formed by the coupling spectively. Blood leaves the lobes of the thyroid by a series of the phenyl rings of two iodinated tyrosine molecules in of thyroid veins that drain into the external jugular and in- an ether linkage. The resulting structure is called an nominate veins. This circulation provides a rich blood sup- iodothyronine. The mechanism of this process is dis- ply to the thyroid gland, giving it a higher rate of blood cussed in detail later. flow per gram than even that of the kidneys. Thyroxine contains four iodine atoms on the 3, 5, 3, The thyroid gland receives adrenergic innervation from and 5 positions of the thyronine ring structure, whereas the cervical ganglia and cholinergic innervation from the triiodothyronine has only three iodine atoms, at ring posi- vagus nerves. This innervation regulates vasomotor func- tions 3, 5, and 3 (see Fig. 33.2). Consequently, thyroxine tion to increase the delivery of TSH, iodide, and metabolic is usually abbreviated as T 4 and triiodothyronine as T 3. Be- substrates to the thyroid gland. The adrenergic system can cause T 4 and T 3 contain the element iodine, their synthesis also affect thyroid function by direct effects on the cells. by the thyroid follicle depends on an adequate supply of iodine in the diet. Thyroxine and Triiodothyronine Are Synthesized and Secreted by the Thyroid Follicle Parafollicular Cells Are the Sites of Calcitonin Synthesis The lobes of the thyroid gland consist of aggregates of many spherical follicles, lined by a single layer of epithelial In addition to the epithelial cells that secrete T 4 and T 3, the cells (Fig. 33.1). The apical membranes of the follicular wall of the thyroid follicle contains small numbers of parafollicular cells (see Fig. 33.1). The parafollicular cell is usually embedded in the wall of the follicle, inside the basal lamina surrounding the follicle. However, its plasma mem- brane does not form part of the wall of the lumen. Parafol- Follicular licular cells produce and secrete the hormone calcitonin. cell Calcitonin and its effects on calcium metabolism are dis- Colloid cussed in Chapter 36. SYNTHESIS, SECRETION, AND METABOLISM OF THE THYROID HORMONES T 4 and T 3 are not directly synthesized by the thyroid folli- cle in their final form. Instead, they are formed by the chemical modification of tyrosine residues in the peptide Capillary structure of thyroglobulin as it is secreted by the follicular cells into the lumen of the follicle. Therefore, the T 4 and T 3 formed by this chemical modification are actually part of the amino acid sequence of thyroglobulin. The high concentration of thyroglobulin in the colloid provides a large reservoir of stored thyroid hormones for Parafollicular cell later processing and secretion by the follicle. The synthesis of T 4 and T 3 is completed when thyroglobulin is retrieved through pinocytosis of the colloid by the follicular cells. A cross-sectional view through a portion of FIGURE 33.1 the human thyroid gland. Thyroglobulin is then hydrolyzed by lysosomal enzymes
598 PART IX ENDOCRINE PHYSIOLOGY 3' 3 tion of iodide present in the blood; therefore, follicular cells are efficient extractors of the small amount of iodide HH circulating in the blood. Once inside follicular cells, the io- HO O CCCOOH dide ions diffuse rapidly to the apical membrane, where they are used for iodination of the thyroglobulin precursor. HNH 2 Formation of the Iodothyronine Residues. The next step 5' 5 in the formation of thyroglobulin is the addition of one or Thyroxine (T ) two iodine atoms to certain tyrosine residues in the precur- 4 sor protein. The precursor of thyroglobulin contains 134 tyrosine residues, but only a small fraction of these become 3' 3 iodinated. A typical thyroglobulin molecule contains only HH 20 to 30 atoms of iodine. The iodination of thyroglobulin is catalyzed by the en- HO O C C COOH zyme thyroid peroxidase, which is bound to the apical membranes of follicular cells. Thyroid peroxidase binds H NH 2 an iodide ion and a tyrosine residue in the thyroglobulin precursor, bringing them in close proximity. The enzyme 5 oxidizes the iodide ion and the tyrosine residue to short- Triiodothyronine (T ) 3 lived free radicals, using hydrogen peroxide that has been generated within the mitochondria of follicular cells. The The molecular structure of the thyroid hor- FIGURE 33.2 free radicals then undergo addition. The product formed mones. The numbering of the iodine atoms on the iodothyronine ring structure is shown in red. is a monoiodotyrosine (MIT) residue, which remains in peptide linkage in the thyroglobulin structure. A second iodine atom may be added to a MIT residue by this same to its constituent amino acids, releasing T 4 and T 3 mole- enzymatic process, forming a diiodotyrosine (DIT) cules from their peptide linkage. T 4 and T 3 are then se- residue (see Fig. 33.3). creted into the blood. Iodinated tyrosine residues that are close together in the thyroglobulin precursor molecule undergo a coupling reaction, which forms the iodothyronine structure. Thy- Follicular Cells Synthesize roid peroxidase, the same enzyme that initially oxidizes Iodinated Thyroglobulin iodine, is believed to catalyze the coupling reaction The steps involved in the synthesis of iodinated thyroglob- through the oxidation of neighboring iodinated tyrosine ulin are shown in Figure 33.3. This process involves the residues to short-lived free radicals. These free radicals synthesis of a thyroglobulin precursor, the uptake of io- undergo addition, as shown in Figure 33.4. The addition dide, and the formation of iodothyronine residues. reaction produces an iodothyronine residue and a dehy- droalanine residue, both of which remain in peptide link- Synthesis and Secretion of the Thyroglobulin Precursor. age in the thyroglobulin structure. For example, when two The synthesis of the protein precursor for thyroglobulin is neighboring DIT residues couple by this mechanism, T 4 is the first step in the formation of T 4 and T 3. This substance formed (see Fig. 33.4). After being iodinated, the thy- is a 660-kDa glycoprotein composed of two similar 330- roglobulin molecule is stored as part of the colloid in the kDa subunits held together by disulfide bridges. The sub- lumen of the follicle. units are synthesized by ribosomes on the rough ER and Only about 20 to 25% of the DIT and MIT residues in then undergo dimerization and glycosylation in the the thyroglobulin molecule become coupled to form smooth ER. The completed glycoprotein is packaged into iodothyronines. For example, a typical thyroglobulin mol- vesicles by the Golgi apparatus. These vesicles migrate to ecule contains five to six uncoupled residues of DIT and the apical membrane of the follicular cell and fuse with it. two to three residues of T 4 . However, T 3 is formed in only The thyroglobulin precursor protein is then extruded onto about one of three thyroglobulin molecules. As a result, the the apical surface of the cell, where iodination takes place. thyroid secretes substantially more T 4 than T 3 . Iodide Uptake. The iodide used for iodination of the thy- Thyroid Hormones Are Formed From the roglobulin precursor protein comes from the blood perfus- ing the thyroid gland. The basal plasma membranes of fol- Hydrolysis of Thyroglobulin licular cells, which are near the capillaries that supply the When the thyroid gland is stimulated to secrete thyroid follicle, contain iodide transporters. These transporters hormones, vigorous pinocytosis occurs at the apical mem- move iodide across the basal membrane and into the cy- branes of follicular cells. Pseudopods from the apical mem- tosol of the follicular cell. The iodide transporter is an ac- brane reach into the lumen of the follicle, engulfing bits of tive transport mechanism that requires ATP, is saturable, the colloid (see Fig. 33.3). Endocytotic vesicles or colloid and can also transport certain other anions, such as bro- droplets formed by this pinocytotic activity migrate to- mide, thiocyanate, and perchlorate. It enables the follicular ward the basal region of the follicular cell. Lysosomes, cell to concentrate iodide many times over the concentra- which are mainly located in the basal region of resting fol-
CHAPTER 33 The Thyroid Gland 599 Blood Follicular cell Lumen Tight junction Iodination and - coupling I MIT - - I I H O 2 T g DIT 2 T Iodide 4 T g transporter T 3 Thyroglobulin (Tg) ER precursor Golgi Deiodination Endosomes Micropinocytosis DIT MIT T 4 T 4 Macropinocytosis Colloid T 3 T 3 Proteolysis droplet Secretion Lysosomes Pseudopod Thyroid hormone synthesis and secretion. (See text for details.) DIT, diiodotyrosine; FIGURE 33.3 MIT, monoiodotyrosine. licular cells, migrate toward the apical region of the stimu- cleared from the blood. This reservoir provides the body lated cells. The lysosomes fuse with the colloid droplets with a buffer against drastic changes in circulating thyroid and hydrolyze the thyroglobulin to its constituent amino hormone levels as a result of sudden changes in the rate of acids. As a result, T 4 and T 3 and the other iodinated amino T 4 and T 3 secretion. The protein-bound T 4 and T 3 mole- acids are released into the cytosol. cules are also protected from metabolic inactivation and excretion in the urine. As a result of these factors, the thy- Secretion of Free T 4 and T 3 . T 4 and T 3 formed from the roid hormones have long half-lives in the bloodstream. hydrolysis of thyroglobulin are released from the follicular The half-life of T 4 is about 7 days; the half-life of T 3 is cell and enter the nearby capillary circulation, however, the about 1 day. mechanism of transport of T 4 and T 3 across the basal plasma membrane has not been defined. The DIT and MIT Thyroid Hormones Are Metabolized by generated by the hydrolysis of thyroglobulin are deiodi- Peripheral Tissues nated in the follicular cell. The released iodide is then re- utilized by the follicular cell for the iodination of thy- Thyroid hormones are both activated and inactivated by roglobulin (see Fig. 33.3). deiodination reactions in the peripheral tissues. The en- zymes that catalyze the various deiodination reactions are regulated, resulting in different thyroid hormone concen- Binding of T 4 and T 3 to Plasma Proteins. Most of the T 4 and T 3 molecules that enter the bloodstream become trations in various tissues in different physiological and bound to plasma proteins. About 70% of the T 4 and 80% of pathophysiological conditions. the T 3 are noncovalently bound to thyroxine-binding globulin (TBG), a 54-kDa glycoprotein that is synthesized Conversion of T 4 to T 3 . As noted earlier, T 4 is the major se- and secreted by the liver. Each molecule of TBG has a sin- cretory product of the thyroid gland and is the predominant gle binding site for a thyroid hormone molecule. The re- thyroid hormone in the blood. However, about 40% of the maining T 4 and T 3 in the blood are bound to transthyretin T 4 secreted by the thyroid gland is converted to T 3 by enzy- or to albumin. Less than 1% of the T 4 and T 3 in blood is in matic removal of the iodine atom at position 5 of the thyro- the free form, and it is in equilibrium with the large protein- nine ring structure (Fig. 33.5). This reaction is catalyzed by a bound fraction. It is this small amount of free thyroid hor- 5-deiodinase (type 1) located in the liver, kidneys, and thy- mone that interacts with target cells. roid gland. The T 3 formed by this deiodination and that se- The protein-bound form of T 4 and T 3 represents a creted by the thyroid react with thyroid hormone receptors large reservoir of preformed hormone that can replenish in target cells; therefore, T 3 is the physiologically active form the small amount of circulating free hormone as it is of the thyroid hormones. A second 5-deiodinase (type 2) is
600 PART IX ENDOCRINE PHYSIOLOGY NH 2 DIT free Regulation of 5-Deiodination. The 5-deiodination reac- CH 2 CH radicals tion is a regulated process influenced by certain physiolog- O CO ical and pathological factors. The result is a change in the relative amounts of T 3 and reverse T 3 produced from T 4 . O NH CH 2 CH For example, a human fetus produces less T 3 from T 4 than CO a child or adult because the 5-deiodination reaction is less active in the fetus. Also, 5-deiodination is inhibited during fasting, particularly in response to carbohydrate restriction, Radical addition but it can be restored to normal when the individual is fed again. Trauma, as well as most acute and chronic illnesses, NH Quinoid also suppresses the 5-deiodination reaction. Under all of CH 2 CH intermediate these circumstances, the amount of T 3 produced from T 4 is O CO reduced and its blood concentration falls. However, the O NH amount of reverse T 3 rises in the circulation, mainly be- CH 2 CH cause its conversion to 3,3-diiodothyronine by 5-deiodi- CO nation is reduced. A rise in reverse T 3 in the blood may sig- nal that the 5-deiodination reaction is suppressed. Electronic rearrangement Note that during fasting or in the disease states mentioned above, the secretion of T 4 is usually not increased, despite the Thyroxine decrease of T 3 in the circulation. This response indicates that, residue under these circumstances, a T 3 decrease in the blood does NH not stimulate the hypothalamic-pituitary-thyroid axis. HO O CH 2 CH CO Minor Degradative Pathways. T 4 and, to a lesser extent, T 3 are also metabolized by conjugation with glucuronic + acid in the liver. The conjugated hormones are secreted into the bile and eliminated in the feces. Many tissues also NH Dehydroalanine CH metabolize thyroid hormones by modifying the three-car- CH 2 residue CO bon side chain of the iodothyronine structure. These mod- ifications include decarboxylation and deamination. The Theoretical model for the coupling reaction FIGURE 33.4 derivatives formed from T 4 , such as tetraiodoacetic acid between two diiodotyrosine (DIT) residues in iodinated thyroglobulin. This model is based on free radical (tetrac), may also undergo deiodinations before being ex- formation catalyzed by thyroid peroxidase. (Adapted from Tau- creted (see Fig. 33.5). rog AM. Hormone synthesis: Thyroid iodine metabolism. In: Braverman LE, Utiger RD, eds. Werner & Ingbar’s The Thyroid: A Fundamental and Clinical Text. 8th Ed. Philadelphia: Lippincott TSH Regulates Thyroid Hormone Synthesis Williams & Wilkins, 2000;61–85.) and Secretion When the concentrations of free T 4 and T 3 fall in the blood, the anterior pituitary gland is stimulated to secrete present in skeletal muscle, the CNS, the pituitary gland, and thyroid-stimulating hormone (TSH), raising the concen- the placenta. Type 2 deiodinase is believed to function pri- tration of TSH in the blood. This action results in increased marily to maintain intracellular T 3 in target tissues, but it may interactions between TSH and its receptors on thyroid fol- also contribute to the generation of circulating T 3 . All of the licular cells. deiodinases contain selenocysteine in the active center. This rare amino acid has properties that make it ideal to catalyze TSH Receptors and Second Messengers. The receptor for deiodination reactions. TSH is a transmembrane glycoprotein thought to be located on the basal plasma membrane of the follicular cell. These re- Deiodinations That Inactivate T 4 and T 3 . Whereas the ceptors are coupled by G s proteins, mainly to the adenylyl cy- 5-deiodination of T 4 to produce T 3 can be viewed as a clase-cAMP-protein kinase A pathway, however, there is also metabolic activation process, both T 4 and T 3 undergo en- evidence for effects via phospholipase C (PLC), inositol zymatic deiodinations, particularly in the liver and kidneys, trisphosphate, and diacylglycerol (see Chapter 1). The phys- iological importance of TSH-stimulated phospholipid me- which inactivate them. For example, about 40% of the T 4 secreted by the human thyroid gland is deiodinated at the tabolism in human follicular cells is unclear, since very high 5 position on the thyronine ring structure by a 5-deiodi- concentrations of TSH are needed to activate PLC. nase. This produces reverse T 3 (see Fig. 33.5). Since reverse T 3 has little or no thyroid hormone activity, this deiodina- TSH and Thyroid Hormone Formation and Secretion. tion reaction is a major pathway for the metabolic inactiva- TSH stimulates most of the processes involved in thyroid tion or disposal of T 4. Triiodothyronine and reverse T 3 also hormone synthesis and secretion by follicular cells. The undergo deiodination to yield 3,3-diiodothyronine. This rise in cAMP produced by TSH is believed to cause many inactivate metabolite may be further deiodinated before be- of these effects. TSH stimulates the uptake of iodide by fol- ing excreted. licular cells, usually after a short interval during which io-
CHAPTER 33 The Thyroid Gland 601 H H HO O C C COOH H NH 2 5'-Deiodinase Triiodothyronine (T ) 3 H H H H HO O C C COOH HO O C C COOH H NH 2 H NH 2 3,3'-Diiodothyronine Thyroxine (T ) 5-Deiodinase 4 H H HO O C C COOH H NH 2 Reverse T 3 H HO O C COOH H Tetraiodoacetic acid (tetrac) The metabolism of thyroxine. Thyroxine is deiodinations (e.g., to 3,3-diiodothyronine) before being ex- FIGURE 33.5 deiodinated by 5-deiodinase to form T 3 , the creted. A small amount of T 4 is also decarboxylated and deami- physiologically active thyroid hormone. Some T 4 is also enzy- nated to form the metabolite, tetraiodoacetic acid (tetrac). Tetrac matically deiodinated at the 5 position to form the inactive may then be deiodinated before being excreted. metabolite, reverse T 3 . T 3 and reverse T 3 undergo additional dide transport is actually depressed. TSH also stimulates verely deficient in iodide, as in some parts of the world, T 4 the iodination of tyrosine residues in the thyroglobulin pre- and T 3 synthesis is limited by the amount of iodide avail- cursor and the coupling of iodinated tyrosines to form able to the thyroid gland. As a result, the concentrations of iodothyronines. Moreover, it stimulates the pinocytosis of T 4 and T 3 in the blood fall, causing a chronic stimulation of colloid by the apical membranes, resulting in a great in- TSH secretion, which, in turn, produces a goiter. Enlarge- crease in endocytosis of thyroglobulin and its hydrolysis. ment of the thyroid gland increases its capacity to accumu- The overall result of these effects of TSH is an increased re- late iodide from the blood and to synthesize T 4 and T 3. lease of T 4 and T 3 into the blood. In addition to its effects However, the degree to which the enlarged gland can pro- on thyroid hormone synthesis and secretion, TSH rapidly duce thyroid hormones to compensate for their deficiency increases energy metabolism in the thyroid follicular cell. in the blood depends on the severity of the deficiency of io- dide in the diet. To prevent iodide deficiency and the con- TSH and Thyroid Size. Over the long term, TSH pro- sequent goiter formation in the human population, iodide motes protein synthesis in thyroid follicular cells, main- is added to the table salt (iodized salt) sold in most devel- taining their size and structural integrity. Evidence of this oped countries. trophic effect of TSH is seen in a hypophysectomized pa- tient, whose thyroid gland atrophies, largely as a result of a reduction in the height of follicular cells. However, the THE MECHANISM OF THYROID chronic exposure of an individual to excessive amounts of HORMONE ACTION TSH causes the thyroid gland to increase in size. This en- Most cells of the body are targets for the action of thyroid largement is due to an increase in follicular cell height and hormones. The sensitivity or responsiveness of a particular number. Such an enlarged thyroid gland is called a goiter. cell to thyroid hormones correlates to some degree with These trophic and proliferative effects of TSH on the thy- the number of receptors for these hormones. The cells of roid are primarily mediated by cAMP. the CNS appear to be an exception. As is discussed later, the thyroid hormones play an important role in CNS de- Dietary Iodide Is Essential for the velopment during fetal and neonatal life, and developing Synthesis of Thyroid Hormones nerve cells in the brain are important targets for thyroid hormones. In the adult, however, brain cells show little re- Because iodine atoms are constituent parts of the T 4 and T 3 sponsiveness to the metabolic regulatory action of thyroid molecules, a continual supply of iodide is required for the hormones, although they have numerous receptors for synthesis of these hormones. If an individual’s diet is se- these hormones. The reason for this discrepancy is unclear.
602 PART IX ENDOCRINE PHYSIOLOGY Thyroid hormone receptors (TR) are located in the nu- TR receptors, including effects on signal transduction path- clei of target cells bound to thyroid hormone response el- ways that alter cellular respiration, cell morphology, vascu- ements (TRE) in the DNA. TRs are protein molecules of lar tone, and ion homeostasis. The physiological relevance about 50 kDa that are structurally similar to the nuclear re- of these effects is currently being investigated. ceptors for steroid hormones and vitamin D. Thyroid re- ceptors bound to the TRE in the absence of T 3 generally act to repress gene expression. ROLE OF THE THYROID HORMONES The free forms of T 3 and T 4 are taken up by target cells IN DEVELOPMENT, GROWTH, AND from the blood through a carrier-mediated process that re- METABOLISM quires ATP. Once inside the cell, T 4 is deiodinated to T 3 , which enters the nucleus of the cell and binds to its recep- Thyroid hormones play a critical role in the development tor in the chromatin. The TR with bound T 3 forms a com- of the central nervous system (CNS). They are also essen- plex with other nuclear receptors (called a heterodimer) or tial for normal body growth during childhood, and in basal with another TR (homodimer) to activate transcription. energy metabolism. Other transcription factors may also complex with the TR heterodimer or homodimer. As a result, the production of mRNA for certain proteins is either increased or decreased, Thyroid Hormones Are Essential for changing the cell’s capacity to make these proteins Development of the Central Nervous System (Fig. 33.6). T 3 can influence differentiation by regulating The human brain undergoes its most active phase of growth the kinds of proteins produced by its target cells and can in- during the last 6 months of fetal life and the first 6 months fluence growth and metabolism by changing the amounts of postnatal life. During the second trimester of pregnancy, of structural and enzymatic proteins present in the cells. the multiplication of neuroblasts in the fetal brain reaches a The mechanisms by which T 3 alters gene expression con- peak and then declines. As pregnancy progresses and the tinue to be investigated. rate of neuroblast division drops, neuroblasts differentiate The gene expression response to T 3 is slow to appear. into neurons and begin the process of synapse formation When T 3 is given to an animal or human, several hours that extends into postnatal life. elapse before its physiological effects can be detected. This Thyroid hormones first appear in the fetal blood during delayed action undoubtedly reflects the time required for the second trimester of pregnancy, and levels continue to changes in gene expression and consequent changes in the rise during the remaining months of fetal life. Thyroid hor- synthesis of key proteins to occur. When T 4 is adminis- mone receptors increase about 10-fold in the fetal brain at tered, its course of action is usually slower than that of T 3 about the time the concentrations of T 4 and T 3 begin to rise because of the additional time required for the body to in the blood. These events are critical for normal brain de- convert T 4 to T 3 . velopment because thyroid hormones are essential for tim- Thyroid hormones also have effects on cells that occur ing the decline in nerve cell division and the initiation of much faster and do not appear to be mediated by nuclear differentiation and maturation of these cells. If thyroid hormones are deficient during these prenatal and postnatal periods of differentiation and maturation of the brain, mental retardation occurs. The cause is thought to be inadequate development of the neuronal circuitry of 5'-Deiodinase T 4 T 3 the CNS. Thyroid hormone therapy must be given to a thyroid hormone-deficient child during the first few Coactivator months of postnatal life to prevent mental retardation. Starting thyroid hormone therapy after behavioral deficits have occurred cannot reverse the mental retardation (i.e., T 3 thyroid hormone must be present when differentiation nor- Transcription mally occurs). Thyroid hormone deficiency during infancy RXR TR RNA polymerase II DNA causes both mental retardation and growth impairment, as discussed below. Fortunately, this occurs rarely today be- cause thyroid hormone deficiency is usually detected in newborn infants and hormone therapy is given at the TRE proper time. Corepressor The exact mechanism by which thyroid hormones influ- ence differentiation of the CNS is unknown. Animal stud- The activation of transcription by thyroid FIGURE 33.6 ies have demonstrated that thyroid hormones inhibit nerve hormone. T 4 is taken up by the cell and deiod- cell replication in the brain and stimulate the growth of inated to T 3, which then binds to the thyroid hormone receptor nerve cell bodies, the branching of dendrites, and the rate (TR). The activated TR heterodimerizes with a second transcrip- tion factor, 9-cis retinoic acid receptor (RXR), and binds to the of myelinization of axons. These effects of thyroid hor- thyroid hormone response element (TRE). The binding of mones are presumably due to their ability to regulate the TR/RXR to the TRE displaces repressors of transcription and re- expression of genes involved in nerve cell replication and cruits additional coactivators. The final result is the activation of differentiation. However, the details, particularly in the hu- RNA polymerase II and the transcription of the target gene. man, are unclear.
CHAPTER 33 The Thyroid Gland 603 Thyroid Hormones Are Essential for involved; the amounts of oxygen consumed and body heat Normal Body Growth produced depend on total body activity. The thyroid hormones are important factors regulating the Thermogenic Action of the Thyroid Hormones. Thyroid growth of the entire body. For example, an individual who hormones regulate the basal rate at which oxidative phos- is deficient in thyroid hormones, who does not receive thy- phorylation takes place in cells. As a result, they set the roid hormone therapy during childhood, will not grow to a basal rate of body heat production and of oxygen con- normal adult height. sumed by the body. This is called the thermogenic action of thyroid hormones. Thyroid Hormones and the Gene for GH. A major way Thyroid hormone levels in the blood must be within thyroid hormones promote normal body growth is by normal limits for basal metabolism to proceed at the rate stimulating the expression of the gene for growth hor- needed for a balanced energy economy of the body. For ex- mone (GH) in the somatotrophs of the anterior pituitary ample, if thyroid hormones are present in excess, oxidative gland. In a thyroid hormone-deficient individual, GH phosphorylation is accelerated, and body heat production synthesis by the somatotrophs is greatly reduced and con- and oxygen consumption are abnormally high. The con- sequently GH secretion is impaired; therefore, a thyroid verse occurs when the blood concentrations of T 4 and T 3 hormone-deficient individual will also be GH-deficient. If are lower than normal. The fact that thyroid hormones af- this condition occurs in a child, it will cause growth retar- fect the amount of oxygen consumed by the body has been dation, largely a result of the lack of the growth-promot- used clinically to assess the status of thyroid function. Oxy- ing action of GH (see Chapter 32). gen consumption is measured under resting conditions and compared with the rate expected of a similar individual Other Effects of Thyroid Hormones on Growth. The with normal thyroid function. This measurement is the thyroid hormones have additional effects on growth. In tis- basal metabolic rate (BMR) test. sues such as skeletal muscle, the heart, and the liver, thyroid hormones have direct effects on the synthesis of a variety of structural and enzymatic proteins. For example, they Tissues Affected by the Thermogenic Action of Thyroid Not all tissues are sensitive to the thermo- stimulate the synthesis of structural proteins of mitochon- Hormones. genic action of thyroid hormones. Tissues and organs that dria, as well as the formation of many enzymes involved in give this response include skeletal muscle, the heart, the intermediary metabolism and oxidative phosphorylation. liver, and the kidneys. These are also tissues in which thy- Thyroid hormones also promote the calcification and, roid hormone receptors are abundant. The adult brain, hence, the closure, of the cartilaginous growth plates of the skin, lymphoid organs, and gonads show little thermogenic bones of the skeleton. This action limits further linear body response to thyroid hormones. With the exception of the growth. How the thyroid hormones promote calcification adult brain, these tissues contain few thyroid hormone re- of the growth plates of bones is not understood. ceptors, which may explain their poor response. Thyroid Hormones Regulate the Basal Molecular and Cellular Mechanisms. The thermo- Energy Economy of the Body genic action of the thyroid hormones is poorly under- stood at the molecular level. The thermogenic effect When the body is at rest, about half of the ATP produced takes many hours to appear after the administration of by its cells is used to drive energy-requiring membrane thyroid hormones to a human or animal, probably be- transport processes. The remainder is used in involuntary cause of the time required for changes in the expression muscular activity, such as respiratory movements, peri- of genes involved. T 3 is known to stimulate the synthesis stalsis, contraction of the heart, and in many metabolic of cytochromes, cytochrome oxidase, and Na /K -AT- reactions requiring ATP, such as protein synthesis. The Pase in certain cells. This action suggests that T 3 may energy required to do this work is eventually released as regulate the number of respiratory units in these cells, af- body heat. fecting their capacity to carry out oxidative phosphory- lation. A greater rate of oxidative phosphorylation would Basal Oxygen Consumption and Body Heat Production. result in greater heat production. The major site of ATP production is the mitochondria, Thyroid hormone also stimulates the synthesis of uncou- where the oxidative phosphorylation of ADP to ATP takes pling protein-1 (UCP-1) in brown adipose tissue. ATP is place. The rate of oxidative phosphorylation depends on synthesized by ATP synthase in the mitochondria when pro- the supply of ADP for electron transport. The ADP supply tons flow down their electrochemical gradient. UCP-1 acts is, in turn, a function of the amount of ATP used to do work. as a channel in the mitochondrial membrane to dissipate the For example, when more work is done per unit time, more ion gradient without making ATP. As the protons move ATP is used and more ADP is generated, increasing the rate down their electrochemical gradient uncoupled from ATP syn- of oxidative phosphorylation. The rate at which oxidative thesis, energy is released as heat. Adult humans have little phosphorylation occurs is reflected in the amount of oxygen brown adipose tissue, so it is not likely that UCP-1 makes a consumed by the body because oxygen is the final electron significant contribution to nutrient oxidation or body heat acceptor at the end of the electron transport chain. production. However, several uncoupling proteins (UCP-2 Activities that occur when the body is not at rest, such and UCP-3) have recently been discovered in many tissues, as voluntary movements, use additional ATP for the work and their expression is regulated by thyroid hormones.
604 PART IX ENDOCRINE PHYSIOLOGY These novel uncoupling proteins may be involved in the The Physiological Actions of thermogenic action of thyroid hormones. TABLE 33.1 Thyroid Hormones Development of CNS Inhibit nerve cell replication Thyroid Hormones Stimulate Intermediary Stimulate growth of nerve cell bodies Metabolism Stimulate branching of dendrites Stimulate rate of axon myelinization In addition to their ability to regulate the rate of basal en- Body growth Stimulate expression of gene for ergy metabolism, thyroid hormones influence the rate at GH in somatotrophs which most of the pathways of intermediary metabolism Stimulate synthesis of many operate in their target cells. When thyroid hormones are structural and enzymatic proteins deficient, pathways of carbohydrate, lipid, and protein me- Promote calcification of growth tabolism are slowed, and their responsiveness to other reg- plates of bones ulatory factors, such as other hormones, is decreased. How- Basal energy economy of Regulate basal rates of oxidative the body phosphorylation, body heat ever, these same metabolic pathways run at an abnormally production, and oxygen high rate when thyroid hormones are present in excess. consumption (thermogenic effect) Thyroid hormones, therefore, can be viewed as amplifiers Intermediary metabolism Stimulate synthetic and degradative of cellular metabolic activity. The amplifying effect of thy- pathways of carbohydrate, lipid, roid hormones on intermediary metabolism is mediated and protein metabolism through the activation of genes encoding enzymes in- Thyroid-stimulating Inhibit TSH secretion by decreasing volved in these metabolic pathways. hormone (TSH) secretion sensitivity of thyrotrophs to thyrotropin-releasing hormone (TRH) Thyroid Hormones Regulate Their Own Secretion An important action of the thyroid hormones is the ability of thyroid hormone deficiency include heritable diseases to regulate their own secretion. As discussed in Chapter 32, that affect certain steps in the biosynthesis of thyroid hor- T 3 exerts an inhibitory effect on TSH secretion by thy- mones and hypothalamic or pituitary diseases that interfere rotrophs in the anterior pituitary gland by decreasing thy- with TRH or TSH secretion. Obviously, radioiodine abla- rotroph sensitivity to thyrotropin-releasing hormone tion or surgical removal of the thyroid gland also causes (TRH). Consequently, when the circulating concentration thyroid hormone deficiency. Hypothyroidism is the dis- of free thyroid hormones is high, thyrotrophs are relatively ease state that results from thyroid hormone deficiency. insensitive to TRH, and the rate of TSH secretion de- Thyroid hormone deficiency impairs the functioning creases. The resulting fall of TSH levels in the blood re- of most tissues in the body. As described earlier, a defi- duces the rate of thyroid hormone release from the follicu- ciency of thyroid hormones at birth that is not treated lar cells in the thyroid. When the free thyroid hormone during the first few months of postnatal life causes irre- level falls in the blood, however, the negative-feedback ef- versible mental retardation. Thyroid hormone deficiency fect of T 3 on thyrotrophs is reduced, and the rate of TSH later in life also influences the function of the nervous sys- secretion increases. The rise in TSH in the blood stimulates tem. For example, all cognitive functions, including the thyroid gland to secrete thyroid hormones at a greater speech and memory, are slowed and body movements rate. This action of T 3 on thyrotrophs is thought to be due may be clumsy. These changes can usually be reversed to changes in gene expression in these cells. with thyroid hormone therapy. The physiological actions of the thyroid hormones de- Metabolism is also reduced in thyroid hormone-defi- scribed above are summarized in Table 33.1. cient individuals. Basal metabolic rate is reduced, resulting in impaired body heat production. Vasoconstriction occurs in the skin as a compensatory mechanism to conserve body THYROID HORMONE DEFICIENCY AND heat. Heart rate and cardiac output are reduced. Food in- EXCESS IN ADULTS take is reduced, and the synthetic and degradative processes of intermediary metabolism are slowed. In severe A deficiency or an excess of thyroid hormones produces hypothyroidism, a substance consisting of hyaluronic acid characteristic changes in the body. These changes result and chondroitin sulfate complexed with protein is de- from dysregulation of nervous system function and altered posited in the extracellular spaces of the skin, causing wa- metabolism. ter to accumulate osmotically. This effect gives a puffy ap- pearance to the face, hands, and feet called myxedema. All of the above disorders can be normalized with thyroid hor- Thyroid Hormone Deficiency Causes Nervous mone therapy. and Metabolic Disorders Thyroid hormone deficiency in humans has a variety of An Excess of Thyroid Hormone Produces causes. For example, iodide deficiency may result in a re- Nervous and Other Disorders duction in thyroid hormone production. Autoimmune dis- eases, such as Hashimoto’s disease, impair thyroid hor- The most common cause of excessive thyroid hormone mone synthesis (see Clinical Focus Box 33.1). Other causes production in humans is Graves’ disease, an autoimmune
CHAPTER 33 The Thyroid Gland 605 CLINICAL FOCUS BOX 33.1 Autoimmune Thyroid Disease—Postpartum Thyroiditis curring in more than 30% of women with antibodies to thy- Certain diseases affecting the function of the thyroid gland roid peroxidase detectable preconception. The disease is occur when an individual’s immune system fails to recog- also observed in patients known to have Graves’ disease. nize particular thyroid proteins as “self” and reacts to the The postpartum occurrence of the disorder is likely due to proteins as if they were foreign. This usually triggers both increased immune system function following the suppres- humoral and cellular immune responses. As a result, anti- sion of its activity during pregnancy. bodies to these proteins are generated, which then alter It has been estimated that 5 to 10% of women develop thyroid function. Two common autoimmune diseases with postpartum thyroiditis. Of these women, about 50% have opposite effects on thyroid function are Hashimoto’s dis- transient thyrotoxicosis alone, 25% have transient hy- ease and Graves’ disease. In Hashimoto’s disease, the thy- pothyroidism alone, and the remaining 25% have both roid gland is infiltrated by lymphocytes, and elevated lev- phases of the disease. The prevalence of the disease has els of antibodies against several components of thyroid prompted a clinical recommendation suggesting that thy- tissue (e.g., antithyroid peroxidase and antithyroglobulin roid function (serum T 4 , T 3 , and TSH levels) be surveyed antibodies) are found in the serum. The thyroid gland is de- postpartum at 2, 4, 6, and 12 months in all women with thy- stroyed, resulting in hypothyroidism. In Graves’ disease, roid peroxidase antibodies or symptoms suggestive of thy- stimulatory antibodies to the TSH receptor activate thyroid roid dysfunction. Patients who have experienced one hormone synthesis, resulting in hyperthyroidism (see text episode of postpartum thyroiditis should also be consid- for details). ered at risk for recurrence after pregnancy. A third, fairly common autoimmune disease is postpar- Treatment for thyrotoxicosis commonly involves in- tum thyroiditis, which usually occurs within 3 to 12 months hibiting thyroid hormone synthesis and secretion. Thion- after delivery. The disease is characterized by a transient amides are a class of drugs that inhibit the oxidation and thyrotoxicosis (hyperthyroidism) often followed by a pe- organic binding of thyroid iodide to reduce thyroid hor- riod of hypothyroidism lasting several months. Many pa- mone production. Some drugs in this class also inhibit the tients eventually return to the euthyroid state. Often only conversion of T 4 to T 3 in the peripheral tissues. Thyroid the hypothyroid phase of the disease may be observed, oc- hormone replacement is required to treat hypothyroidism. disorder caused by antibodies directed against the TSH re- hyperthyroidism or thyrotoxicosis, is characterized by ceptor in the plasma membranes of thyroid follicular cells. many changes in the functioning of the body that are the These antibodies bind to the TSH receptor, resulting in an opposite of those caused by thyroid hormone deficiency. increase in the activity of adenylyl cyclase. The consequent Hyperthyroid individuals are nervous and emotionally rise in cAMP in follicular cells produces effects similar to irritable, with a compulsion to be constantly moving those caused by the action of TSH. The thyroid gland en- around. However, they also experience physical weakness larges to form a diffuse toxic goiter, which synthesizes and and fatigue. Basal metabolic rate is increased and, as a re- secretes thyroid hormones at an accelerated rate, causing sult, body heat production is increased. Vasodilation in thyroid hormones to be chronically elevated in the blood. the skin and sweating occur as compensatory mechanisms Feedback inhibition of thyroid hormone production by the to dissipate excessive body heat. Heart rate and cardiac thyroid hormones is also lost. output are increased. Energy metabolism increases, as Less common conditions that cause chronic elevations does appetite. However, despite the increase in food in- in circulating thyroid hormones include adenomas of the take, a net degradation of protein and lipid stores occurs, thyroid gland that secrete thyroid hormones and excessive resulting in weight loss. All of these changes can be re- TSH secretion caused by malfunctions of the hypothala- versed by reducing the rate of thyroid hormone secretion mic-pituitary-thyroid axis. The disease state that develops with drugs or by removal of the thyroid gland by radioac- in response to excessive thyroid hormone secretion, called tive ablation or surgery. REVIEW QUESTIONS DIRECTIONS: Each of the numbered (A) Stimulation of endocytosis of (E) Stimulation of the binding of T 4 items or incomplete statements in this thyroglobulin stored in the colloid and T 3 to thyroxine-binding globulin section is followed by answers or by (B) Release of a large pool of T 4 and (F) Increased cAMP hydrolysis completions of the statement. Select the T 3 stored in secretory vesicles in the 2. A child is born with a rare disorder in ONE lettered answer or completion that is cell which the thyroid gland does not the BEST in each case. (C) Stimulation of the uptake of iodide respond to TSH. What would be the from the thyroglobulin stored in the predicted effects on mental ability, body 1. The effects of TSH on thyroid colloid growth rate, and thyroid gland size follicular cells include (D) Increase in perfusion by the blood when the child reaches 6 years of age? (continued)
606 PART IX ENDOCRINE PHYSIOLOGY (A) Mental ability would be impaired, (B) Are decreased by thyroid hormones (F) Couples dehydroalanine with a body growth rate would be slowed, (C) Dissipate the proton gradient thyroxine residue and thyroid gland size would be larger across the mitochondrial membrane to 8. A 25-year-old woman complains of than normal generate heat weight loss, heat intolerance, excessive (B) Mental ability would be unaffected, (D) Are present exclusively in brown fat sweating, and weakness. TSH and body growth rate would be slowed, (E) Uncouple fatty acid oxidation from thyroid hormones are elevated, goiter and thyroid gland size would be glucose oxidation in mitochondria is present, but no antithyroid smaller than normal (F) Are essential for maintaining body antibodies are detected. Which of the (C) Mental ability would be impaired, temperature in mammals following diagnoses is consistent with body growth rate would be slowed, 5. Triiodothyronine (T 3 ) these symptoms? and thyroid gland size would be (A) Is produced in greater amounts by (A) Graves’ disease smaller than normal the thyroid gland than T 4 (B) Resistance to thyroid hormone (D) Mental ability would be (B) Is bound by the thyroid receptor action unaffected, body growth rate would be present in the cytosol of target cells (C) Plummer’s disease (thyroid gland unaffected, and thyroid gland size (C) Is formed from T 4 through the adenoma) would be smaller than normal action of a 5-deiodinase (D) A 5-deiodinase deficiency (E) Mental ability would be impaired, (D) Has a half-life of a few minutes in (E) Acute Hashimoto’s disease body growth rate would be slowed, the bloodstream (F) TSH-secreting pituitary tumor and thyroid gland size would be (E) Is released from thyroglobulin normal through the action of thyroid SUGGESTED READING (F) Mental ability would be unaffected, peroxidase Apriletti JW, Ribeiro RC, Wagner RL, et body growth rate would be unaffected, (F) Can be produced by the al. Molecular and structural biology of and thyroid gland size would be deiodination of T 4 in pituitary thyroid hormone receptors. Clin Exp unaffected thyrotrophs Pharmacol Physiol Suppl 3. If the 6-year-old child described in the 6. A 40-year-old man complains of 1998;25:S2–S11. chronic fatigue, aching muscles, and previous question is now treated with occasional numbness in his fingers. Braverman LE, Utiger RD. Werner and thyroid hormones, how would mental Physical examination reveals a modest Ingbar’s The Thyroid: A Fundamental ability, body growth rate, and thyroid weight gain but no goiter is detected. and Clinical Text. 8th Ed. gland size be affected? Laboratory findings include TSH 10 Philadelphia: Lippincott Williams & (A) Mental ability would remain U/L (normal range, 0.5 to 5 U/L); Wilkins, 2000. impaired, body growth rate would be free T 4, low to low-normal. These Goglia F, Moreno M, Lanni A. Action of improved, and thyroid gland size findings are most consistent with a thyroid hormones at the cellular level: would be smaller than normal diagnosis of The mitochondrial target. FEBS Lett (B) Mental ability would be improved, (A) Hypothyroidism secondary to a 1999;452:115–120. body growth rate would be improved, hypothalamic-pituitary defect Larsen PR, Davies TF, Hay ID. The thy- and thyroid gland size would be (B) Hyperthyroidism secondary to a roid gland. In: Wilson JD, Foster DW, normal hypothalamic-pituitary defect Kronenberg HM, Larsen PR, eds: (C) Mental ability would remain (C) Hyperthyroidism as a result of Williams Textbook of Endocrinology. impaired, body growth rate would be iodine excess 9th Ed. Philadelphia: WB Saunders, improved, and thyroid gland size (D) Hypothyroidism as a result of 1998. would be normal autoimmune thyroid disease Meier CA. Thyroid hormone and develop- (D) Mental ability would remain (E) Hypothyroidism as a result of ment: Brain and peripheral tissue In: impaired, body growth rate would be iodine deficiency Hauser P, Rovet J, eds. Thyroid Dis- improved, and thyroid gland size (F) Hyperthyroidism as a result of eases of Infancy and Childhood. Wash- would be larger than normal autoimmune thyroid disease ington, DC: American Psychiatric (E) Mental ability would be improved, 7. The reaction catalyzed by thyroid Press, 1999. body growth rate would remain peroxidase Motomura K, Brent GA. Mechanisms of slowed, and thyroid gland size would (A) Produces hydrogen peroxide as an thyroid hormone action. Endocrinol be normal end-product Metab Clin North Am 1998;27:1–23. (F) Mental ability would be improved, (B) Couples two iodotyrosine residues Munoz A, Bernal J. Biological activities of body growth rate would remain to form an iodothyronine residue thyroid hormone receptors. Eur J En- slowed, and thyroid gland size would (C) Occurs on the basal membrane of docrinol 1997;137:433–445. larger than normal the follicular cell Reitman ML, He Y, Gong D-W. Thyroid 4. Uncoupling proteins (D) Catalyzes the release of thyroid hormone and other regulators of un- (A) Utilize the proton gradient across hormones into the circulation coupling proteins. Int J Obes Relat the mitochondrial membrane to (E) Couples MIT and DIT to Metab Disord 1999;23(Suppl facilitate ATP synthesis thyroglobulin 6):S56–S59.
The Adrenal Gland CHAPTER 34 Robert V. Considine, Ph.D. 34 CHAPTER OUTLINE ■ FUNCTIONAL ANATOMY OF THE ADRENAL GLAND ■ PRODUCTS OF THE ADRENAL MEDULLA ■ HORMONES OF THE ADRENAL CORTEX KEY CONCEPTS 1. The adrenal gland is comprised of an outer cortex sur- ularis by increasing intracellular cAMP. ACTH also has a rounding an inner medulla. The cortex contains three his- trophic effect on these cells. tologically distinct zones (from outside to inside): the zona 9. Angiotensin II and angiotensin III stimulate aldosterone glomerulosa, zona fasciculata, and zona reticularis. synthesis in the cells of the zona glomerulosa by increas- 2. Hormones secreted by the adrenal cortex include glucocor- ing cytosolic calcium and activating protein kinase C. ticoids, aldosterone, and adrenal androgens. 10. Glucocorticoids bind to glucocorticoid receptors in the cy- 3. The glucocorticoids cortisol and corticosterone are synthe- tosol of target cells. The glucocorticoid-bound receptor sized in the zona fasciculata and zona reticularis of the ad- translocates to the nucleus and then binds to glucocorti- renal cortex. coid response elements in the DNA to increase or decrease 4. The mineralocorticoid aldosterone is synthesized in the the transcription of specific genes. zona glomerulosa of the adrenal cortex. 11. Glucocorticoids are essential to the adaptation of the body 5. Cholesterol, used in the synthesis of the adrenal cortical to fasting, injury, and stress. hormones, comes from cholesterol esters stored in the 12. The catecholamines epinephrine and norepinephrine are cells. Stored cholesterol is derived mainly from low-den- synthesized and secreted by the chromaffin cells of the ad- sity lipoprotein particles circulating in the blood, but it can renal medulla. also be synthesized de novo from acetate within the adre- 13. Catecholamines interact with four adrenergic receptors ( 1 , nal gland. 2 , 1 , and 2 ) that mediate the cellular effects of the hor- 6. The conversion of cholesterol to pregnenolone in mito- mones. chondria is the common first step in the synthesis of all ad- 14. Stimuli such as injury, anger, pain, cold, strenuous exer- renal steroids and occurs in all three zones of the cortex. cise, and hypoglycemia generate impulses in the choliner- 7. The liver is the main site for the metabolism of adrenal gic preganglionic fibers innervating the chromaffin cells, steroids, which are conjugated to glucuronic acid and ex- resulting in the secretion of catecholamines. creted in the urine. 15. To counteract hypoglycemia, catecholamines stimulate 8. ACTH increases glucocorticoid and androgen synthesis in glucose production in the liver, lactate release from mus- adrenal cortical cells in the zona fasciculata and zona retic- cle, and lipolysis in adipose tissue. o remain alive, the organs and tissues of the human lar environment are replenished by the intake of food and Tbody must have a finely regulated extracellular envi- liquids. However, a person can survive for weeks on little ronment. This environment must contain the correct con- else but water because the body has a remarkable capacity centrations of ions to maintain body fluid volume and to for adjusting the functions of its organs and tissues to pre- enable excitable cells to function. The extracellular envi- serve body fluid volume and composition. ronment must also have an adequate supply of metabolic The adrenal glands play a key role in making these ad- substrates for cells to generate ATP. Salts, water, and other justments. This is readily apparent from the fact that an organic substances are continually lost from the body as a adrenalectomized animal, unlike its normal counterpart, result of perspiration, respiration, and excretion. Metabolic cannot survive prolonged fasting. Its blood glucose supply substrates are constantly used by cells. Under normal con- diminishes, ATP generation by the cells becomes inade- ditions, these critical constituents of the body’s extracellu- quate to support life, and the animal eventually dies. Even 607
608 PART IX ENDOCRINE PHYSIOLOGY when fed a normal diet, an adrenalectomized animal typi- Zona glomerulosa cally loses body sodium and water over time, and eventu- Zona fasciculata Cortex: 80–90% ally dies of circulatory collapse. Its death is caused by a lack Zona reticularis of certain steroid hormones that are produced and secreted by the cortex of the adrenal gland. The glucocorticoid hormones, cortisol and corticos- terone, play essential roles in adjusting the metabolism of Medulla: 10–20% carbohydrates, lipids, and proteins in liver, muscle, and adi- pose tissues during fasting, which assures an adequate sup- ply of glucose and fatty acids for energy metabolism de- spite the absence of food. The mineralocorticoid hormone aldosterone, another steroid hormone produced by the ad- renal cortex, stimulates the kidneys to conserve sodium Catecholamines and, hence, body fluid volume. The glucocorticoids also enable the body to cope with Androgens physical and emotional traumas or stresses. The physiological importance of this action of the glucocorticoids is empha- Cortisol sized by the fact that adrenalectomized animals lose their ability to cope with physical or emotional stresses. Even when Aldosterone given an appropriate diet to prevent blood glucose and body sodium depletion, an adrenalectomized animal may die when exposed to traumas that are not fatal to normal animals. Hormones produced by the other endocrine component FIGURE 34.1 The three zones of the adrenal cortex and of the adrenal gland, the medulla, are also involved in com- corresponding hormone secretion. pensatory reactions of the body to trauma or life-threaten- ing situations. These hormones are the catecholamines, ep- androgen dehydroepiandrosterone, which is related chem- inephrine and norepinephrine, which have widespread ically to the male sex hormone testosterone. The molecu- effects on the cardiovascular system and muscular system lar structures of these hormones are shown in Figure 34.2. and on carbohydrate and lipid metabolism in liver, muscle, Like all endocrine organs, the adrenal cortex is highly and adipose tissues. vascularized. Many small arteries branch from the aorta and renal arteries and enter the cortex. These vessels give rise to capillaries that course radially through the cortex and ter- FUNCTIONAL ANATOMY OF THE minate in venous sinuses in the zona reticularis and adrenal ADRENAL GLAND medulla; therefore, the hormones produced by the cells of the cortex have ready access to the circulation. The human adrenal glands are paired, pyramid-shaped or- The cells of the adrenal cortex contain abundant lipid gans located on the upper poles of each kidney. The ad- droplets. This stored lipid is functionally significant be- renal gland is actually a composite of two separate en- cause cholesterol esters present in the droplets are an im- docrine organs, one inside the other, each secreting portant source of the cholesterol used as a precursor for the separate hormones and each regulated by different mech- synthesis of steroid hormones. anisms. The outer portion or cortex of the adrenal gland completely surrounds the inner portion or medulla and makes up most of the gland. During embryonic develop- The Adrenal Medulla Is a Modified ment, the cortex forms from mesoderm; the medulla arises Sympathetic Ganglion from neural ectoderm. The adrenal medulla can be considered a modified sympa- thetic ganglion. The medulla consists of clumps and strands The Adrenal Cortex Consists of of chromaffin cells interspersed with venous sinuses. Chro- Three Distinct Zones maffin cells, like the modified postganglionic neurons that receive sympathetic preganglionic cholinergic innervation In the adult human, the adrenal cortex consists of three his- from the splanchnic nerves, produce catecholamine hor- tologically distinct zones or layers (Fig. 34.1). The outer mones, principally epinephrine and norepinephrine. Epi- zone, which lies immediately under the capsule of the nephrine and NE are stored in granules in chromaffin cells gland, is called the zona glomerulosa and consists of small and discharged into venous sinuses of the adrenal medulla clumps of cells that produce the mineralocorticoid aldos- when the adrenal branches of splanchnic nerves are stimu- terone. The zona fasciculata is the middle and thickest lated (see Fig. 6.5). layer of the cortex and consists of cords of cells oriented ra- dial to the center of the gland. The inner layer is comprised of interlaced strands of cells called the zona reticularis. HORMONES OF THE ADRENAL CORTEX The zona fasciculata and zona reticularis both produce the physiologically important glucocorticoids, cortisol and Only small amounts of the glucocorticoids, aldosterone, corticosterone. These layers of the cortex also produce the and adrenal androgens are found in adrenal cortical cells at
CHAPTER 34 The Adrenal Gland 609 Zona glomerulosa Comparison of Shared Activities of TABLE 34.2 Adrenal Cortical Hormones Glucocorticoid Mineralocorticoid Hormone Activity a Activity b Cortisol 100 0.25 Corticosterone 20 0.5 Aldosterone 10 100 a Percentage activity, with cortisol being 100% Aldosterone b Percentage activity, with aldosterone being 100% Zona fasciculata and zona reticularis ple, cortisol and corticosterone have some mineralocorti- coid activity; conversely, aldosterone has some glucocorti- coid activity. However, given the amounts of these hor- mones secreted under normal circumstances and their relative activities, glucocorticoids are not physiologically important mineralocorticoids, nor does aldosterone func- tion physiologically as a glucocorticoid. As discussed in detail later, the amounts of glucocorti- coids and aldosterone secreted by an individual can vary Cortisol Corticosterone greatly from those given in Table 34.1. The amount se- creted depends on the person’s physiological state. For ex- ample, in an individual subjected to severe physical or emo- tional trauma, the rate of cortisol secretion may be 10 times greater than the resting rate shown in Table 34.1. Certain diseases of the adrenal cortex that involve steroid hormone biosynthesis can significantly increase or decrease the amount of hormones produced. Dehydroepiandrosterone The adrenal cortex also produces and secretes substan- Molecular structures of the important hor- FIGURE 34.2 tial amounts of androgenic steroids. Dehydroepiandros- mones secreted by the adrenal cortex. terone (DHEA) in both the free form and the sulfated form (DHEAS) is the main androgen secreted by the adrenal cortex of both men and women (see Table 34.1). Lesser a given time because those cells produce and secrete these amounts of other androgens are also produced. The adrenal hormones on demand, rather than storing them. Table 34.1 cortex is the main source of androgens in the blood in hu- shows the daily production of adrenal cortex hormones in man females. In the human male, however, androgens pro- a healthy adult under resting (unstimulated) conditions. Be- duced by the testes and adrenal cortex contribute to the cause the molecular weights of these substances do not vary male sex hormones circulating in the blood. Adrenal an- greatly, comparing the amounts secreted indicates the rel- drogens normally have little physiological effect other than ative number of molecules of each hormone produced a role in development before the start of puberty in both daily. Humans secrete about 10 times more cortisol than girls and boys. This is because the male sex hormone activ- corticosterone during an average day, and corticosterone ity of the adrenal androgens is weak. Exceptions occur in has only one fifth of the glucocorticoid activity of cortisol individuals who produce inappropriately large amounts of (Table 34.2). Cortisol is considered the physiologically im- certain adrenal androgens as a result of diseases affecting portant glucocorticoid in humans. Compared with the glu- the pathways of steroid biosynthesis in the adrenal cortex. cocorticoids, a much smaller amount of aldosterone is se- creted each day. Because of similarities in their structures, the glucocorti- Adrenal Steroid Hormones Are Synthesized coids and aldosterone have overlapping actions. For exam- From Cholesterol Cholesterol is the starting material for the synthesis of steroid hormones. A cholesterol molecule consists of four The Average Daily Production of Hor- TABLE 34.1 interconnected rings of carbon atoms and a side chain of mones by the Adrenal Cortex eight carbon atoms extending from one ring (Fig. 34.3). In all, there are 27 carbon atoms in cholesterol, numbered as Hormone Amount Produced (mg/day) shown in the figure. Cortisol 20 Corticosterone 2 Sources of Cholesterol. The immediate source of choles- Aldosterone 0.1 terol used in the biosynthesis of steroid hormones is the Dehydroepiandrosterone 30 abundant lipid droplets in adrenal cortical cells. The cho-
610 PART IX ENDOCRINE PHYSIOLOGY 21 22 24 26 20 23 25 Blood 18 Apoprotein 12 LDL 17 27 11 16 Coated pit Plasma membrane 19 13 1 9 C D 2 14 15 10 8 A B Endocytosis 3 5 7 4 6 OH Cholesterol ester OH CEH Fatty acid cholesterol Steroids ACAT CEH Cholesterol ester HMG CoA reductase O Acetate Lipid HO droplet O Adrenal cortical cell Sources of cholesterol for steroid biosyn- FIGURE 34.4 thesis by the adrenal cortex. Most choles- terol comes from low-density lipoprotein (LDL) particles in the blood, which bind to receptors in the plasma membrane and are The formation of pregnenolone from cho- taken up by endocytosis. The cholesterol in the LDL particle is FIGURE 34.3 lesterol by the action of cholesterol side- used directly for steroidogenesis or stored in lipid droplets for chain cleavage enzyme (CYP11A1). Note the chemical struc- later use. Some cholesterol is synthesized directly from acetate. ture of cholesterol, how the four rings are lettered (A to D), and CEH, cholesterol ester hydrolase; ACAT, acyl-CoA:cholesterol how the carbons are numbered. The hydrogen atoms on the car- acyltransferase; HMG, 3-hydroxy-3-methylglutaryl. bons composing the rings are omitted from the figure. lesterol present in these lipid droplets is mainly in the form are taken up by the cell through endocytosis. The endo- of cholesterol esters, single molecules of cholesterol ester- cytic vesicle containing the LDL particles fuses with a lyso- ified to single fatty acid molecules. The free cholesterol some and the particle is degraded. The cholesterol esters in used in steroid biosynthesis is generated from these choles- the core of the particle are hydrolyzed to free cholesterol terol esters by the action of cholesterol esterase (choles- and fatty acid by the action of CEH. terol ester hydrolase [CEH]), which hydrolyzes the ester Any cholesterol not immediately used by the cell is con- bond. The free cholesterol generated by that cleavage en- verted again to cholesterol esters by the action of the en- ters mitochondria located in close proximity to the lipid zyme acyl-CoA:cholesterol acyltransferase (ACAT). The droplet. The process of remodeling the cholesterol mole- esters are then stored in the lipid droplets of the cell to be cule into steroid hormones is then initiated. used later. The cholesterol that has been removed from the lipid When steroid biosynthesis is proceeding at a high rate, droplets for steroid hormone biosynthesis is replenished in cholesterol delivered to the adrenal cell may be diverted di- two ways (Fig. 34.4). Most of the cholesterol converted to rectly to mitochondria for steroid production rather than steroid hormones by the human adrenal gland comes from reesterified and stored. Accumulating evidence suggests cholesterol esters contained in low-density lipoprotein that high-density lipoprotein (HDL) cholesterol may also (LDL) particles circulating in the blood. The LDL particles be used as a substrate for adrenal steroidogenesis. consist of a core of cholesterol esters surrounded by a coat In humans, cholesterol that has been synthesized de novo of cholesterol and phospholipids. A 400-kDa protein mol- from acetate by the adrenal glands is a significant but minor ecule called apoprotein B 100 is also present on the surface source of cholesterol for steroid hormone formation. The of the LDL particle; it is recognized by LDL receptors lo- rate-limiting step in this process is catalyzed by the enzyme calized to coated pits on the plasma membrane of adrenal 3-hydroxy-3-methylglutaryl CoA reductase (HMG CoA cortical cells (see Fig. 34.4). The apoprotein binds to the reductase). The newly synthesized cholesterol is then in- LDL receptor, and both the LDL particle and the receptor corporated into cellular structures, such as membranes, or
CHAPTER 34 The Adrenal Gland 611 converted to cholesterol esters through the action of In cells of the zona fasciculata and zona reticularis, most ACAT and stored in lipid droplets (see Fig. 34.4). of the pregnenolone is converted to cortisol and the main adrenal androgen dehydroepiandrosterone (DHEA). Preg- Pathways for the Synthesis of Steroid Hormones. nenolone molecules bind to the enzyme 17-hydroxylase Adrenal steroid hormones are synthesized by four CYP (CYP17), embedded in the ER membrane, which hydroxy- enzymes. The CYPs are a large family of oxidative en- lates pregnenolone at carbon 17. The product formed by zymes with a 450 nm absorbance maximum when com- this reaction is 17-hydroxypregnenolone (see Fig. 34.5). plexed with carbon monoxide; hence, these molecules The 17-hydroxylase has an additional enzymatic ac- were once referred to as cytochrome P450 enzymes. The tion that becomes important at this step in the steroido- adrenal CYPs are more commonly known by their trivial genic process. Once the enzyme has hydroxylated carbon names, which denote their function in steroid biosynthe- 17 of pregnenolone to form 17-hydroxypregnenolone, sis (see Table 34.3). it has the ability to lyse or cleave the carbon 20–21 side The conversion of cholesterol into steroid hormones be- chain from the steroid structure. Some molecules of 17- gins with the formation of free cholesterol from the cho- hydroxypregnenolone undergo this reaction and are con- lesterol esters stored in intracellular lipid droplets. Free verted to the 19-carbon steroid DHEA. This action of cholesterol molecules enter the mitochondria, which are 17-hydroxylase is essential for the formation of andro- located close to the lipid droplets, by a mechanism that is gens (19 carbon steroids) and estrogens (18 carbon not well understood. Evidence indicates that free choles- steroids), which lack the carbon 20–21 side chain. There- terol associates with a small protein called sterol carrier fore, this lyase activity of 17-hydroxylase is important in protein 2, which facilitates its entry into the mitochon- the gonads, where androgens and estrogens are primarily drion in some manner. Several other proteins, as well as made. 17-hydroxylase does not exert significant lyase cAMP, appear to be involved in cholesterol transport into activity in children before age 7 or 8. As a result, young mitochondria, but the process is still unclear. boys and girls do not secrete significant amounts of adre- Once inside a mitochondrion, single cholesterol mole- nal androgens. The appearance of significant adrenal an- cules bind to the cholesterol side-chain cleavage enzyme drogen secretion in children of both sexes is termed (CYP11A1), embedded in the inner mitochondrial mem- adrenarche. It is not related to the onset of puberty, since brane. This enzyme catalyzes the first and rate-limiting re- it normally occurs before the activation of the hypothala- action in steroidogenesis, which remodels the cholesterol mic-pituitary-gonad axis, which initiates puberty. The ad- molecule into a 21-carbon steroid intermediate called preg- renal androgens produced as a result of adrenarche are a nenolone. The reaction occurs in three steps, as shown in stimulus for the growth of pubic and axillary hair. Figure 34.3. The first two steps consist of the hydroxylation Those molecules of 17-hydroxypregnenolone that dis- of carbons 20 and 22 by cholesterol side-chain cleavage en- sociate as such from 17-hydroxylase bind next to another zyme. Then the enzyme cleaves the side chain of choles- ER enzyme, 3-hydroxysteroid dehydrogenase (3-HSD terol between carbons 20 and 22, yielding pregnenolone II). This enzyme acts on 17-hydroxypregnenolone to iso- and isocaproic acid. merize the double bond in ring B to ring A and to dehydro- Once formed, pregnenolone molecules dissociate from genate the 3-hydroxy group, forming a 3-keto group. The cholesterol side-chain cleavage enzyme, leave the mito- product formed is 17-hydroxyprogesterone (see Fig. 34.5). chondrion, and enter the smooth ER nearby. This mecha- This intermediate then binds to another enzyme, 21-hy- nism is not understood. At this point, the further remodel- droxylase (CYP21A2), which hydroxylates it at carbon 21. ing of pregnenolone into steroid hormones can vary, The mechanism of this hydroxylation is similar to that per- depending on whether the process occurs in the zona fas- formed by the 17-hydroxylase. The product formed is 11- ciculata and zona reticularis or the zona glomerulosa. We deoxycortisol, which is the immediate precursor for cortisol. first consider what occurs in the zona fasciculata and zona To be converted to cortisol, 11-deoxycortisol molecules reticularis. These biosynthetic events are summarized in must be transferred back into the mitochondrion to be Figure 34.5. acted on by 11-hydroxylase (CYP11B1) embedded in the inner mitochondrial membrane. This enzyme hydroxylates 11-deoxycortisol on carbon 11, converting it into cortisol. The 11-hydroxyl group is the molecular feature that con- Nomenclature for the Steroidogenic En- fers glucocorticoid activity on the steroid. Cortisol is then TABLE 34.3 zymes secreted into the bloodstream. Some of the pregnenolone molecules generated in cells Previous Current Common Name Form Form Gene of the zona fasciculata and zona reticularis first bind to 3- hydroxysteroid dehydrogenase when they enter the endo- Cholesterol side-chain P450 SCC CYP11A1 CYP11A1 plasmic reticulum. As a result, they are converted to prog- cleavage enzyme esterone. Some of these progesterone molecules are 3-Hydroxysteroid 3-HSD 3-HSD II HSD3B2 hydroxylated by 21-hydroxylase to form the mineralocor- dehydrogenase ticoid 11-deoxycorticosterone (DOC) (see Fig. 34.5). The 17-Hydroxylase P450 C17 CYP17 CYP17 11-deoxycorticosterone formed may be either secreted or 21-Hydroxylase P450 C21 CYP21A2 CYP21A2 11-Hydroxylase P450 C11 CYP11B1 CYP11B1 transferred back into the mitochondrion. There it is acted Aldosterone synthase P450 C11AS CYP11B2 CYP11B2 on by 11-hydroxylase to form corticosterone, which is then secreted into the circulation.
612 PART IX ENDOCRINE PHYSIOLOGY Cholesterol Cholesterol CH 3 side-chain cleavage CO O (CYPIIAI) OH 17α-Hydroxylase 17α-Hydroxylase (CYP17) (CYP17) Pregnenolone 17-OH Pregnenolone Dehydroepiandrosterone 3β-Hydroxysteroid 3β-Hydroxysteroid dehydrogenase dehydrogenase (3β-HSD II) (3β-HSD II) O 17α-Hydroxylase 17α-Hydroxylase (CYP17) (CYP17) OO Progesterone 17-OH Progesterone Androstenedione CH 2 OH 21-Hydroxylase CH 2 OH (CYP21A2) 11-Deoxycorticosterone 11-Deoxycortisol 11β-Hydroxylase (CYPIIBI) HO HO Corticosterone Cortisol Aldosterone synthase (CYPIIB2) O CH HO The synthesis of steroids in the adrenal cortex. Aldosterone FIGURE 34.5 Progesterone may also undergo 17-hydroxylation in 17-hydroxylation in these cells, and cortisol and adrenal the zona fasciculata and zona reticularis. It is then con- androgens are not formed by these cells. Instead, the enzy- verted to either cortisol or the adrenal androgen an- matic pathway leading to the formation of aldosterone is drostenedione. followed (see Fig. 34.5). Pregnenolone is converted by en- The 17-hydroxylase is not present in cells of the zona zymes in the endoplasmic reticulum to progesterone and glomerulosa; therefore, pregnenolone does not undergo 11-deoxycorticosterone. The latter compound then moves
CHAPTER 34 The Adrenal Gland 613 into the mitochondrion, where it is converted to aldos- adrenal glands by microorganisms or autoimmune disease. terone. This conversion involves three steps: the hydroxy- This disorder is called Addison’s disease. If sufficient adrenal lation of carbon 11 to form corticosterone, the hydroxyla- cortical tissue is lost, the resulting decrease in aldosterone tion of carbon 18 to form 18-hydroxycorticosterone, and production can lead to vascular collapse and death, unless the oxidation of the 18-hydroxymethyl group to form al- hormone therapy is given (see Clinical Focus Box 34.1). dosterone. In humans, these three reactions are catalyzed by a single enzyme, aldosterone synthase (CYP11B2), an Transport of Adrenal Steroids in Blood. As noted earlier, isozyme of 11-hydroxylase (CYP11B1), expressed only in steroid hormones are not stored to any extent by cells of the glomerulosa cells. The 11-hydroxylase enzyme, which is adrenal cortex but are continually synthesized and secreted. expressed in the zona fasciculata and zona reticularis, al- The rate of secretion may change dramatically, however, de- though closely related to aldosterone synthase, cannot cat- pending on stimuli received by the adrenal cortical cells. The alyze all three reactions involved in the conversion of 11- process by which steroid hormones are secreted is not well deoxycorticosterone to aldosterone; therefore, aldosterone studied. It has been assumed that the accumulation of the fi- is not synthesized in the zona fasciculata and zona reticu- nal products of the steroidogenic pathways creates a con- laris of the adrenal cortex. centration gradient for steroid hormone between cells and blood. This gradient is thought to be the driving force for Genetic Defects in Adrenal Steroidogenesis. Inherited diffusion of the lipid-soluble steroids through cellular mem- genetic defects can cause relative or absolute deficiencies in branes and into the circulation. the enzymes involved in the steroid hormone biosynthetic A large fraction of the adrenal steroids that enter the pathways. The immediate consequences of these defects bloodstream become bound noncovalently to certain are changes in the types and amounts of steroid hormones plasma proteins. One of these is corticosteroid-binding secreted by the adrenal cortex. The end result is disease. globulin (CBG), a glycoprotein produced by the liver. Most of the genetic defects affecting the steroidogenic CBG binds glucocorticoids and aldosterone, but has a enzymes impair the formation of cortisol. As discussed in greater affinity for the glucocorticoids. Serum albumin also Chapter 32, a drop in cortisol concentration in the blood binds steroid molecules. Albumin has a high capacity for stimulates the secretion of adrenocorticotropic hormone binding steroids, but its interaction with steroids is weak. (ACTH) by the anterior pituitary. The consequent rise in The binding of a steroid hormone to a circulating protein ACTH in the blood exerts a trophic (growth-promoting) molecule prevents it from being taken up by cells or being effect on the adrenal cortex, resulting in adrenal hypertro- excreted in the urine. phy. Because of this mechanism, individuals with genetic Circulating steroid hormone molecules not bound to defects affecting adrenal steroidogenesis usually have hy- plasma proteins are free to interact with receptors on cells pertrophied adrenal glands. These diseases are collectively and, therefore, are cleared from the blood. As this occurs, called congenital adrenal hyperplasia. bound hormone dissociates from its binding protein and re- In humans, inherited genetic defects occur that affect plenishes the circulating pool of free hormone. Because of cholesterol side-chain cleavage enzyme, 17-hydroxylase, this process, adrenal steroid hormones have long half-lives 3-hydroxysteroid dehydrogenase, 21-hydroxylase, 11- in the body, ranging from many minutes to hours. hydroxylase, and aldosterone synthase. The most common defect involves mutations in the gene for 21-hydroxylase Metabolism of Adrenal Steroids in the Liver. Adrenal and occurs in 1 of 7,000 people. The gene for 21-hydroxy- steroid hormones are eliminated from the body primarily lase may be deleted entirely, or mutant genes may code for by excretion in the urine after they have been structurally forms of 21-hydroxylase with impaired enzyme activity. modified to destroy their hormone activity and increase The consequent reduction in the amount of active 21-hy- their water solubility. Although many cells are capable of droxylase in the adrenal cortex interferes with the forma- carrying out these modifications, they primarily occur in tion of cortisol, corticosterone, and aldosterone, all of the liver. which are hydroxylated at carbon 21. Because of the re- The most common structural modifications made in ad- duction of cortisol (and corticosterone) secretion in these renal steroids involve reduction of the double bond in ring individuals, ACTH secretion is stimulated. This, in turn, A and conjugation of the resultant hydroxyl group formed causes hypertrophy of the adrenal glands and stimulates the on carbon 3 with glucuronic acid. Figure 34.6 shows how glands to produce steroids. cortisol is modified in this manner to produce a major exc- Because 21-hydroxylation is impaired, the ACTH stim- retable metabolite, tetrahydrocortisol glucuronide. Corti- ulus causes pregnenolone to be converted to adrenal an- sol, and other 21-carbon steroids with a 17-hydroxyl drogens in inappropriately high amounts. Thus, women af- group and a 20-keto group, may undergo lysis of the carbon flicted with 21-hydroxylase deficiency exhibit virilization 20–21 side chain as well. The resultant metabolite, with a from the masculinizing effects of excessive adrenal andro- keto group on carbon 17, appears as one of the 17-ketos- gen secretion. In severe cases, the deficiency in aldosterone teroids in the urine. Adrenal androgens are also 17-ketos- production can lead to sodium depletion, dehydration, vas- teroids. They are usually conjugated with sulfuric acid or cular collapse, and death, if appropriate hormone therapy is glucuronic acid before being excreted and normally com- not given. prise the bulk of the 17-ketosteroids in the urine. Before the development of specific methods to measure androgens Addison’s Disease. Glucocorticoid and aldosterone defi- and 17-hydroxycorticosteroids in body fluids, the amount ciency also occur as a result of pathological destruction of the of 17-ketosteroids in urine was used clinically as a crude in-
614 PART IX ENDOCRINE PHYSIOLOGY CLINICAL FOCUS BOX 34.1 Primary Adrenal Insufficiency: Addison’s Disease most of their androgen from the testes) as decreased pubic Adrenal insufficiency may be caused by destruction of the and axillary hair and decreased libido. adrenal cortex (primary adrenal insufficiency), low pituitary Antibodies that react with all three zones of the adrenal ACTH secretion (secondary adrenal insufficiency), or defi- cortex have been identified in autoimmune adrenalitis and cient hypothalamic release of CRH (tertiary adrenal insuffi- are more common in women than in men. The presence of ciency). Addison’s disease (primary adrenal insuffi- antibodies appears to precede the development of adrenal ciency) results from the destruction of the adrenal gland by insufficiency by several years. Antiadrenal antibodies are microorganisms or autoimmune disease. When Addison’s mainly directed to the steroidogenic enzymes cholesterol first described primary adrenal insufficiency in the mid- side-chain cleavage enzyme (CYP11A1), 17-hydroxylase 1800s, bilateral adrenal destruction by tuberculosis was the (CYP17) and 21-hydroxylase (CYP21A2), although antibod- most common cause of the disease. Today, autoimmune ies to other steroidogenic enzymes may also be present. In destruction accounts for 70 to 90% of all cases, with the re- the initial stages of the disease, the adrenal glands may be mainder the resulting from infection, cancer, or adrenal enlarged with extensive lymphocyte infiltration. Genetic hemorrhage. The prevalence of primary adrenal insuffi- susceptibility to autoimmune adrenal insufficiency is ciency is about 40 to 110 cases per 1 million adults, with an strongly linked with the HLA-B8, HLA-DR3, and HLA-DR4 incidence of about 6 cases per 1 million adults per year. alleles of human leukocyte antigen (HLA). The earliest sign In primary adrenal insufficiency, all three zones of the of adrenal insufficiency is an increase in plasma renin ac- adrenal cortex are usually involved. The result is inade- tivity, with a low or normal aldosterone level, which sug- quate secretion of glucocorticoids, mineralocorticoids, and gests that the zona glomerulosa is affected first during dis- androgens. Major symptoms are not usually detected until ease progression. 90% of the gland has been destroyed. The initial symptoms Treatment for acute adrenal insufficiency should be di- generally have a gradual onset, with only a partial gluco- rected at reversal of the hypotension and electrolyte ab- corticoid deficiency resulting in inadequate cortisol in- normalities. Large volumes of 0.9% saline or 5% dextrose crease in response to stress. Mineralocorticoid deficiency in saline should be infused as quickly as possible. Dexam- may only appear as a mild postural hypotension. Progres- ethasone or a soluble form of injectable cortisol should sion to complete glucocorticoid deficiency results in a de- also be given. Daily glucocorticoid and mineralocorticoid creased sense of well-being and abnormal glucose metab- replacement allows the patient to lead a normal active life. olism. Lack of mineralocorticoid leads to decreased renal potassium secretion and reduced sodium retention, the Reference loss of which results in hypotension and dehydration. The Orth DN, Kovacs WJ. The adrenal cortex. In: Wilson JD, combined lack of glucocorticoid and mineralocorticoid can Foster DW, Kronenberg HM, Larsen PR, eds. Williams Text- lead to vascular collapse, shock, and death. Adrenal an- book of Endocrinology. 9th Ed. Philadelphia: WB Saun- drogen deficiency is observed in women only (men derive ders, 1998;517–664. dicator of the production of these substances by the adre- in the cell. cAMP activates protein kinase A (PKA), which nal gland. phosphorylates proteins that regulate steroidogenesis. The rapid rise in cAMP produced by ACTH stimulates the mechanism that transfers cholesterol into the inner mi- ACTH Regulates the Synthesis of tochondrial membrane. This action provides abundant cho- Adrenal Steroids lesterol for side-chain cleavage enzyme, which carries out Adrenocorticotropic hormone (ACTH) is the physiologi- the rate-limiting step in steroidogenesis. As a result, the rates cal regulator of the synthesis and secretion of glucocorti- of steroid hormone formation and secretion rise greatly. coids and androgens by the zona fasciculata and zona retic- ularis. It has a very rapid stimulatory effect on Gene Expression for Steroidogenic Enzymes. Adreno- steroidogenesis in these cells, which can result in a great corticotropic hormone maintains the capacity of the cells rise in blood glucocorticoids within seconds. It also exerts of the zona fasciculata and zona reticularis to produce several long-term trophic effects on these cells, all directed steroid hormones by stimulating the transcription of the toward maintaining the cellular machinery necessary to genes for many of the enzymes involved in steroidogenesis. carry out steroidogenesis at a high, sustained rate. These For example, transcription of the genes for side-chain actions of ACTH are summarized in Figure 34.7. cleavage enzyme, 17-hydroxylase, 21-hydroxylase, and 11-hydroxylase, is increased several hours after adrenal Role of cAMP. When the level of ACTH in the blood cortical cells have been stimulated by ACTH. Because nor- rises, increased numbers of ACTH molecules interact with mal individuals are continually exposed to episodes of receptors on the plasma membranes of adrenal cortical ACTH secretion (see Fig. 32.7), the mRNA for these en- cells. These ACTH receptors are coupled to the enzyme zymes is well maintained in the cells. Again, this long-term adenylyl cyclase by stimulatory guanine nucleotide-bind- or maintenance effect of ACTH is due to its ability to in- ing proteins (G s proteins). The production of cAMP from crease cAMP in the cells (see Fig. 34.7). ATP greatly increases, and the concentration of cAMP rises The importance of ACTH in gene transcription be-
CHAPTER 34 The Adrenal Gland 615 CH OH CH 2 OH Zona fasciculata cell or 2 zona reticularis cell C O CO HO OH HO OH Nucleus O O Cortisol Dihydrocortisol cAMP PKA P proteins OH CH 2 AC C O mRNAs ATP Lipid HO OH G s droplets Steroidogenic enzymes ACTH Cholesterol Mitochondrion H Tetrahydrocortisol Pregnenolone CH OH 2 CO Smooth HO OH ER COO - H O O H Glucocorticoids Androgens H Blood OH H Urine HO H FIGURE 34.7 The main actions of ACTH on steroidogen- esis. ACTH binds to plasma membrane recep- H OH tors, which are coupled to adenylyl cyclase (AC) by stimulatory Tetrahydrocortisol glucuronide G proteins (G s ). cAMP rises in the cells and activates protein ki- nase A (PKA), which then phosphorylates certain proteins (P- The metabolism of cortisol to tetrahydro- FIGURE 34.6 Proteins). These proteins presumably initiate steroidogenesis and cortisol glucuronide in the liver. The re- stimulate the expression of genes for steroidogenic enzymes. duced and conjugated steroid is inactive. Because it is more water- soluble than cortisol, it is easily excreted in the urine. comes evident in hypophysectomized animals or humans steroidogenesis in the zona fasciculata and zona reticularis. with ACTH deficiency. An example of the latter is a human It increases the abundance of LDL receptors and the activ- treated chronically with large doses of cortisol or related ity of the enzyme HMG-CoA reductase in these cells. steroids, which causes prolonged suppression of ACTH se- These actions increase the availability of cholesterol for cretion by the anterior pituitary. The chronic lack of steroidogenesis. It is not clear whether ACTH exerts these ACTH decreases the transcription of the genes for effects directly. The abundance of LDL receptors in the steroidogenic enzymes, causing a deficiency in these en- plasma membrane and the activity of HMG-CoA reductase zymes in the adrenals. As a result, the administration of in most cells are inversely related to the amount of cellular ACTH to such an individual does not cause a marked in- cholesterol. By stimulating steroidogenesis, ACTH reduces crease in glucocorticoid secretion. Chronic exposure to the amount of cholesterol in adrenal cells; therefore, the in- ACTH is required to restore mRNA levels for the steroido- creased abundance of LDL receptors and high HMG-CoA genic enzymes and, hence, the enzymes themselves, to ob- reductase activity in ACTH-stimulated cells may merely re- tain normal steroidogenic responses to ACTH. A patient sult from the normal compensatory mechanisms that func- receiving long-term treatment with glucocorticoid may suf- tion to maintain cell cholesterol levels. fer serious glucocorticoid deficiency if hormone therapy is ACTH also stimulates the activity of cholesterol es- halted abruptly; withdrawing glucocorticoid therapy grad- terase in adrenal cells, which promotes the hydrolysis of ually allows time for endogenous ACTH to restore the cholesterol esters stored in the lipid droplets of these steroidogenic enzyme levels to normal. cells, making free cholesterol available for steroidogenesis. The cholesterol esterase in the adrenal cortex appears to be Effects on Cholesterol Metabolism. ACTH has several identical to hormone-sensitive lipase, which is activated long-term effects on cholesterol metabolism that support when it is phosphorylated by a cAMP-dependent protein
616 PART IX ENDOCRINE PHYSIOLOGY kinase. The rise in cAMP concentration produced by Cleavage of the N-terminal aspartate from angiotensin II ACTH might account for its effect on the enzyme. results in the formation of angiotensin III, which circulates at a concentration of 20% that of angiotensin II. An- Trophic Action on Adrenal Cortical Cell Size. ACTH giotensin III is as potent a stimulator of aldosterone secre- maintains the size of the two inner zones of the adrenal cor- tion as angiotensin II. tex, presumably by stimulating the synthesis of structural elements of the cells; however, it does not affect the size of Action of Angiotensin II on Aldosterone Secretion. An- the cells of the zona glomerulosa. The trophic effect of giotensin II stimulates aldosterone synthesis by promoting ACTH is clearly evident in states of ACTH deficiency or the rate-limiting step in steroidogenesis (i.e., the move- excess. In hypophysectomized or ACTH-deficient individ- ment of cholesterol into the inner mitochondrial mem- uals, the cells of the two inner zones atrophy. Chronic brane and its conversion to pregnenolone). The primary stimulation of these cells with ACTH causes them to hy- mechanism is shown in Figure 34.9. pertrophy. The mechanisms involved in this trophic action The stimulation of aldosterone synthesis is initiated of ACTH are unclear. when angiotensin II binds to its receptors on the plasma membranes of zona glomerulosa cells. The signal generated ACTH and Aldosterone Production. The cells of the by the interaction of angiotensin II with its receptors is zona glomerulosa have ACTH receptors, which are cou- transmitted to phospholipase C (PLC) by a G protein, and pled to adenylyl cyclase. In these cells, cAMP increases in the enzyme becomes activated. The PLC then hydrolyzes response to ACTH, resulting in some increase in aldos- phosphatidylinositol 4,5 bisphosphate (PIP 2 ) in the plasma terone secretion. However, angiotensin II is the important membrane, producing the intracellular second messengers physiological regulator of aldosterone secretion, not inositol trisphosphate (IP 3 ) and diacylglycerol (DAG). The ACTH. Other factors, such as an increase in serum potas- IP 3 mobilizes calcium, which is bound to intracellular struc- sium, can also stimulate aldosterone secretion, but nor- tures, increasing the calcium concentration in the cytosol. mally, they play only a secondary role. This increase in intracellular calcium and DAG activates protein kinase C (PKC). The rise in intracellular calcium Formation of Angiotensin II. Angiotensin II is a short also activates calmodulin-dependent protein kinase peptide consisting of eight amino acid residues. It is (CMK). These enzymes phosphorylate proteins, which formed in the bloodstream by the proteolysis of the 2 - then become involved in initiating steroidogenesis. globulin angiotensinogen, which is secreted by the liver. The formation of angiotensin II occurs in two stages Signals for Increased Angiotensin II Formation. Al- (Fig. 34.8). Angiotensinogen is first cleaved at its N-ter- though angiotensin II is the final mediator in the physio- minal end by the circulating protease renin, releasing the logical regulation of aldosterone secretion, its formation inactive decapeptide angiotensin I. Renin is produced and from angiotensinogen is dependent on the secretion of secreted by granular (juxtaglomerular) cells in the kidneys renin by the kidneys. The rate of renin secretion ultimately (see Chapter 23). A dipeptide is then removed from the determines the rate of aldosterone secretion. Renin is se- C-terminal end of angiotensin I, producing angiotensin II. creted by the granular cells in the walls of the afferent arte- This cleavage is performed by the protease angiotensin- rioles of renal glomeruli. These cells are stimulated to se- converting enzyme present on the endothelial cells lining crete renin by three signals that indicate a possible loss of the vasculature. This step usually occurs as angiotensin I body fluid: a fall in blood pressure in the afferent arterioles molecules traverse the pulmonary circulation. The rate- of the glomeruli, a drop in sodium chloride concentration limiting factor for the formation of angiotensin II is the in renal tubular fluid at the macula densa, and an increase in renin concentration of the blood. renal sympathetic nerve activity (see Chapters 23 and 24). ASP Arg Val Tyr Ile His Pro Phe His Leu Leu Val R Angiotensinogen Renin ASP Arg Val Tyr Ile His Pro Phe His Leu Leu Val R Angiotensin I Converting enzyme ASP Arg Val Tyr Ile His Pro Phe His Leu Angiotensin II Aminopeptidase The formation of an- FIGURE 34.8 ASP Arg Val Tyr Ile His Pro Phe Angiotensin III giotensins I, II, and III from angiotensinogen.
CHAPTER 34 The Adrenal Gland 617 Zona glomerulosa cell channels in the membranes. The consequent rise in cytoso- lic calcium is thought to stimulate aldosterone synthesis by the mechanisms described above for the action of an- giotensin II. Ca 2+ Ca 2+ Aldosterone and Sodium Reabsorption by Kidney AII Tubules. The physiological action of aldosterone is to Ca 2+ stimulate sodium reabsorption in the kidneys by the distal tubule and collecting duct of the nephron and to promote G q 2+ IP 3 Ca CMK the excretion of potassium and hydrogen ions. The mech- anism of action of aldosterone on the kidneys and its role in PLC water and electrolyte balance are discussed in Chapter 24. Lipid P proteins PIP 2 droplets Glucocorticoids Play a Role in the Reactions to Fasting, Injury, and Stress DAG PKC Cholesterol Glucocorticoids widely influence physiological processes. In Mitochondrion fact, most cells have receptors for glucocorticoids and are potential targets for their actions. Consequently, glucocorti- coids have been used extensively as therapeutic agents, and much is known about their pharmacological effects. Smooth Pregnenolone ER Actions on Transcription. Unlike many other hor- mones, glucocorticoids influence physiological processes slowly, sometimes taking hours to produce their effects. Glucocorticoids that are free in the blood diffuse through the plasma membranes of target cells; once inside, they bind tightly but noncovalently to receptor proteins pres- ent in the cytoplasm. The interaction between the gluco- Aldosterone Blood corticoid molecule and its receptor molecule produces an The action of angiotensin II on aldosterone activated glucocorticoid-receptor complex, which FIGURE 34.9 synthesis. Angiotensin II (AII) binds to recep- translocates into the nucleus. tors on the plasma membrane of zona glomerulosa cells. This ac- These complexes then bind to specific regions of DNA tivates phospholipase C (PLC), which is coupled to the an- called glucocorticoid response elements (GREs), which giotensin II receptor by G proteins (G q ). PLC hydrolyzes are near glucocorticoid-sensitive target genes. The binding phosphatidylinositol 4,5 bisphosphate (PIP 2) in the plasma mem- triggers events that either stimulate or inhibit the transcrip- brane, producing inositol trisphosphate (IP 3) and diacylglycerol tion of the target gene. As a result of the change in tran- 2 (DAG). IP 3 mobilizes intracellularly bound Ca . The rise in scription, amounts of mRNA for certain proteins are either Ca 2 and DAG activates protein kinase C (PKC) and calmodulin- increased or decreased. This, in turn, affects the abundance dependent protein kinase (CMK). These enzymes phosphorylate proteins (P-Proteins) involved in initiating aldosterone synthesis. of these proteins in the cell, which produces the physio- logical effects of the glucocorticoids. The apparent slow- ness of glucocorticoid action is due to the time required by Increased renin secretion results in an increase in an- the mechanism to change the protein composition of a tar- giotensin II formation in the blood, thereby stimulating al- get cell. dosterone secretion by the zona glomerulosa. This series of events tends to conserve body fluid volume because aldos- Glucocorticoids and the Metabolic Response to Fasting. terone stimulates sodium reabsorption by the kidneys. During the fasting periods between food intake in humans, metabolic adaptations prevent hypoglycemia. The mainte- Extracellular Potassium Concentration and Aldosterone nance of sufficient blood glucose is necessary because the Secretion. Aldosterone secretion is also stimulated by an brain depends on glucose for its energy needs. Many of the increase in the potassium concentration in extracellular adaptations that prevent hypoglycemia are not fully ex- fluid, caused by a direct effect of potassium on zona pressed in the course of daily life because the individual glomerulosa cells. Glomerulosa cells are sensitive to this ef- eats before they fully develop. Full expression of these fect of extracellular potassium and, therefore, increase their changes is seen only after many days to weeks of fasting. rate of aldosterone secretion in response to small increases Glucocorticoids are necessary for the metabolic adaptation in blood and interstitial fluid potassium concentration. This to fasting. signal for aldosterone secretion is appropriate from a phys- At the onset of a prolonged fast, there is a gradual de- iological point of view because aldosterone promotes the cline in the concentration of glucose in the blood. Within renal excretion of potassium (see Chapter 24). 1 to 2 days, the blood glucose level stabilizes at a concen- A rise in extracellular potassium depolarizes glomerulosa tration of 60 to 70 mg/dL, where it remains even if the fast cell membranes, activating voltage-dependent calcium is prolonged for many days (Fig. 34.10). The blood glucose
618 PART IX ENDOCRINE PHYSIOLOGY As a consequence, the individual cannot respond to fasting Blood fatty acids with accelerated gluconeogenesis and will die from hypo- Blood ketone bodies glycemia. In essence, the glucocorticoids maintain the liver and kidney in a state that enables them to carry out accel- erated gluconeogenesis should the need arise. () during fasting involves the mobilization and use of stored Change from fed state 0 Days of fasting Gluconeogenesis fat. Within the first few hours of the start of a fast, the The other important metabolic adaptation that occurs concentration of free fatty acids rises in the blood (see 510 Fig. 34.10). This action is due to the acceleration of lipol- mone-sensitive lipase (HSL). HSL hydrolyzes the stored () Blood glucose ysis in the fat depots, as a result of the activation of hor- triglyceride to free fatty acids and glycerol, which are re- leased into the blood. HSL is activated when it is phosphorylated by a cAMP- dependent protein kinase. As the level of insulin falls in the blood during fasting, the inhibitory effect of insulin on cAMP accumulation in the fat cell diminishes. There is a Metabolic adaptations during fasting. This rise in the cellular level of cAMP, and HSL is activated. The FIGURE 34.10 graphs shows the changes in the concentrations glucocorticoids are essential for maintaining fat cells in an of blood glucose, fatty acids, and ketone bodies and the rate of glu- enzymatic state that permits lipolysis to occur during a fast. coneogenesis during the course of a prolonged fast. Only the direc- This is evident from the fact that accelerated lipolysis does tion of change over time is indicated: increase () or decrease (). not occur when a glucocorticoid-deficient individual fasts. The abundant fatty acids produced by lipolysis are taken up by many tissues. The fatty acids enter mitochondria, un- dergo -oxidation to acetyl CoA, and become the substrate level is stabilized by the production of glucose by the body and the restriction of its use by tissues other than the brain. for ATP synthesis. The enhanced use of fatty acids for en- Although a limited supply of glucose is available from ergy metabolism spares the blood glucose supply. There is glycogen stored in the liver, the more important source of also significant gluconeogenesis in liver from the glycerol blood glucose during the first days of a fast is gluconeoge- released from triglyceride by lipolysis. In prolonged fast- nesis in the liver and, to some extent, in the kidneys. ing, when the rate of glucose production from body protein Gluconeogenesis begins several hours after the start of a has declined, a significant fraction of blood glucose is de- fast. Amino acids derived from tissue protein are the main rived from triglyceride glycerol. substrates. Fasting results in protein breakdown in the Within a few hours of the start of a fast, the increased skeletal muscle and accelerated release of amino acids into delivery to and oxidation of fatty acids in the liver results in the bloodstream. Protein breakdown and protein accretion the production of the ketone bodies. As a result of these in adult humans are regulated by two opposing hormones, events in the liver, a gradual rise in ketone bodies occurs in insulin and glucocorticoids. During fasting, insulin secre- the blood as a fast continues over many days (Fig. 34.10). tion is suppressed and the inhibitory effect of insulin on Ketone bodies become the principal energy source used by protein breakdown is lost. As proteins are broken down, the CNS during the later stages of fasting. glucocorticoids inhibit the reuse of amino acids derived The increased use of fatty acids for energy metabolism from tissue proteins for new protein synthesis, promoting by skeletal muscle results in less use of glucose in this tissue, the release of these amino acids from the muscle. Amino sparing blood glucose for use by the CNS. Two products acids released into the blood by the skeletal muscle are ex- resulting from the breakdown of fatty acids, acetyl CoA tracted from the blood at an accelerated rate by the liver and citrate, inhibit glycolysis. As a result, the uptake and and kidneys. The amino acids then undergo metabolic use of glucose from the blood is reduced. transformations in these tissues, leading to the synthesis of In summary, the strategy behind the metabolic adapta- glucose. The newly synthesized glucose is then delivered tion to fasting is to provide the body with glucose pro- to the bloodstream. duced primarily from protein until the ketone bodies be- The glucocorticoids are essential for the acceleration of come abundant enough in the blood to be a principal gluconeogenesis during fasting. They play a permissive role source of energy for the brain. From that point on, the in this process by maintaining gene expression and, there- body uses mainly fat for energy metabolism, and it can fore, the intracellular concentrations of many of the en- survive until the fat depots are exhausted. Glucocorticoids zymes needed to carry out gluconeogenesis in the liver and do not trigger the metabolic adaptations to fasting but kidneys. For example, glucocorticoids maintain the only provide the metabolic machinery necessary for the amounts of transaminases, pyruvate carboxylase, phospho- adaptations to occur. enolpyruvate carboxykinase, fructose-1,6-diphosphatase, fructose-6-phosphatase, and glucose-6-phosphatase Cushing’s Disease. When present in excessive amounts, needed to carry out gluconeogenesis at an accelerated rate. glucocorticoids can trigger many of the metabolic adapta- In an untreated, glucocorticoid-deficient individual, the tions to the fasting state. Cushing’s disease is the name of amounts of these enzymes in the liver are greatly reduced. such pathological hypercortisolic states. Cushing’s disease
CHAPTER 34 The Adrenal Gland 619 may be ACTH-dependent or ACTH-independent. One plasma membrane phospholipids by the hydrolytic action type of ACTH-dependent syndrome (actually called Cush- of phospholipase A 2 . Glucocorticoids stimulate the syn- ing’s disease) is caused by a corticotroph adenoma, which thesis of a family of proteins called lipocortins in their tar- secretes excessive ACTH and stimulates the adrenal cortex get cells. Lipocortins inhibit the activity of phospholipase to produce large amounts of cortisol. ACTH-independent A 2 , reducing the amount of arachidonic acid available for Cushing’s syndrome is usually due toa result of an adreno- conversion to prostaglandins and leukotrienes. cortical adenoma that secretes large amounts of cortisol. Whatever the cause, prolonged exposure of the body to Effects on the Immune System. Glucocorticoids have large amounts of glucocorticoids causes the breakdown of little influence on the human immune system under normal skeletal muscle protein, increased glucose production by physiological conditions. When administered in large the liver, and mobilization of lipid from the fat depots. De- doses over a prolonged period, however, they can suppress spite the increased mobilization of lipid, there is also an ab- antibody formation and interfere with cell-mediated immu- normal deposition of fat in the abdominal region, between nity. Glucocorticoid therapy, therefore, is used to suppress the shoulders, and in the face. The increased mobilization the rejection of surgically transplanted organs and tissues. of lipid provides abundant fatty acids for metabolism and Immature T cells in the thymus and immature B cells and the increased oxidation of fatty acids by tissues reduces T cells in lymph nodes can be killed by exposure to high their ability to use glucose. The underutilization of glucose concentrations of glucocorticoids, decreasing the number by skeletal muscle, coupled with increased glucose produc- of circulating lymphocytes. The destruction of immature T tion by the liver, results in hyperglycemia, which, in turn, and B cells by glucocorticoids also causes some reduction in stimulates the pancreas to secrete insulin. In this instance, the size of the thymus and lymph nodes. however, the rise in insulin is not effective in reducing the blood glucose concentration because glucose uptake and Maintenance of the Vascular Response to Norepinephrine. use are decreased in the skeletal muscle and adipose tissue. Glucocorticoids are required for the normal responses of vas- Evidence also indicates that excessive glucocorticoids de- cular smooth muscle to the vasoconstrictor action of norep- crease the affinity of insulin receptors for insulin. The net inephrine. NE is much less active on vascular smooth muscle result is that the individual becomes insensitive or resistant in the absence of glucocorticoids and is another example of to the action of insulin and little glucose is removed from the permissive action of glucocorticoids. the blood, despite the high level of circulating insulin. The persisting hyperglycemia continually stimulates the pan- Glucocorticoids and Stress. Perhaps the most interest- creas to secrete insulin. The result is a form of “diabetes” ing, but least understood, of all glucocorticoid action is the similar to Type 2 diabetes mellitus (see Chapter 35). ability to protect the body against stress. All that is really The opposite situation occurs in the glucocorticoid-de- known is that the body cannot cope successfully with even ficient individual. Little lipid mobilization and use occur, so mild stresses in the absence of glucocorticoids. One must there is little restriction on the rate of glucose use by tis- presume that the processes that enable the body to defend sues. The glucocorticoid-deficient individual is sensitive to itself against physical or emotional trauma require gluco- insulin in that a given concentration of blood insulin is corticoids. This, again, emphasizes the permissive role they more effective in clearing the blood of glucose than it is in play in physiological processes. a healthy person. The administration of even small doses of Stress stimulates the secretion of ACTH, which in- insulin to such individuals may produce hypoglycemia. creases the secretion of glucocorticoids by the adrenal cor- tex (see Chapter 32). In humans, this increase in glucocor- The Anti-inflammatory Action of Glucocorticoids. Tis- ticoid secretion during stress appears to be important for sue injury triggers a complex mechanism called inflamma- the appropriate defense mechanisms to be put into place. It tion that precedes the actual repair of damaged tissue. A is well known, for example, that glucocorticoid-deficient host of chemical mediators are released into the damaged individuals receiving replacement therapy require larger area by neighboring cells, adjacent vasculature, and phago- doses of glucocorticoid to maintain their well-being during cytic cells that migrate to the damaged site. Mediators re- periods of stress. leased under these circumstances include prostaglandins, leukotrienes, kinins, histamine, serotonin, and lym- Regulation of Glucocorticoid Secretion. An important phokines. These substances exert a multitude of actions at physiological action of glucocorticoids is the ability to reg- the site of injury and directly or indirectly promote the lo- ulate their own secretion. This effect is achieved by a neg- cal vasodilation, increased capillary permeability, and ative-feedback mechanism of glucocorticoids on the secre- edema formation that characterize the inflammatory re- tion of corticotropin-releasing hormone (CRH) and sponse (see Chapter 11). ACTH and on proopiomelanocortin (POMC) gene ex- Because glucocorticoids inhibit the inflammatory re- pression (see Chapter 32). sponse to injury, they are used extensively as therapeutic anti-inflammatory agents; however, the mechanisms are not clear. Their regulation of the production of PRODUCTS OF THE ADRENAL MEDULLA prostaglandins and leukotrienes is the best understood. These substances play a major role in mediating the in- The catecholamines, epinephrine and norepinephrine, are flammatory reaction. They are synthesized from the unsat- the two hormones synthesized by the chromaffin cells of urated fatty acid arachidonic acid, which is released from the adrenal medulla. The human adrenal medulla produces
620 PART IX ENDOCRINE PHYSIOLOGY and secretes about 4 times more epinephrine than norepi- found hypoglycemia can be tolerated depends on its sever- nephrine. Postganglionic sympathetic neurons also pro- ity and the individual’s sensitivity. duce and release NE from their nerve terminals but do not When the blood glucose concentration drops toward produce epinephrine. the hypoglycemic range, CNS receptors monitoring blood Epinephrine and NE are formed in the chromaffin cells glucose are activated, stimulating the neural pathway lead- from the amino acid tyrosine. The pathway for the synthe- ing to the fibers innervating the chromaffin cells. As a re- sis of catecholamines is illustrated in Figure 3.18. sult, the adrenal medulla discharges catecholamines. Sym- pathetic postganglionic nerve terminals also release norepinephrine. Trauma, Exercise, and Hypoglycemia Stimulate Catecholamines act on the liver to stimulate glucose the Medulla to Release Catecholamines production. They activate glycogen phosphorylase, result- Epinephrine and some NE are released from chromaffin ing in the hydrolysis of stored glycogen, and stimulate glu- cells by the fusion of secretory granules with the plasma coneogenesis from lactate and amino acids. Cate- membrane. The contents of the granules are extruded into cholamines also activate glycogen phosphorylase in the interstitial fluid. The catecholamines diffuse into capil- skeletal muscle and adipose cells by interacting with re- laries and are transported in the bloodstream. ceptors, activating adenylyl cyclase and increasing cAMP Neural stimulation of the cholinergic preganglionic in the cells. The elevated cAMP activates glycogen phos- fibers that innervate chromaffin cells triggers the secretion phorylase. The glucose 6-phosphate generated in these of catecholamines. Stimuli such as injury, anger, anxiety, cells is metabolized, although glucose is not released into pain, cold, strenuous exercise, and hypoglycemia generate the blood, since the cells lack glucose-6-phosphatase. The impulses in these fibers, causing a rapid discharge of the glucose 6-phosphate in muscle is converted by glycolysis catecholamines into the bloodstream. to lactate, much of which is released into the blood. The lactate taken up by the liver is converted to glucose via glu- coneogenesis and returned to the blood. Catecholamines Have Rapid, Widespread Effects In adipose cells, the rise in cAMP produced by cate- cholamines activates hormone-sensitive lipase, causing the Most cells of the body have receptors for catecholamines hydrolysis of triglycerides and the release of fatty acids and and, thus, are their target cells. There are four structurally glycerol into the bloodstream. These fatty acids provide an related forms of catecholamine receptors, all of which are alternative substrate for energy metabolism in other tissues, transmembrane proteins: 1 , 2 , 1 , and 2 . All can bind primarily skeletal muscle, and block the phosphorylation epinephrine or NE, to varying extents (see Chapter 3). and metabolism of glucose. During profound hypoglycemia, the rapid rise in blood Fight-or-Flight Response. Epinephrine and NE produce catecholamine levels triggers some of the same metabolic widespread effects on the cardiovascular system, muscular adjustments that occur more slowly during fasting. During system, and carbohydrate and lipid metabolism in liver, fasting, these adjustments are triggered mainly in response muscle, and adipose tissues. In response to a sudden rise in to the gradual rise in the ratio of glucagon to insulin in the catecholamines in the blood, the heart rate accelerates, blood. The ratio also rises during profound hypoglycemia, coronary blood vessels dilate, and blood flow to the skele- reinforcing the actions of the catecholamines on tal muscles is increased as a result of vasodilation (but vaso- glycogenolysis, gluconeogenesis, and lipolysis. The cate- constriction occurs in the skin). Smooth muscles in the air- cholamines released during hypoglycemia are thought to ways of the lungs, gastrointestinal tract, and urinary be partly responsible for the rise in the glucagon-to-insulin bladder relax. Muscles in the hair follicles contract, causing ratio by directly influencing the secretion of these hor- piloerection. Blood glucose level also rises. This overall re- mones by the pancreas. Catecholamines stimulate the se- action to the sudden release of catecholamines is known as cretion of glucagon by the alpha cells and inhibit the se- the fight-or-flight response (see Chapter 6). cretion of insulin by beta cells (see Chapter 35). These catecholamine-mediated responses to hypoglycemia are Catecholamines and the Metabolic Response to Hypo- summarized in Table 34.4. glycemia. Catecholamines secreted by the adrenal medulla and NE released from sympathetic postganglionic nerve terminals are key agents in the body’s defense against hypoglycemia. Catecholamine release usually Catecholamine-Mediated Responses starts when the blood glucose concentration falls to the TABLE 34.4 to Hypoglycemia low end of the physiological range (60 to 70 mg/dL). A fur- ther decline in blood glucose concentration into the hy- Liver Stimulation of glycogenolysis poglycemic range produces marked catecholamine release. Stimulation of gluconeogenesis Hypoglycemia can result from a variety of situations, such Skeletal muscle Simulation of glycogenolysis as insulin overdosing, catecholamine antagonists, or drugs Adipose tissue Simulation of glycogenolysis that block fatty acid oxidation. Hypoglycemia is always a Stimulation of triglyceride lipolysis dangerous condition because the CNS will die of ATP Pancreatic islets Inhibition of insulin secretion by beta cells deprivation in extended cases. The length of time pro- Stimulation of glucagon secretion by alpha cells
CHAPTER 34 The Adrenal Gland 621 REVIEW QUESTIONS DIRECTIONS: Each of the numbered (F) Defects in aldosterone synthase (C) Cholesterol side-chain cleavage items or incomplete statements in this 4. What is the mechanism through which enzyme section is followed by answers or by catecholamines stabilize blood glucose (D) 11-Hydroxylase completions of the statement. Select the concentration in response to (E) 3-Hydroxy-3-methylglutaryl CoA ONE lettered answer or completion that is hypoglycemia? reductase the BEST in each case. (A) Catecholamines stimulate glycogen (F) 17-Hydroxylase phosphorylase to release glucose from 8. A patient complains of generalized 1. Which of the following sources of muscle weakness and fatigue, anorexia, and cholesterol is most important for (B) Catecholamines inhibit weight loss associated with sustaining adrenal steroidogenesis glycogenolysis in the liver gastrointestinal symptoms (nausea, when it occurs at a high rate for a long (C) Catecholamines stimulate the vomiting). Physical examination notes time? release of insulin from the pancreas hyperpigmentation and hypotension. (A) De novo synthesis of cholesterol (D) Catecholamines inhibit the release Laboratory findings include hyponatremia (low plasma sodium) and from acetate of fatty acids from adipose tissue hyperkalemia (high plasma potassium). (B) Cholesterol in LDL particles (E) Catecholamines stimulate The most likely diagnosis is (C) Cholesterol in the plasma gluconeogenesis in the liver (A) Cushing’s disease membrane (F) Catecholamines inhibit the release (B) Addison’s disease (D) Cholesterol in lipid droplets within of lactate from muscle (C) Primary hypoaldosteronism adrenal cortical cells 5. A patient receiving long-term (D) Congenital adrenal hyperplasia (E) Cholesterol from the endoplasmic glucocorticoid therapy plans to (E) Hypopituitarism reticulum undergo hip replacement surgery. (F) Glucocorticoid-suppressible (F) Cholesterol in lipid droplets within What would the physician recommend hyperaldosteronism adrenal medullary cells prior to surgery and why? 9. Through what “permissive action” do 2. A 7-year-old boy comes to the (A) Glucocorticoids should be glucocorticoids accelerate pediatric endocrine unit for evaluation decreased to prevent serious gluconeogenesis during fasting? of excess body weight. Review of his hypoglycemia during recovery (A) Glucocorticoids stimulate the growth charts indicates substantial (B) Glucocorticoids should be secretion of insulin, which activates weight gain over the previous 3 years increased to stimulate immune function gluconeogenic enzymes in the liver but little increase in height. To and prevent possible infection (B) Glucocorticoids inhibit the use of differentiate between the development (C) Glucocorticoids should be glucose by skeletal muscle of obesity and Cushing’s disease, blood decreased to minimize potential (C) Glucocorticoids maintain the and urine samples are taken. Which of interactions with anesthetics vascular response to norepinephrine the following would be most (D) Glucocorticoids should be (D) Glucocorticoids inhibit diagnostic of Cushing’s disease? increased to stimulate ACTH secretion glycogenolysis (A) Increased serum ACTH, decreased during surgery to promote wound (E) Glucocorticoids maintain the serum cortisol, and increased urinary healing intracellular concentrations of many of free cortisol (E) Glucocorticoids should be the enzymes needed to carry out (B) Decreased serum ACTH, increased decreased to prevent inadequate gluconeogenesis through effects on serum cortisol, and increased serum vascular response to catecholamines transcription insulin during recovery (F) Glucocorticoids inhibit the release (C) Increased serum ACTH, increased (F) Glucocorticoids should be of fatty acids from adipose tissue serum cortisol, and increased serum increased to compensate for the SUGGESTED READING insulin increased stress associated with surgery Bornstein SR, Chrousos GP. Clinical re- (D) Increased serum ACTH, decreased 6. Which of the following is most likely view 104. Adrenocorticotropin serum cortisol, and decreased serum to result in a decreased rate of (ACTH)- and non-ACTH-mediated insulin aldosterone release? regulation of the adrenal cortex: Neural (E) Increased serum ACTH, decreased (A) An increase in renin secretion by and immune inputs. J Clin Endocrinol serum cortisol, and decreased urinary the kidney Metab 1999;84:1729–1736. free cortisol (B) A rise in serum potassium Lumbers ER. Angiotensin and aldosterone. (F) Decreased serum ACTH, decreased (C) A fall in blood pressure in the Regul Pept 1999;80:91–100. serum cortisol, and increased serum kidney Miller WL: Early steps in androgen insulin (D) A decrease in tubule fluid sodium biosynthesis: From cholesterol to 3. Congenital adrenal hyperplasia is most concentration at the macula densa DHEA. Baillieres Clin Endocrinol likely a result of (E) An increase in renal sympathetic Metab 1998;12:67–81. (A) Defects in adrenal steroidogenic nerve activity Nordenstrom A, Thilen A, Hagenfeldt L, enzymes (F) A decrease in IP 3 in cells of the Larsson A, Wedell A. Genotyping is a (B) Addison’s disease zona glomerulosa valuable diagnostic complement to (C) Defects in ACTH secretion 7. The rate-limiting step in the synthesis neonatal screening for congenital adre- (D) Defects in corticosteroid-binding of cortisol is catalyzed by nal hyperplasia due to steroid 21-hy- globulin (A) 21-Hydroxylase droxylase deficiency. J Clin Endocrinol (E) Cushing’s disease (B) 3-Hydroxysteroid dehydrogenase Metab 1999;84:1505–1509. (continued)
622 PART IX ENDOCRINE PHYSIOLOGY Orth DN, Kovacs WJ. The adrenal cortex. Sapolsky RM, Romero LM, Munck AU. Young JB, Landsberg L. Catecholamines In: Wilson JD, Foster DW, Kronen- How do glucocorticoids influence and the adrenal medulla. In: Wilson berg HM, Larsen PR, eds. Williams stress responses? Integrating permis- JD, Foster DW, Kronenberg Textbook of Endocrinology. 9th sive, suppressive, stimulatory, and HM, Larsen PR, eds: Williams Text- Ed. Philadelphia: WB Saunders, preparative actions. Endocr Rev book of Endocrinology. 9th Ed. 1998. 2000;21:55–89. Philadelphia: WB Saunders, 1998.
The Endocrine Pancreas CHAPTER 35 35 Daniel E. Peavy, Ph.D. CHAPTER OUTLINE ■ SYNTHESIS AND SECRETION OF THE ISLET ■ METABOLIC EFFECTS OF INSULIN AND GLUCAGON HORMONES ■ DIABETES MELLITUS KEY CONCEPTS 1. The relative distribution of alpha, beta, and delta cells 4. Effects of glucagon on carbohydrate, lipid, and protein me- within each islet of Langerhans shows a distinctive pattern tabolism occur primarily in the liver and are catabolic in and suggests that there may be some paracrine regulation nature. of secretion. 5. Type 1 diabetes mellitus results from the destruction of 2. Plasma glucose is the primary physiological regulator of beta cells, whereas type 2 diabetes often results from a insulin and glucagon secretion, but amino acids, fatty lack of responsiveness to circulating insulin. acids, and some GI hormones also play a role. 6. Diabetes mellitus may produce both acute complications, 3. Insulin has anabolic effects on carbohydrate, lipid, and pro- such as ketoacidosis, and chronic secondary complica- tein metabolism in its target tissues, where it promotes the tions, such as peripheral vascular disease, neuropathy, and storage of nutrients. nephropathy. he development of mechanisms for the storage of large are located throughout the pancreatic mass. The islets Tamounts of metabolic fuel was an important adaptation contain specific types of cells responsible for the secretion in the evolution of complex organisms. The processes in- of the hormones insulin, glucagon, and somatostatin. Se- volved in the digestion, storage, and use of fuels require a cretion of these hormones is regulated by a variety of cir- high degree of regulation and coordination. The pancreas, culating nutrients. which plays a vital role in these processes, consists of two functionally different groups of cells. Cells of the exocrine pancreas produce and secrete di- The Islets of Langerhans Are the Functional gestive enzymes and fluids into the upper part of the small Units of the Endocrine Pancreas intestine. The endocrine pancreas, an anatomically small The islets of Langerhans contain from a few hundred to sev- portion of the pancreas (1 to 2% of the total mass), pro- eral thousand hormone-secreting endocrine cells. The islets duces hormones involved in regulating fuel storage and use. are found throughout the pancreas but are most abundant in For convenience, functions of the exocrine and en- the tail region of the gland. The human pancreas contains, docrine portions of the pancreas are usually discussed sep- on average, about 1 million islets, which vary in size from 50 arately. While this chapter focuses primarily on hormones to 300 m in diameter. Each islet is separated from the sur- of the endocrine pancreas, the overall function of the pan- rounding acinar tissue by a connective tissue sheath. creas is to coordinate and direct a wide variety of processes Islets are composed of four hormone-producing cell related to the digestion, uptake, and use of metabolic fuels. types: insulin-secreting beta cells, glucagon-secreting alpha cells, somatostatin-secreting delta cells, and pancreatic polypeptide-secreting F cells. Immunofluorescent staining SYNTHESIS AND SECRETION OF THE techniques have shown that the four cell types are arranged ISLET HORMONES in each islet in a pattern suggesting a highly organized cel- lular community, in which paracrine influences may play an The endocrine pancreas consists of numerous discrete important role in determining hormone secretion rates clusters of cells, known as the islets of Langerhans, which (Fig. 35.1). Further evidence that cell-to-cell communica- 623
624 PART IX ENDOCRINE PHYSIOLOGY Therefore, islet hormones arrive in high concentrations in some areas of the exocrine pancreas before reaching pe- ripheral tissues. However, the exact physiological signifi- cance of these arrangements is unknown. Neural inputs also influence islet cell hormone secretion. Islet cells receive sympathetic and parasympathetic inner- vation. Responses to neural input occur as a result of acti- vation of various adrenergic and cholinergic receptors (de- scribed below). Neuropeptides released together with the neurotransmitters may also be involved in regulating hor- mone secretion. Beta Cells. In the early 1900s, M. A. Lane established a histochemical method by which two kinds of islet cells could be distinguished. He found that alcohol-based fixa- tives dissolved the secretory granules in most of the islet cells but preserved them in a small minority of cells. Water- based fixatives had the opposite effect.He named cells con- taining alcohol-insoluble granules A cells or alpha cells and those containing alcohol-soluble granules B cells or beta cells. Many years later, other investigators used immuno- fluorescence techniques to demonstrate that beta cells pro- duce insulin and alpha cells produce glucagon. Alpha cells (Glucagon) Insulin-secreting beta cells are the most numerous cell type of the islet, comprising 70 to 90% of the endocrine Delta cells (Somatostatin) cells. Beta cells typically occupy the most central space of the islets (see Fig. 35.1). They are generally 10 to 15 m Beta cells (Insulin) in diameter and contain secretory granules that measure 0.25 m. Major cell types in a typical islet of Langer- FIGURE 35.1 hans. Note the distinct anatomical arrange- Alpha Cells. Alpha cells comprise most of the remaining ment of the various cell types. (Modified from Orci L, Unger RH. cells of the islets. They are generally located near the pe- Functional subdivision of islets of Langerhans and possible role of D cells. Lancet 1975;2:1243–1244.) riphery, where they form a cortex of cells surrounding the more centrally located beta cells. Blood vessels pass through the outer zone of the islet before extensive branch- ing occurs. Inward extensions of the cortex may be present tion within the islet may play a role in regulating hormone along the axes of blood vessels toward the center of the secretion comes from the finding that islet cells have both islet, giving the appearance that the islet is subdivided into gap junctions and tight junctions. Gap junctions link dif- small lobules. ferent cell types in the islets cells and potentially provide a means for the transfer of ions, nucleotides, or electrical cur- Delta Cells. Delta cells are the sites of production of so- rent between cells. The presence of tight junctions between matostatin in the pancreas. These cells are typically located outer membrane leaflets of contiguous cells could result in in the periphery of the islet, often between beta cells and the formation of microdomains in the interstitial space, the surrounding mantle of alpha cells. Somatostatin pro- which may also be important for paracrine communication. duced by pancreatic delta cells is identical to that previ- Although the existence of gap junctions and tight junctions ously described in a neurotransmitter role (see Chapter 3) in pancreatic islets is well documented, their exact function and as a hypothalamic hormone that inhibits growth hor- has not been fully defined. mone secretion by the anterior pituitary (see Chapter 32). The arrangement of the vascular supply to islets is also consistent with paracrine involvement in regulating islet se- F Cells. F cells are the least abundant of the hormone-se- cretion. Afferent blood vessels penetrate nearly to the cen- creting cells of islets, representing only about 1% of the to- ter of the islet before branching out and returning to the tal cell population. The distribution of F cells is generally surface of the islet. The innermost cells of the islet, there- similar to that of delta cells. F cells secrete pancreatic fore, receive arterial blood, while those cells nearer the sur- polypeptide. face receive blood-containing secretions from inner cells. Since there is a definite anatomical arrangement of cells in Increased Blood Glucose Stimulates the the islet (see Fig. 35.1), one cell type could affect the se- cretion of others. In general, the effluent from smaller islets Secretion of Insulin passes through neighboring pancreatic acinar tissue before A variety of factors, including other pancreatic hormones, entering into the hepatic portal venous system. By contrast, are known to influence insulin secretion. The primary the effluent from larger islets passes directly into the ve- physiological regulator of insulin secretion, however, is the nous system without first perfusing adjacent acinar tissue. blood glucose concentration.
CHAPTER 35 The Endocrine Pancreas 625 Proinsulin Synthesis. The gene for insulin is located on ously, an elevated blood glucose level is the most important the short arm of chromosome 11 in humans. Like other regulator of insulin secretion. In humans, the threshold hormones and secretory proteins, insulin is first synthe- value for glucose-stimulated insulin secretion is a plasma sized by ribosomes of the rough ER as a larger precursor glucose concentration of approximately 100 mg/dL (5.6 peptide that is then converted to the mature hormone prior mmol/L). to secretion (see Chapter 31). Based on studies using isolated animal pancreas prepara- The insulin gene product is a 110-amino acid peptide, tions maintained in vitro, it has been determined that insulin preproinsulin. Proinsulin consists of 86 amino acids is secreted in a biphasic manner in response to a marked in- (Fig. 35.2); residues 1 to 30 constitute what will form the B crease in blood glucose. An initial burst of insulin secretion chain of insulin, residues 31 to 65 form the connecting pep- may last 5 to 15 minutes, resulting from the secretion of tide, and residues 66 to 86 constitute the A chain. (Note preformed insulin secretory granules. This response is fol- that “connecting peptide” should not be confused with “C- lowed by more gradual and sustained insulin secretion that peptide.”) In the process of converting proinsulin to insulin, results largely from the synthesis of new insulin molecules. two pairs of basic amino acid residues are clipped out of the In addition to glucose, several other factors serve as im- proinsulin molecule, resulting in the formation of insulin portant regulators of insulin secretion (see Table 35.1). and C-peptide, which are ultimately secreted from the beta These include dietary constituents, such as amino acids and cell in equimolar amounts. fatty acids, as well as hormones and drugs. Among the It is of clinical significance that insulin and C-peptide amino acids, arginine is the most potent secretagogue for are co-secreted in equal amounts. Measurements of circu- insulin. Among the fatty acids, long-chain fatty acids (16 to lating C-peptide levels may sometimes provide important 18 carbons) generally are considered the most potent stim- information regarding beta cell secretory capacity that ulators of insulin secretion. Several hormones secreted by could not be obtained by measuring circulating insulin lev- the gastrointestinal tract, including gastric inhibitory pep- els alone. tide (GIP), gastrin, and secretin, promote insulin secretion. An oral dose of glucose produces a greater increment in in- Insulin Secretion. Table 35.1 lists the physiologically sulin secretion than an equivalent intravenous dose because relevant regulators of insulin secretion. As indicated previ- oral glucose promotes the secretion of GI hormones that Connecting peptide NH 2 COOH Proinsulin C-peptide NH 2 COOH A chain NH 2 COOH B chain Insulin The structure of proinsulin, C-peptide, and pairs of basic amino acids, proinsulin is converted into insulin and FIGURE 35.2 insulin. Note that with the removal of two C-peptide.
626 PART IX ENDOCRINE PHYSIOLOGY Factors Regulating Insulin Secretion Factors Regulating Glucagon Se- TABLE 35.1 TABLE 35.2 from the Pancreas cretion From the Pancreas Stimulatory agents or Hyperglycemia Stimulatory agents or conditions Hypoglycemia conditions Amino acids Amino acids Fatty acids, especially long-chain Acetylcholine Gastrointestinal hormones, especially gastric Norepinephrine inhibitory peptide (GIP), gastrin, and Epinephrine secretin Inhibitory agents or conditions Fatty acids Acetylcholine Somatostatin Sulfonylureas Insulin Inhibitory agents or Somatostatin conditions Norepinephrine Epinephrine augment insulin secretion by the pancreas. Direct infusion pecially arginine, are potent stimulators of glucagon secre- of acetylcholine into the pancreatic circulation stimulates tion. Somatostatin inhibits glucagon secretion, as it does insulin secretion, reflecting the role of parasympathetic in- insulin secretion. nervation in regulating insulin secretion. Sulfonylureas, a class of drugs used orally in the treatment of type 2 dia- betes, promote insulin’s action in peripheral tissues but also Increased Blood Glucose and Glucagon Stimulate directly stimulate insulin secretion. the Secretion of Somatostatin In addition to factors that stimulate insulin secretion, there are several potent inhibitors. Exogenously adminis- Somatostatin is first synthesized as a larger peptide precur- tered somatostatin is a strong inhibitor. It is presumed that sor, preprosomatostatin. The hypothalamus also produces pancreatic somatostatin plays a role in regulating insulin se- this protein, but the regulation of somatostatin secretion cretion, but the importance of this effect has not been fully from the hypothalamus is independent of that from the established. Epinephrine and norepinephrine, the primary pancreatic delta cells. Upon insertion of preprosomato- catecholamines, are also potent inhibitors of insulin secre- statin into the rough ER, it is initially cleaved and converted tion. This response would appear appropriate because dur- to prosomatostatin. The prohormone is converted into ac- ing periods of stress and high catecholamine secretion, the tive hormone during packaging and processing in the Golgi desired response is mobilization of glucose and other nutri- apparatus. ent stores. Insulin generally promotes the opposite re- Factors that stimulate pancreatic somatostatin secretion sponse, and by inhibiting insulin secretion, the cate- include hyperglycemia, glucagon, and amino acids. Glu- cholamines produce their full effect without the opposing cose and glucagon are generally considered the most im- actions of insulin. portant regulators of somatostatin secretion. The exact role of somatostatin in regulating islet hor- mone secretion has not been fully established. Somato- Decreased Blood Glucose Stimulates statin clearly inhibits both glucagon and insulin secretion the Secretion of Glucagon from the alpha and beta cells of the pancreas, respectively, Similar to insulin, glucagon is first synthesized as part of a when it is given exogenously. The anatomic and vascular larger precursor protein. Glucagon secretion is regulated by relationships of delta cells to alpha and beta cells further many of the factors that also regulate insulin secretion. In suggest that somatostatin may play a role in regulating both most cases, however, these factors have the opposite effect glucagon and insulin secretion. Although many of the data on glucagon secretion. are circumstantial, it is generally accepted that somato- statin plays a paracrine role in regulating insulin and Synthesis of Proglucagon. Glucagon is a simple 29-amino glucagon secretion from the pancreas. acid peptide. The initial gene product for glucagon, pre- proglucagon, is a much larger peptide. Like other peptide hormones, the “pre” piece is removed in the ER, and the pro- METABOLIC EFFECTS OF INSULIN hormone is converted into a mature hormone as it is pack- aged and processed in secretory granules (see Chapter 31). AND GLUCAGON The endocrine pancreas secretes hormones that direct the Secretion of Glucagon. The principal factors that influ- storage and use of fuels during times of nutrient abundance ence glucagon secretion are listed in Table 35.2. With a few (fed state) and nutrient deficiency (fasting). Insulin is se- exceptions, this table is nearly a mirror image of Table 35.1, creted in the fed state and is called the “hormone of nutri- the factors that regulate insulin secretion. The primary reg- ent abundance.” By contrast, glucagon is secreted in re- ulator of glucagon secretion is blood glucose; specifically, a sponse to an overall deficit in nutrient supply. These two decrease in blood glucose below about 100 mg/dL pro- hormones play an important role in directing the flow of motes glucagon secretion. As with insulin, amino acids, es- metabolic fuels.
CHAPTER 35 The Endocrine Pancreas 627 Insulin Affects the Metabolism of Carbohydrates, dient. The carriers shuttle glucose across the membrane Lipids, and Proteins in Liver, Muscle, and faster than would occur by diffusion alone. Considerable Adipose Tissues recent work has revealed not just one transporter, but a family of about seven different glucose transporters The primary targets for insulin are liver, skeletal muscle, and (GLUT), commonly called GLUT 1 to GLUT 7. These adipose tissues. Insulin has multiple individual actions in transporters are expressed in different tissues and, in some each of these tissues, the net result of which is fuel storage. cases, at different times during fetal development. GLUT 4, the insulin-stimulated glucose transporter, is Mechanism of Insulin Action. Although insulin was one of the primary form of the transporter present in skeletal mus- the first peptide hormones to be identified, isolated, and cle tissue and adipose tissue. It is present in plasma mem- characterized, its exact mechanism of action remains elusive. branes and in intracellular vesicles of the smooth ER. In tar- The insulin receptor is a heterotetramer, consisting of a pair get cells, the effect of insulin is to promote the of / subunit complexes held together by disulfide bonds translocation of GLUT 4 transporters from the intracellular (Fig. 35.3). The subunit is an extracellular protein contain- pool into plasma membranes. As a result, more transporters ing the insulin-binding component of the receptor. The are available in the plasma membrane, and glucose uptake subunit is a transmembrane protein that couples the extra- by target cells is, thereby, increased. cellular event of insulin binding to its intracellular actions. Activation of the subunit of the insulin receptor results Insulin and the Synthesis of Glycogen. Besides promot- in autophosphorylation, involving the phosphorylation of ing glucose uptake into target cells, insulin promotes its a few selected tyrosine residues in the intracellular portion storage. Glucose carbon is stored in the body in two pri- of the receptor. This event further activates the tyrosine ki- mary forms: as glycogen and (by metabolic conversion) as nase portion of the subunit, leading to tyrosine phospho- triglycerides. Glycogen is a short-term storage form that rylation of specific intracellular substrates. A cascade of plays an important role in maintaining normal blood glu- events follows, leading to the pleiotropic actions of insulin cose levels. The primary glycogen storage sites are the liver in its target cells. While tyrosine phosphorylation events and skeletal muscle; other tissues, such as adipose tissue, appear to be the early steps in insulin action, serine/threo- also store glycogen but in quantitatively small amounts. In- nine phosphorylation or dephosphorylation is involved in sulin promotes glycogen storage primarily through two en- many of the final steps of insulin action. zymes (Fig. 35.4). It activates glycogen synthase by pro- moting its dephosphorylation and concomitantly Insulin and Glucose Transport. Perhaps one of the most inactivates glycogen phosphorylase, also by promoting its important functions of insulin is to promote the uptake of dephosphorylation. The result is that glycogen synthesis is glucose from blood into cells. Glucose uptake into many promoted and glycogen breakdown is inhibited. cell types is by facilitated diffusion. A specific cell mem- brane carrier is involved but no energy is required, and the Insulin and Glycolysis. Insulin also enhances glycolysis. process cannot move glucose against a concentration gra- In addition to increasing glucose uptake and providing a mass action stimulus for glycolysis, insulin activates the en- zymes glucokinase and hexokinase and phosphofructoki- nase, pyruvate kinase, and pyruvate dehydrogenase of the glycolytic pathway (see Fig. 35.4). α subunit Lipogenic and Antilipolytic Effects of Insulin. In adipose tissue and liver tissue, insulin promotes lipogenesis and in- hibits lipolysis (Fig. 35.5). Insulin has similar actions in SS muscle, but since muscle is not a major site of lipid storage, the discussion here focuses on actions in adipose tissue and the liver. By promoting the flow of intermediates through S S glycolysis, insulin promotes the formation of -glycerol S S phosphate and fatty acids necessary for triglyceride forma- Extracellular tion. In addition, it stimulates fatty acid synthase, leading directly to increased fatty acid synthesis. Insulin inhibits the breakdown of triglycerides by inhibiting hormone-sen- sitive lipase, which is activated by a variety of counterreg- ulatory hormones, such as epinephrine and adrenal gluco- corticoids. By inhibiting this enzyme, insulin promotes the Intracellular β subunit accumulation of triglycerides in adipose tissue. In addition to promoting de novo fatty acid synthesis in The structure of the insulin receptor. The FIGURE 35.3 adipose tissue, insulin increases the activity of lipoprotein insulin receptor is a heterotetramer consisting of two extracellular insulin-binding subunits linked by disulfide lipase, which plays a role in the uptake of fatty acids from bonds to two transmembrane subunits. The subunits contain the blood into adipose tissue. As a result, lipoproteins syn- an intrinsic tyrosine kinase that is activated upon insulin binding thesized in the liver are taken up by adipose tissue, and to the subunit. fatty acids are ultimately stored as triglycerides.
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