shown in Figure 78-1, each gland is composed of two major parts, the adrenal medulla and the adrenal cor- tex. The adrenal medulla, the central 20% of the gland, is functionally related to the sympathetic nervous system; it secretes the hormones epinephrine and norepinephrine in response to sympathetic stimulation. In turn, these hor- mones cause almost the same effects as direct stimulation of the sympathetic nerves in all parts of the body. These hormones and their effects are discussed in detail in Chapter 61 in relation to the sympathetic nervous system. The adrenal cortex secretes an entirely different group of hormones, called corticosteroids. These hormones are all synthesized from the steroid cholesterol, and they all have similar chemical formulas. However, slight differ- ences in their molecular structures give them several dif- ferent but very important functions. CORTICOSTEROIDS: MINERALOCORTICOIDS, GLUCOCORTICOIDS, AND ANDROGENS Two major types of adrenocortical hormones, the min- eralocorticoids and the glucocorticoids, are secreted by the adrenal cortex. In addition to these hormones, small amounts of sex hormones are secreted, especially andro- genic hormones, which exhibit about the same effects in the body as the male sex hormone testosterone. They are normally of only slight importance, although in certain abnormalities of the adrenal cortices, extreme quantities can be secreted (which is discussed later in the chapter) and can result in masculinizing effects. The mineralocorticoids gained this name because they especially affect the electrolytes (the “minerals”) of the extracellular fluids, especially sodium and potassium. The glucocorticoids gained their name because they exhibit important effects that increase blood glucose concentration. They have additional effects on protein and fat metabolism that are equally as important to body function as their effects on carbohydrate metabolism. More than 30 steroids have been isolated from the adrenal cortex, but two are of exceptional importance to the normal endocrine function of the human body: aldo- sterone, which is the principal mineralocorticoid, and cor- tisol, which is the principal glucocorticoid. SYNTHESIS AND SECRETION OF ADRENOCORTICAL HORMONES THE ADRENAL CORTEX HAS THREE DIS- TINCT LAYERS Figure 78-1 shows that the adrenal cortex is composed of three relatively distinct layers: 1. The zona glomerulosa, a thin layer of cells that lies just underneath the capsule, constitutes about 15% of the adrenal cortex. These cells are the only ones in the adrenal gland capable of secreting significant amounts of aldosterone because they contain the enzyme aldosterone synthase, which is necessary for synthesis of aldosterone. The secretion of these cells Adrenocortical Hormones CHAPTER 7 8 Cortisol and androgens Magnified section Zona glomerulosa aldosterone Zona fasciculata Zona reticularis Cortex Medulla (catecholamines) Figure 78-1. Secretion of adrenocortical hormones by the different zones of the adrenal cortex and secretion of catecholamines by the adrenal medulla. UNIT XIV Endocrinology and Reproduction 956 is controlled mainly by the extracellular fluid con- centrations of angiotensin II and potassium, both of which stimulate aldosterone secretion. 2. The zona fasciculata, the middle and widest zone, constitutes about 75% of the adrenal cortex and se- cretes the glucocorticoids cortisol and corticoster- one, as well as small amounts of adrenal androgens and estrogens. The secretion of these cells is con- trolled in large part by the hypothalamic-pituitary axis via adrenocorticotropic hormone (ACTH). 3. The zona reticularis, the inner zone of the cortex, secretes the adrenal androgens dehydroepiandroster- one and androstenedione, as well as small amounts of estrogens and some glucocorticoids. ACTH also regulates secretion of these cells, although other fac- tors such as cortical androgen-stimulating hormone, released from the pituitary, may also be involved. The mechanisms for controlling adrenal androgen pro- duction, however, are not nearly as well understood as those for glucocorticoids and mineralocorticoids. Aldosterone and cortisol secretion are regulated by independent mechanisms. Factors such as angiotensin II that specifically increase the output of aldosterone and cause hypertrophy of the zona glomerulosa have no effect on the other two zones. Similarly, factors such as ACTH that increase secretion of cortisol and adrenal androgens and cause hypertrophy of the zona fasciculata and zona reticularis have little effect on the zona glomerulosa. Adrenocortical Hormones Are Steroids Derived From Cholesterol. All human steroid hormones, including those produced by the adrenal cortex, are synthesized from cho- lesterol. Although the cells of the adrenal cortex can synthe- size de novo small amounts of cholesterol from acetate, ap- proximately 80% of the cholesterol used for steroid synthesis is provided by low-density lipoproteins (LDLs) in the circu- lating plasma. The LDLs, which have high concentrations of cholesterol, diffuse from the plasma into the interstitial fluid and attach to specific receptors contained in structures called coated pits on the adrenocortical cell membranes. The coated pits are then internalized by endocytosis, forming vesicles that eventually fuse with cell lysosomes and release cholesterol that can be used to synthesize adrenal steroid hormones. Transport of cholesterol into the adrenal cells is regu- lated by feedback mechanisms that can markedly alter the amount available for steroid synthesis. For example, ACTH, which stimulates adrenal steroid synthesis, increases the number of adrenocortical cell receptors for LDL, as well as the activity of enzymes that liberate cholesterol from LDL. Once the cholesterol enters the cell, it is delivered to the mitochondria, where it is cleaved by the enzyme cholesterol desmolase to form pregnenolone; this is the rate-limiting step in the eventual formation of adrenal steroids (Figure 78-2). In all three zones of the adrenal cortex, this initial step in ster- oid synthesis is stimulated by the different factors that control secretion of the major hormone products aldosterone and cortisol. For example, both ACTH, which stimulates cortisol secretion, and angiotensin II, which stimulates aldosterone secretion, increase conversion of cholesterol to pregnenolone. Synthetic Pathways for Adrenal Steroids. Figure 78-2 gives the principal steps in the formation of the important steroid products of the adrenal cortex: aldosterone, cortisol, and the androgens. Essentially all these steps occur in two of the organelles of the cell, the mitochondria and the endo- plasmic reticulum, with some steps occurring in one of these organelles and some in the other. Each step is catalyzed by a specific enzyme system. A change in even a single enzyme in the schema can cause vastly different types and relative pro- portions of hormones to be formed. For example, very large quantities of masculinizing sex hormones or other steroid compounds not normally present in the blood can occur with altered activity of only one of the enzymes in this pathway. The chemical formulas of aldosterone and cortisol, which are the major mineralocorticoid and glucocorticoid hormones, respectively, are shown in Figure 78-2. Cortisol has a keto oxygen on carbon number 3 and is hydroxylated at carbon numbers 11 and 21. The mineralocorticoid aldos- terone has an oxygen atom bound at the number 18 carbon. In addition to aldosterone and cortisol, other steroids having glucocorticoid or mineralocorticoid activities, or both, are normally secreted in small amounts by the adrenal cortex. Furthermore, several additional potent steroid hor- mones not normally formed in the adrenal glands have been synthesized and are used in various forms of therapy. Some of the more important of the corticosteroid hormones, in- cluding the synthetic ones, are the following, as summarized in Table 78-1. Mineralocorticoids • Aldosterone (very potent; accounts for ≈90% of all min- eralocorticoid activity) • Deoxycorticosterone (1/30 as potent as aldosterone, but very small quantities are secreted) • Corticosterone (slight mineralocorticoid activity) • 9α-Fluorocortisol (synthetic; slightly more potent than aldosterone) • Cortisol (slight mineralocorticoid activity, but a large quantity is secreted) • Cortisone (slight mineralocorticoid activity) Glucocorticoids • Cortisol (very potent; accounts for ≈95% of all glucocor- ticoid activity) • Corticosterone (provides ≈4% of total glucocorticoid ac- tivity, but is much less potent than cortisol) • Cortisone (almost as potent as cortisol) • Prednisone (synthetic; four times as potent as cortisol) • Methylprednisone (synthetic; five times as potent as cor- tisol) • Dexamethasone (synthetic; 30 times as potent as cortisol) It is clear from this list that some of these hormones and synthetic steroids have both glucocorticoid and miner- alocorticoid activities. It is especially significant that corti- sol normally has some mineralocorticoid activity, because some syndromes of excess cortisol secretion can cause significant mineralocorticoid effects, along with its much more potent glucocorticoid effects. The intense glucocorticoid activity of the synthetic hor- mone dexamethasone, which has almost zero mineralocor- ticoid activity, makes it an especially important drug for stimulating specific glucocorticoid activity. Chapter 78 Adrenocortical Hormones 957 UNIT XIV Adrenocortical Hormones Are Bound to Plasma Pro- teins. Approximately 90% to 95% of the cortisol in plas- ma binds to plasma proteins, especially a globulin called cortisol-binding globulin or transcortin and, to a lesser extent, to albumin. This high degree of binding to plasma proteins slows the elimination of cortisol from the plasma; therefore, cortisol has a relatively long half-life of 60 to 90 minutes. Only about 60% of circulating aldosterone com- bines with the plasma proteins, and about 40% is in the free form; as a result, aldosterone has a relatively short half- life of about 20 minutes. These hormones are transported throughout the extracellular fluid compartment in both the combined and free forms. Binding of adrenal steroids to the plasma proteins may serve as a reservoir to lessen rapid fluctuations in free hor- mone concentrations, as would occur, for example, with cortisol during brief periods of stress and episodic secre- tion of ACTH. This reservoir function may also help ensure Cholesterol desmolase (P450 scc) 17α-Hydroxylase (P450 c17) 3β-Hydroxysteroid dehydrogenase HO C O CH3 C D A HO 3 2 1 10 14 15 19 11 12 13 18 17 16 21 20 22 23 24 26 27 25 4 6 9 7 8 5 B 17α-Hydroxylase (P450 c17) 21β-Hydroxylase (P450 c21) O C O CH3 11β-Hydroxylase (P450 c11) O C O CH2OH Aldosterone synthase (P450 c11AS) O HO C O CH2OH 17, 20 Lyase (P450 c17) 17, 20 Lyase (P450 c17) HO C O OH OH OH OH CH3 O C O CH3 O C O CH2OH HO O O O O HO C O CH2OH O HO HC C O O CH2OH Pregnenolone Progesterone 11-Deoxycorticosterone Corticosterone 17-Hydroxypregnenolone 17-Hydroxyprogesterone Dehydroepi- androsterone Androstenedione 11-Deoxycortisol Cortisol Aldosterone Cholesterol Figure 78-2. Pathways for synthesis of steroid hormones by the adrenal cortex. The enzymes are shown in italics. UNIT XIV Endocrinology and Reproduction 958 a relatively uniform distribution of the adrenal hormones to the tissues. Adrenocortical Hormones Are Metabolized in the Liv- er. The adrenal steroids are degraded mainly in the liver and are conjugated especially to glucuronic acid and, to a lesser extent, to sulfates. These substances are inactive and do not have mineralocorticoid or glucocorticoid activity. About 25% of these conjugates are excreted in the bile and then in the feces. The remaining conjugates formed by the liver enter the circulation but are not bound to plasma pro- teins, are highly soluble in the plasma, and are therefore filtered readily by the kidneys and excreted in the urine. Diseases of the liver markedly depress the rate of inactiva- tion of adrenocortical hormones, and kidney diseases re- duce the excretion of the inactive conjugates. The normal concentration of aldosterone in blood is about 6 nanograms (6 billionths of a gram) per 100 millilit- ers, and the average secretory rate is approximately 150 μg/ day (0.15 mg/day). The blood concentration of aldosterone, however, depends greatly on several factors, including di- etary intake of sodium and potassium. The concentration of cortisol in the blood averages 12 μg/100 ml, and the secretory rate averages 15 to 20 mg/day. However, blood concentration and secretion rate of corti- sol fluctuate throughout the day, rising in the early morning and declining in the evening, as discussed later. FUNCTIONS OF MINERALOCORTICOIDS— ALDOSTERONE Mineralocorticoid Deficiency Causes Severe Renal Sodium Chloride Wasting and Hyperkalemia. Total loss of adrenocortical secretion may cause death within 3 to 14 days unless the person receives extensive salt thera- py or injection of mineralocorticoids. Without mineralocorticoids, potassium ion concen- tration of the extracellular fluid rises markedly, sodium and chloride are rapidly lost from the body, and the total extracellular fluid volume and blood volume become greatly reduced. Diminished cardiac output soon devel- ops, which progresses to a shock-like state, followed by death. This entire sequence can be prevented by admin- istration of aldosterone or some other mineralocorticoid. Therefore, the mineralocorticoids are said to be the acute “lifesaving” portion of the adrenocortical hormones. The glucocorticoids are equally necessary, however, because they allow the person to resist the destructive effects of life’s intermittent physical and mental “stresses,” as dis- cussed later in the chapter. Aldosterone Is the Major Mineralocorticoid Secreted by the Adrenals. In humans, aldosterone exerts nearly 90% of the mineralocorticoid activity of the adrenocorti- cal secretions, but cortisol, the major glucocorticoid se- creted by the adrenal cortex, also provides a significant amount of mineralocorticoid activity. The mineralocorti- coid activity of aldosterone is about 3000 times greater than that of cortisol, but the plasma concentration of cor- tisol is nearly 2000 times that of aldosterone. Cortisol can also bind to mineralocorticoid recep- tors with high affinity. However, the renal epithelial cells express the enzyme 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2), which has actions that prevent cor- tisol from activating mineralocorticoid receptors. One action of 11β-HSD2 is to convert cortisol to cortisone, which does not avidly bind mineralocorticoid receptors. There is also evidence that 11β-HSD2 may have effects on the intracellular redox (reduction and oxidation) state that prevent cortisol from activating the mineralocor- ticoid receptors. In patients with genetic deficiency of 11β-HSD2 activity, cortisol may have substantial min- eralocorticoid effects. This condition is called appar- ent mineralocorticoid excess syndrome (AME) because the patient has essentially the same pathophysiological Table 78-1 Adrenal Steroid Hormones in Adults; Synthetic Steroids and Their Relative Glucocorticoid and Mineralocorticoid Activities Steroids Average Plasma Concentration (free and bound, μg/100 ml) Average Amount Secreted (mg/24 hr) Glucocorticoid Activity Mineralocorticoid Activity Adrenal steroids Cortisol 12 15 1.0 1.0 Corticosterone 0.4 3 0.3 15.0 Aldosterone 0.006 0.15 0.3 3000 Deoxycorticosterone 0.006 0.2 0.2 100 Dehydroepiandrosterone 175 20 — — Synthetic steroids Cortisone — — 0.7 0.5 Prednisolone — — 4 0.8 Methylprednisone — — 5 — Dexamethasone — — 30 — 9α-Fluorocortisol — — 10 125 Glucocorticoid and mineralocorticoid activities of the steroids are relative to cortisol, with cortisol being 1.0. Chapter 78 Adrenocortical Hormones 959 UNIT XIV changes as a patient with excess aldosterone secretion, except that plasma aldosterone levels are very low in the patient with AME. Ingestion of large amounts of licorice, which contains glycyrrhetinic acid, may also cause AME because of its ability to block 11β-HSD2 enzyme activity. RENAL AND CIRCULATORY EFFECTS OF ALDOSTERONE Aldosterone Increases Renal Tubular Reabsorption of Sodium and Secretion of Potassium. As discussed in Chapter 28, aldosterone increases reabsorption of sodium and simultaneously increases secretion of potassium by the renal tubular epithelial cells, especially in the principal cells of the collecting tubules and, to a lesser extent, in the distal tubules and collecting ducts. Therefore, aldosterone causes sodium to be conserved in the extracellular fluid while increasing potassium excretion in the urine. A high concentration of aldosterone in the plasma can transiently decrease the sodium loss into the urine to as little as a few milliequivalents per day. At the same time, potassium loss into the urine transiently increases sever- alfold. Therefore, the net effect of excess aldosterone in the plasma is to increase the total quantity of sodium in the extracellular fluid while decreasing the potassium. Conversely, total lack of aldosterone secretion can cause transient loss of 10 to 20 grams of sodium in the urine a day, an amount equal to one tenth to one fifth of all the sodium in the body. At the same time, potassium is conserved tenaciously in the extracellular fluid. Excess Aldosterone Increases Extracellular Fluid Volume and Arterial Pressure But Has Only a Small Effect on Plasma Sodium Concentration; Aldosterone Deficiency Causes Hyponatremia. Although aldoster- one has a potent effect to decrease the rate of sodium ex- cretion by the kidneys, the concentration of sodium in the extracellular fluid often rises only a few milliequivalents. The reason for this is that when sodium is reabsorbed by the tubules, simultaneous osmotic absorption of almost equivalent amounts of water occurs. Also, small increas- es in extracellular fluid sodium concentration stimulate thirst and increased water intake, if water is available, and increase secretion of antidiuretic hormone, which enhances water reabsorption by the distal and collecting tubules of the kidneys. Therefore, the extracellular fluid volume increases almost as much as the retained sodium, but without much change in sodium concentration. Even though aldosterone is one of the body’s most pow- erful sodium-retaining hormones, only transient sodium retention occurs when excess amounts are secreted. An aldosterone-mediated increase in extracellular fluid vol- ume lasting more than 1 to 2 days also leads to an increase in arterial pressure, as explained in Chapter 19. The rise in arterial pressure then increases kidney excretion of both sodium and water, called pressure natriuresis and pres- sure diuresis, respectively. Thus, after the extracellular fluid volume increases 5% to 15% above normal, arterial pressure also increases 15 to 25 mm Hg, and this elevated blood pressure returns the renal output of sodium and water to normal despite excess aldosterone (Figure 78-3). This return to normal sodium and water excretion by the kidneys as a result of pressure natriuresis and diuresis is called aldosterone escape. Thereafter, the rate of gain of sodium and water by the body is zero, and balance is maintained between sodium and water intake and out- put by the kidneys, despite continued excess aldosterone. In the meantime, however, hypertension has developed, which lasts as long as the person remains exposed to high levels of aldosterone. In contrast, severe aldosterone deficiency may cause substantial reductions in plasma sodium concentration (hyponatremia) due to reduced renal sodium reabsorp- tion and increased sodium excretion. The renal sodium wasting causes reductions in extracellular fluid volume, arterial pressure, and cardiac output, which stimulate secretion of antidiuretic hormone (ADH). Increased lev- els of ADH attenuate renal water excretion and contrib- ute to hyponatremia, along with increases in thirst and water intake that are also stimulated by hypovolemia and hypotension. When aldosterone secretion becomes zero, large amounts of sodium are lost in the urine, not only 100 400 300 200 –4 –2 0 2 4 6 8 10 12 14 Urinary sodium excretion (mEq/day) 100 90 120 110 Extracellular fluid volume (% Normal) 100 80 120 Mean arterial pressure (mm Hg) Time (days) Aldosterone Figure 78-3. Effect of aldosterone infusion on arterial pressure, ex- tracellular fluid volume, and sodium excretion in dogs. Although al- dosterone was infused at a rate that raised plasma concentrations to about 20 times normal, note the “escape” from sodium retention on the second day of infusion as arterial pressure increased and urinary sodium excretion returned to normal. (Data from Hall JE, Granger JP, Smith MJ Jr, et al: Role of hemodynamics and arterial pressure in aldosterone “escape.” Hypertension 6[suppl I]:I183-I192, 1984.) UNIT XIV Endocrinology and Reproduction 960 diminishing the amount of sodium chloride in the extra- cellular fluid but also decreasing the extracellular fluid volume. The result is severe extracellular fluid dehydra- tion and low blood volume, leading to circulatory shock. Without therapy, this usually causes death within a few days after the adrenal glands suddenly stop secreting aldosterone. Excess Aldosterone Causes Hypokalemia and Muscle Weakness; Aldosterone Deficiency Causes Hyper- kalemia and Cardiac Toxicity. Excess aldosterone not only causes loss of potassium ions from the extracellular fluid into the urine but also stimulates transport of po- tassium from the extracellular fluid into most cells of the body. Therefore, excessive secretion of aldosterone, as occurs with some types of adrenal tumors, may cause a serious decrease in the plasma potassium concentration (hypokalemia), sometimes from the normal value of 4.5 mEq/L to as low as 2 mEq/L. When plasma potassium ion concentration falls below about one-half normal, se- vere muscle weakness often develops. This muscle weak- ness is caused by alteration of the electrical excitability of the nerve and muscle fiber membranes (see Chapter 5), which prevents transmission of normal action potentials. Conversely, when aldosterone is deficient, the extracel- lular fluid potassium ion concentration can rise far above normal. When it rises to 60% to 100% above normal, seri- ous cardiac toxicity, including weakness of heart contrac- tion and development of arrhythmia, becomes evident, and progressively higher concentrations of potassium lead inevitably to heart failure. Excess Aldosterone Increases Tubular Hydrogen Ion Secretion and Causes Alkalosis. Aldosterone not only causes potassium to be secreted into the tubules in ex- change for sodium reabsorption in the principal cells of the renal collecting tubules but also causes secretion of hydrogen ions in exchange for potassium in the interca- lated cells of the cortical collecting tubules, as discussed in Chapters 28 and 31. This decreases the hydrogen ion concentration in the extracellular fluid, causing metabolic alkalosis. ALDOSTERONE STIMULATES SODIUM AND POTASSIUM TRANSPORT IN SWEAT GLANDS, SALIVARY GLANDS, AND INTESTINAL EPITHELIAL CELLS Aldosterone has almost the same effects on sweat glands and salivary glands as it has on the renal tubules. Both these glands form a primary secretion that contains large quantities of sodium chloride, but much of the sodium chloride, upon passing through the excretory ducts, is reabsorbed, whereas potassium and bicarbonate ions are secreted. Aldosterone greatly increases the reabsorption of sodium chloride and the secretion of potassium by the ducts. The effect on the sweat glands is important to con- serve body salt in hot environments (see Chapter 74), and the effect on the salivary glands is necessary to conserve salt when excessive quantities of saliva are lost. Aldosterone also greatly enhances sodium absorption by the intestines, especially in the colon, which prevents loss of sodium in the stools. Conversely, in the absence of aldosterone, sodium absorption can be poor, leading to failure to absorb chloride and other anions and water as well. The unabsorbed sodium chloride and water then lead to diarrhea, with further loss of salt from the body. CELLULAR MECHANISM OF ALDOSTERONE ACTION Although for many years we have known the overall effects of mineralocorticoids on the body, the molecular mechanisms of the actions of aldosterone on the tubu- lar cells to increase transport of sodium are still not fully understood. However, the cellular sequence of events that leads to increased sodium reabsorption seems to unfold as follows. First, because of its lipid solubility in the cellular mem- branes, aldosterone diffuses readily to the interior of the tubular epithelial cells. Second, in the cytoplasm of the tubular cells, aldoste- rone combines with a highly specific cytoplasmic miner- alocorticoid receptor (MR) protein (Figure 78-4), which has a stereomolecular configuration that allows only aldosterone or similar compounds to combine with it. Although renal tubular epithelial cell MR receptors also have a high affinity for cortisol, the enzyme 11β-HSD2 ATP Na+ K+ ENaC ROMK Renal interstitial fluid Spironolactone Aldosterone mRNA Proteins Amiloride Mitochondrial enzymes Tubular lumen Principal cells MR Na+ K+ Nucleus Figure 78-4. Aldosterone-responsive epithelial cell signaling path- ways. Activation of the mineralocorticoid receptor (MR) by aldoster- one can be antagonized with spironolactone. Amiloride is a drug that can be used to block epithelial sodium channel (ENaC) proteins. ATP, ROMK, Renal outer medullary potassium channel. Chapter 78 Adrenocortical Hormones 961 UNIT XIV normally converts most of the cortisol to cortisone, which does not readily bind to MR receptors, as discussed previously. Third, the aldosterone-receptor complex or a product of this complex diffuses into the nucleus, where it may undergo further alterations, finally inducing one or more specific portions of the DNA to form one or more types of messenger RNA (mRNA) related to the process of sodium and potassium transport. Fourth, the mRNA diffuses back into the cytoplasm where, operating in conjunction with the ribosomes, it causes protein formation. The proteins formed are a mixture of (1) one or more enzymes and (2) membrane transport proteins that, all acting together, are required for sodium, potassium, and hydrogen transport through the cell membrane (see Figure 78-4). One of the enzymes especially increased is sodium-potassium adenosine tri- phosphatase (Na+-K+ ATPase), which serves as the princi- pal part of the pump for sodium and potassium exchange at the basolateral membranes of the renal tubular cells. Additional proteins, perhaps equally important, are epi- thelial sodium channels and potassium channels inserted into the luminal membrane of the same tubular cells; these channels allow rapid diffusion of sodium ions from the tubular lumen into the cell and diffusion of potassium from the cell interior to the tubular lumen. (See Chapters 28 and 30 for further discussion of the effects of aldoste- rone on sodium, potassium, and hydrogen transport by renal tubular epithelial cells.) Thus, aldosterone does not have a major immediate effect on sodium transport; rather, this effect must await the sequence of events that leads to the formation of the specific intracellular substances required for sodium transport. About 30 minutes is required before new RNA appears in the cells, and about 45 minutes is required before the rates of sodium and potassium transport begin to increase; these effects reach a maximum only after sev- eral hours. POSSIBLE NONGENOMIC ACTIONS OF ALDOSTERONE AND OTHER STEROID HORMONES Some studies suggest that many steroids, including aldo- sterone, elicit not only slowly developing genomic effects that have a latency of 45 to 60 minutes and require gene transcription and synthesis of new proteins but also more rapid nongenomic effects that take place in a few seconds or minutes. These nongenomic actions are believed to be medi- ated by binding of steroids to cell membrane receptors that are coupled to second messenger systems, similar to those used for peptide hormone signal transduction. For example, aldosterone has been shown to increase forma- tion of cyclic adenosine monophosphate (cAMP) in vas- cular smooth muscle cells and in epithelial cells of the renal collecting tubules in less than 2 minutes, a period that is far too short for gene transcription and synthesis of new proteins. In other cell types, aldosterone has been shown to rapidly stimulate the phosphatidylinositol sec- ond messenger system. However, the precise structure of receptors responsible for the rapid effects of aldoste- rone has not been determined, nor is the physiological significance of these nongenomic actions of steroids well understood. REGULATION OF ALDOSTERONE SECRETION Regulation of aldosterone secretion is so deeply inter- twined with regulation of extracellular fluid electrolyte concentrations, extracellular fluid volume, blood volume, arterial pressure, and many special aspects of renal func- tion that it is difficult to discuss control of aldosterone secretion independently of all these other factors. This subject is presented in more detail in Chapters 28 and 30, to which the reader is referred. However, it is important to list here some of the more important points of aldoste- rone secretion control. Regulation of aldosterone secretion by the zona glo- merulosa cells is almost entirely independent of regula- tion of cortisol and androgens by the zona fasciculata and zona reticularis. The following factors are known to play roles in regula- tion of aldosterone: 1. Increased potassium ion concentration in the extra- cellular fluid greatly increases aldosterone secretion. 2. Increased angiotensin II concentration in the extracel- lular fluid also greatly increases aldosterone secretion. 3. Increased sodium ion concentration in the extracel- lular fluid slightly decreases aldosterone secretion. 4. Increased atrial natriuretic peptide (ANP), a hor- mone secreted by the heart when specific cells of the cardiac atria are stretched (see Chapter 28), de- creases aldosterone secretion. 5. ACTH from the anterior pituitary gland is neces- sary for aldosterone secretion but has little effect in controlling the rate of secretion in most physiologi- cal conditions. Of these factors, potassium ion concentration and the angiotensin II are by far the most potent in regulat- ing aldosterone secretion. A small percentage increase in potassium concentration can cause a severalfold increase in aldosterone secretion. Likewise, increased angiotensin II,, usually in response to diminished blood flow to the kidneys or to sodium loss, can increase aldosterone secre- tion severalfold. In turn, the aldosterone acts on the kid- neys (1) to help them excrete the excess potassium ions and (2) to increase the blood volume and arterial pres- sure, thus returning the renin-angiotensin system toward its normal level of activity. These feedback control mecha- nisms are essential for maintaining life, and the reader is referred again to Chapters 28 and 30 for a more complete description of their functions. UNIT XIV Endocrinology and Reproduction 962 Figure 78-5 shows the effects on plasma aldosterone concentration caused by blocking formation of angioten- sin II with an angiotensin-converting enzyme inhibitor after several weeks of a low-sodium diet that increases plasma aldosterone concentration. Note that blockade of angiotensin II formation markedly decreased plasma aldosterone concentration without significantly chang- ing cortisol concentration, which indicates the important role of angiotensin II in stimulating aldosterone secretion when sodium intake and extracellular fluid volume are reduced. By contrast, the effects of ANP, sodium ion concen- tration per se, and ACTH in controlling aldosterone secretion are usually minor. Nevertheless, a 10% to 20% decrease in extracellular fluid sodium ion con- centration, which occurs on rare occasions, can per- haps increase aldosterone secretion by about 50%. An increase in ANP concentration, secondary to plasma volume expansion and stretch of the cardiac atria, may induce natriuresis, in part by inhibiting aldoste- rone secretion. In the case of ACTH, if even a small amount is secreted by the anterior pituitary gland, it is usually enough to permit the adrenal glands to secrete whatever amount of aldosterone is required, but total absence of ACTH can significantly reduce aldosterone secretion. Therefore, ACTH appears to play a “permissive” role in regulation of aldosterone secretion. FUNCTIONS OF GLUCOCORTICOIDS Even though mineralocorticoids can save the life of an acutely adrenalectomized animal, the animal still is far from normal. Instead, the animal’s metabolic sys- tems for utilization of proteins, carbohydrates, and fats remain considerably deranged. Furthermore, the ani- mal cannot resist different types of physical or even mental stress, and minor illnesses such as respiratory tract infections can lead to death. Therefore, the glu- cocorticoids have functions just as important to the long-continued life of the animal as those of the min- eralocorticoids. These functions are explained in the following sections. At least 95% of the glucocorticoid activity of the adre- nocortical secretions results from the secretion of corti- sol, known also as hydrocortisone. In addition, a small but significant amount of glucocorticoid activity is provided by corticosterone. EFFECTS OF CORTISOL ON CARBOHYDRATE METABOLISM Stimulation of Gluconeogenesis. The best-known metabolic effect of cortisol and other glucocorticoids on metabolism is the ability to stimulate gluconeogenesis (i.e., the formation of carbohydrate from proteins and some other substances) by the liver, often increasing the rate of gluconeogenesis as much as 6- to 10-fold. This in- creased rate of gluconeogenesis results mainly from direct effects of cortisol on the liver, as well as by antagonizing the effects of insulin. 1. Cortisol increases the enzymes required to convert ami- no acids into glucose in liver cells. Glucocorticoids ac- tivate DNA transcription in the liver cell nuclei in the same way that aldosterone functions in renal tubular cells, with formation of mRNAs that in turn lead to the array of enzymes required for gluconeogenesis. 2. Cortisol causes mobilization of amino acids from ex- trahepatic tissues, mainly from muscle. As a result, more amino acids become available in the plasma to enter into the gluconeogenesis process of the liver and thereby to promote formation of glucose. 3. Cortisol antagonizes insulin’s effects to inhibit gluco- neogenesis in the liver. As discussed in Chapter 79, in- sulin stimulates glycogen synthesis in the liver and in- hibits enzymes involved in glucose production by the liver. The net effect of cortisol is to increase glucose production by the liver. The marked increase in glycogen storage in liver cells that accompanies increased gluconeogenesis potentiates the effects of other glycolytic hormones, such as epineph- rine and glucagon, to mobilize glucose in times of need, such as between meals. 0.0 3.0 2.0 1.0 Control ACE inhibitor + Ang II infusion ACE inhibitor Plasma cortisol (µg/100 ml) 20 50 40 30 Plasma aldosterone (ng/100 ml) Figure 78-5. Effects of treating sodium-depleted dogs with an angiotensin-converting enzyme (ACE) inhibitor for 7 days to block formation of angiotensin II (Ang II) and of infusing exogenous Ang II to restore plasma Ang II levels after ACE inhibition. Note that block- ing Ang II formation reduced plasma aldosterone concentration with little effect on cortisol, demonstrating the important role of Ang II in stimulating aldosterone secretion during sodium depletion. (Data from Hall JE, Guyton AC, Smith MJ Jr, et al: Chronic blockade of angiotensin II formation during sodium deprivation. Am J Physiol 237:F424, 1979.) Chapter 78 Adrenocortical Hormones 963 UNIT XIV Decreased Glucose Utilization by Cells. Cortisol also causes a moderate decrease in glucose utilization by most cells in the body. Although the precise cause of this de- crease is unclear, one important effect of cortisol is to de- crease translocation of the glucose transporter GLUT 4 to the cell membrane, especially in skeletal muscle cells, leading to insulin resistance. Glucocorticoids may also de- press the expression and phosphorylation of other signal- ing cascades that influence glucose utilization directly or indirectly by affecting protein and lipid metabolism. For example, glucocorticoids reduce the expression of insulin receptor substrate–1 and phosphatidylinositol 3 kinase, both of which are involved in mediating the actions of insulin, as well as oxidation of nicotinamide-adenine di- nucleotide (NADH) to form NAD+. Because NADH must be oxidized to allow glycolysis, this effect could also con- tribute to diminished utilization of glucose by the cells. Elevated Blood Glucose Concentration and “Adre- nal Diabetes.” Both the increased gluconeogenesis and moderate reduction in glucose utilization by the cells cause the blood glucose concentrations to rise. The rise in blood glucose in turn stimulates insulin secretion. The increased plasma levels of insulin, however, are not as ef- fective in maintaining plasma glucose as they are under normal conditions. For reasons that were discussed previ- ously, high levels of glucocorticoid reduce the sensitivity of many tissues, especially skeletal muscle and adipose tis- sue, to the stimulatory effects of insulin on glucose uptake and utilization. Besides potential direct effects of cortisol on expression of glucose transporters and enzymes in- volved in glucose regulation, the high levels of fatty acids, caused by the effect of glucocorticoids to mobilize lipids from fat depots, may impair the actions of insulin on the tissues. In this way, excess secretion of glucocorticoids produce disturbances of carbohydrate metabolism simi- lar to those found in patients with excess levels of growth hormone. The increase in blood glucose concentration is occa- sionally great enough (≥50% normal) that the condition is called adrenal diabetes. Administration of insulin lowers the blood glucose concentration only a moderate amount in adrenal diabetes—not nearly as much as it does in pan- creatic diabetes—because the tissues are resistant to the effects of insulin. EFFECTS OF CORTISOL ON PROTEIN METABOLISM Reduction in Cellular Protein. One of the principal ef- fects of cortisol on the metabolic systems of the body is reduction of protein stores in essentially all cells of the body, except those of the liver. This reduction is caused by both decreased protein synthesis and increased catabo- lism of protein already in the cells. Both these effects may result partly from decreased amino acid transport into extrahepatic tissues, as discussed later, but this is prob- ably not the major cause because cortisol also depresses formation of RNA and subsequent protein synthesis in many extrahepatic tissues, especially in muscle and lym- phoid tissue. In the presence of great excesses of cortisol, the mus- cles can become so weak that the person cannot rise from the squatting position. In addition, the immunity func- tions of the lymphoid tissue can be decreased to a small fraction of normal. Cortisol Increases Liver and Plasma Proteins. Coinci- dentally with the effect of glucocorticoids to reduce pro- teins elsewhere in the body, the liver proteins are increased. Furthermore, the plasma proteins (which are produced by the liver and then released into the blood) are also in- creased. These increases are exceptions to the protein depletion that occurs elsewhere in the body. It is believed that this difference results from a possible effect of cortisol to enhance amino acid transport into liver cells—but not into most other cells—and to enhance the liver enzymes required for protein synthesis. Increased Blood Amino Acids, Diminished Transport of Amino Acids Into Extrahepatic Cells, and Enhanced Transport Into Hepatic Cells. Studies in isolated tissues have demonstrated that cortisol depresses amino acid transport into muscle cells and perhaps into other extra- hepatic cells. The decreased transport of amino acids into extrahe- patic cells decreases their intracellular amino acid con- centrations and consequently decreases the synthesis of protein. Yet, cell catabolism of proteins continues to release amino acids that diffuse out of the cells to increase the plasma amino acid concentration. Therefore, corti- sol mobilizes amino acids from nonhepatic tissues and in doing so diminishes tissue stores of protein. The increased plasma concentration of amino acids and enhanced amino acid transport into the hepatic cells by cortisol could also account for enhanced utili- zation of amino acids by the liver to cause such effects as (1) increased rate of deamination of amino acids by the liver, (2) increased protein synthesis in the liver, (3) increased formation of plasma proteins by the liver, and (4) increased conversion of amino acids to glucose—that is, enhanced gluconeogenesis. Thus, it is possible that many of the effects of cortisol on the metabolic systems of the body result mainly from this ability of cortisol to mobilize amino acids from the peripheral tissues while at the same time increasing the liver enzymes required for the hepatic effects. EFFECTS OF CORTISOL ON FAT METABOLISM Mobilization of Fatty Acids. In much the same man- ner that cortisol promotes amino acid mobilization from muscle, it also promotes mobilization of fatty acids from UNIT XIV Endocrinology and Reproduction 964 adipose tissue. This mobilization increases the concentra- tion of free fatty acids in the plasma, which also increases their utilization for energy. Cortisol also seems to have a direct effect to enhance the oxidation of fatty acids in the cells. The mechanism by which cortisol promotes fatty acid mobilization is not completely understood. However, part of the effect probably results from diminished transport of glucose into the fat cells. Recall that α-glycerophosphate, which is derived from glucose, is required for both depo- sition and maintenance of triglycerides in these cells. In its absence, the fat cells begin to release fatty acids. The increased mobilization of fats by cortisol, com- bined with increased oxidation of fatty acids in the cells, helps shift the metabolic systems of the cells from utiliza- tion of glucose for energy to utilization of fatty acids in times of starvation or other stresses. This cortisol mecha- nism, however, requires several hours to become fully developed—not nearly so rapid or so powerful an effect as a similar shift elicited by a decrease in insulin, as we discuss in Chapter 79. Nevertheless, the increased use of fatty acids for metabolic energy is an important factor for long-term conservation of body glucose and glycogen. Excess Cortisol Causes Obesity. Although cortisol can cause a moderate degree of fatty acid mobilization from adipose tissue, a peculiar type of obesity develops in many people with excess cortisol secretion, with excess deposi- tion of fat in the chest and head regions of the body, giving a buffalo-like torso and a rounded “moon face.” Although the cause is unclear, it has been suggested that this obesity results from excess stimulation of food intake, with fat be- ing generated in some tissues of the body more rapidly than it is mobilized and oxidized. CORTISOL IS IMPORTANT IN RESISTING STRESS AND INFLAMMATION Almost any type of stress, whether physical or neu- rogenic, causes an immediate and marked increase in ACTH secretion by the anterior pituitary gland, fol- lowed within minutes by greatly increased adrenocor- tical secretion of cortisol. This effect is demonstrated dramatically by the experiment shown in Figure 78-6, in which corticosteroid formation and secretion increased sixfold in a rat within 4 to 20 minutes after fracture of two leg bones. The following list details some of the different types of stress that increase cortisol release: 1. Trauma 2. Infection 3. Intense heat or cold 4. Injection of norepinephrine and other sympatho- mimetic drugs 5. Surgery 6. Injection of necrotizing substances beneath the skin 7. Restraining an animal so it cannot move 8. Debilitating diseases Even though cortisol secretion often increases greatly in stressful situations, we are not sure why this is of signif- icant benefit to the animal. One possibility is that the glu- cocorticoids cause rapid mobilization of amino acids and fats from their cellular stores, making them immediately available both for energy and for synthesis of other com- pounds, including glucose, needed by different tissues of the body. Indeed, it has been shown in a few instances that damaged tissues that are momentarily depleted of pro- teins can use the newly available amino acids to form new proteins that are essential to the lives of the cells. Also, the amino acids are perhaps used to synthesize other essen- tial intracellular substances, such as purines, pyrimidines, and creatine phosphate, which are necessary for mainte- nance of cellular life and reproduction of new cells. All this is mainly supposition and is supported only by the fact that cortisol usually does not mobilize the basic functional proteins of the cells, such as the muscle con- tractile proteins and the proteins of neurons, until almost all other proteins have been released. This preferential effect of cortisol in mobilizing labile proteins could make amino acids available to needy cells to synthesize sub- stances essential to life. Anti-inflammatory Effects of High Levels of Cortisol When tissues are damaged by trauma, by infection with bacteria, or in other ways, they almost always become “inflamed.” In some conditions, such as in rheumatoid arthritis, the inflammation is more damaging than the trauma or disease itself. Administration of large amounts of cortisol can usually block this inflammation or even reverse many of its effects once it has begun. Before attempting to explain the way in which cortisol functions –0 45 40 35 30 25 20 15 10 5 55 50 45 40 35 30 25 20 15 10 5 Seconds Minutes 15 30 45 60 90 2 3 4 5 6 8101215202530 Plasma corticosterone concentration (µg/100 ml) Adrenal corticosterone concentration (µg/g) Figure 78-6. Rapid reaction of the adrenal cortex of a rat to stress caused by fracture of the tibia and fibula at time zero. (In the rat, corticosterone is secreted in place of cortisol.) Chapter 78 Adrenocortical Hormones 965 UNIT XIV to block inflammation, let us review the basic steps in the inflammation process, which are discussed in more detail in Chapter 34. Five main stages of inflammation occur: (1) release from the damaged tissue cells of chemicals such as his- tamine, bradykinin, proteolytic enzymes, prostaglandins, and leukotrienes that activate the inflammation process; (2) an increase in blood flow in the inflamed area caused by some of the released products from the tissues, an effect called erythema; (3) leakage of large quantities of almost pure plasma out of the capillaries into the damaged areas because of increased capillary permeability, followed by clotting of the tissue fluid, thus causing a nonpitting type of edema; (4) infiltration of the area by leukocytes; and (5) after days or weeks, ingrowth of fibrous tissue that often helps in the healing process. When large amounts of cortisol are secreted or injected into a person, the glucocorticoid has two basic anti- inflammatory effects: (1) it can block the early stages of the inflammation process before noticeable inflammation even begins, or (2) if inflammation has already begun, it causes rapid resolution of the inflammation and increased rapidity of healing. These effects are explained further in the following sections. Cortisol Prevents the Development of Inflammation by Stabilizing Lysosomes and by Other Effects. Cor- tisol has the following effects in preventing inflammation: 1. Cortisol stabilizes lysosomal membranes. This stabilization is one of its most important anti- inflammatory effects because it is much more difficult than normal for the membranes of the intracellular lysosomes to rupture. Therefore, the proteolytic enzymes that are stored in lysosomes and are released by damaged cells to cause inflam- mation are released in greatly decreased quantities. 2. Cortisol decreases permeability of the capillaries, probably as a secondary effect of the reduced re- lease of proteolytic enzymes. This decrease in per- meability prevents loss of plasma into the tissues. 3. Cortisol decreases migration of white blood cells into the inflamed area and phagocytosis of the damaged cells. These effects probably result from the fact that cortisol diminishes formation of prostaglandins and leukot- rienes that otherwise would increase vasodilation, cap- illary permeability, and mobility of white blood cells. 4. Cortisol suppresses the immune system, causing lymphocyte reproduction to decrease markedly. The T lymphocytes are especially suppressed. In turn, reduced amounts of T cells and antibodies in the inflamed area lessen tissue reactions that would otherwise promote inflammation. 5. Cortisol attenuates fever mainly because it reduces release of interleukin-1 from white blood cells, which is one of the principal excitants to the hypothalamic temperature control system. The decreased temper- ature in turn reduces the degree of vasodilation. Thus, cortisol has an almost global effect in reducing all aspects of the inflammatory process. It is unclear how much of this reduction results from the simple effect of cortisol in stabilizing lysosomal and cell membranes ver- sus its effect in reducing the formation of prostaglandins and leukotrienes from arachidonic acid in damaged cell membranes and other effects of cortisol. Cortisol Causes Resolution of Inflammation. Even after inflammation has become well established, admin- istration of cortisol can often reduce inflammation with- in hours to a few days. The immediate effect is to block most of the factors that promote inflammation. In addi- tion, however, the rate of healing is enhanced. This prob- ably results from the same, mainly undefined, factors that allow the body to resist many other types of physi- cal stress when large quantities of cortisol are secreted. Perhaps this results from (1) mobilization of amino acids and use of these acids to repair the damaged tissues; (2) increased glucogenesis that makes extra glucose available in critical metabolic systems; (3) increased amounts of fatty acids available for cellular energy; or (4) some effect of cortisol for inactivating or removing inflammatory products. Regardless of the precise mechanisms by which the anti- inflammatory effect occurs, this effect of cortisol plays a major role in combating certain types of diseases, such as rheumatoid arthritis, rheumatic fever, and acute glomerulo- nephritis. All these diseases are characterized by severe local inflammation, and the harmful effects on the body are caused mainly by the inflammation associated with the disease. When cortisol or other glucocorticoids are adminis- tered to patients with these diseases, almost invariably the inflammation begins to subside within 24 hours. Even though the cortisol does not correct the basic disease condition, preventing the damaging effects of the inflam- matory response can often be a lifesaving measure. Other Effects of Cortisol Cortisol Blocks the Inflammatory Response to Allergic Reactions. The basic allergic reaction between antigen and antibody is not affected by cortisol, and even some of the secondary effects of the allergic reaction still occur. How- ever, because the inflammatory response is responsible for many of the serious and sometimes lethal effects of allergic reactions, administration of cortisol, followed by its effect in reducing inflammation and release of inflammatory prod- ucts, can be lifesaving. For instance, cortisol effectively pre- vents shock or death as a result of anaphylaxis, a condition that otherwise kills many people, as explained in Chapter 35. Effect on Blood Cells and on Immunity in Infectious Diseases. Cortisol decreases the number of eosinophils and lymphocytes in the blood; this effect begins within a few minutes after injection of cortisol and becomes marked within a few hours. Indeed, a finding of lymphocytopenia or eosinopenia is an important diagnostic criterion for overproduction of cortisol by the adrenal gland. UNIT XIV Endocrinology and Reproduction 966 Likewise, administration of large doses of cortisol causes significant atrophy of lymphoid tissue throughout the body, which in turn decreases output of T cells and antibodies from the lymphoid tissue. As a result, the level of immunity for almost all foreign invaders of the body is decreased. This decrease occasionally can lead to fulminat- ing infection and death from diseases that would otherwise not be lethal, such as fulminating tuberculosis in a person whose disease had previously been arrested. However, this ability of cortisol and other glucocorticoids to suppress im- munity makes them useful drugs in preventing immuno- logical rejection of transplanted hearts, kidneys, and other tissues. Cortisol increases production of red blood cells by mechanisms that are unclear. When excess cortisol is se- creted by the adrenal glands, polycythemia often results, and conversely, when the adrenal glands secrete no cortisol, anemia often results. Cellular Mechanism of Cortisol Action Cortisol, like other steroid hormones, exerts its effects by first interacting with intracellular receptors in target cells. Because cortisol is lipid soluble, it can easily diffuse through the cell membrane. Once inside the cell, cortisol binds with its protein receptor in the cytoplasm, and the hormone-receptor complex then interacts with specific regulatory DNA sequences, called glucocorticoid response elements, to induce or repress gene transcription. Other proteins in the cell, called transcription factors, are also necessary for the hormone-receptor complex to interact appropriately with the glucocorticoid response elements. Glucocorticoids increase or decrease transcription of many genes to alter synthesis of mRNA for the proteins that mediate their multiple physiological effects. Thus, most of the metabolic effects of cortisol are not immedi- ate but require 45 to 60 minutes for proteins to be syn- thesized, and up to several hours or days to fully develop. Some evidence suggests that glucocorticoids, especially at high concentrations, may also have some rapid nongenomic effects on cell membrane ion transport that may contribute to their therapeutic benefits. Modulation of Glucocorticoid Effects by 11β- Hydroxysteroid Dehydrogenase An important mechanism for modulating the physi- ological effects of cortisol is local tissue expression of isoforms of the enzyme 11β-hydroxysteroid dehydroge- nase (11β-HSD). As discussed previously, one isoform, 11β-HSD2, metabolizes cortisol to inactive cortisone at the pre-receptor level in the renal tubules and therefore protects the mineralocorticoid receptor from activation by cortisol. This enzyme is also present in other tissues such as the colon, sweat glands, salivary glands, and the placenta (Figure 78-7). When 11β-HSD2 is deficient, as in apparent mineralocorticoid excess syndrome due to ge- netic mutations or excessive licorice ingestion, or when circulating cortisol concentrations are extremely high, as in Cushing’s syndrome, this mechanism for cortisol metabolism may be overwhelmed. As a result, the high levels of cortisol strongly activate the mineralocorticoid receptor and cause sodium retention, hypertension, and hypokalemia. Conversely, tissues such as the liver, brain, adipose tis- sue, skeletal muscle, lung, and skin express another iso- form, 11β-HSD1, which converts inactive cortisone to ac- tive cortisol (see Figure 78-7). Thus, 11β-HSD1 expression amplifies the physiological effects of glucocorticoids in tis- sues whereas 11β-HSD2 has the opposite effect. For this reason the isoforms of 11β-HSD2 may serve as intracellular “gate-keepers” of tissue glucocorticoid action. Some studies suggest that increased adipose tissue ex- pression of 11β-HSD1 and excessive glucocorticoid activity may contribute to the metabolic abnormalities, including insulin resistance and diabetes mellitus, associated with obesity. Elevated brain 11β-HSD1 has also been associated with cognitive decline in aging. However, the physiological factors that regulate these isoforms of 11β-HSD and their role in common diseases such as obesity and dementia are still poorly understood. REGULATION OF CORTISOL SECRETION BY ADRENOCORTICOTROPIC HORMONE FROM THE PITUITARY GLAND ACTH Stimulates Cortisol Secretion. Unlike aldosterone secretion by the zona glomerulosa, which is controlled mainly by potassium and angiotensin II acting directly on the adrenocortical cells, secretion of cortisol is controlled almost entirely by ACTH that is secreted by the anterior pituitary gland. This hormone, also called corticotropin or adrenocorticotropin, also enhances the production of ad- renal androgens. Chemistry of ACTH. ACTH has been isolated in pure form from the anterior pituitary. It is a large polypep- tide, having a chain length of 39 amino acids. A smaller polypeptide, a digested product of ACTH having a chain Cortisol (active) Cortisol (active) 11HSD2 11HSD1 Cortisone (inactive) Cortisone (inactive) Cortisol Cortisone Kidney Colon Sweat glands Salivary glands Liver Skin Brain Adipose tissue Placenta Mineralocorticoid receptor Glucocorticoid receptor Figure 78-7. Interconversion of active cortisol and inactive cortisone by the two 11β-hydroxysteroid dehydrogenase isoforms (11β-HSD1 and 11β-HSD2) in various tissues. Chapter 78 Adrenocortical Hormones 967 UNIT XIV Hypothalamus Cortisol ACTH Portal vessel (CRF) Inhibits Adrenal cortex Relieves Stress Excites Median eminence 1. Gluconeogenesis 2. Protein mobilization 3. Fat mobilization 4. Stabilizes lysosomes Figure 78-8. Mechanism for regulation of glucocorticoid secretion. ACTH, Adrenocorticotropic hormone; CRF, corticotropin-releasing factor. length of 24 amino acids, has all the effects of the total molecule. ACTH Secretion Is Controlled by Corticotropin- Releasing Factor From the Hypothalamus. In the same way that other pituitary hormones are controlled by releas- ing factors from the hypothalamus, an important releasing factor also controls ACTH secretion. This factor is called corticotropin-releasing factor (CRF). It is secreted into the primary capillary plexus of the hypophysial portal system in the median eminence of the hypothalamus and then car- ried to the anterior pituitary gland, where it induces ACTH secretion. CRF is a peptide composed of 41 amino acids. The cell bodies of the neurons that secrete CRF are located mainly in the paraventricular nucleus of the hypothalamus. This nucleus in turn receives many nervous connections from the limbic system and lower brain stem. The anterior pituitary gland can secrete only minute quantities of ACTH in the absence of CRF. Instead, most conditions that cause high ACTH secretory rates initiate this secretion by signals that begin in the basal regions of the brain, including the hypothalamus, and are then transmitted by CRF to the anterior pituitary gland. ACTH Activates Adrenocortical Cells to Produce Ster- oids by Increasing cAMP. The principal effect of ACTH on the adrenocortical cells is to activate adenylyl cyclase in the cell membrane. This activation then induces forma- tion of cAMP in the cell cytoplasm, reaching its maximal effect in about 3 minutes. The cAMP in turn activates the intracellular enzymes that cause formation of the adreno- cortical hormones, which is another example of cAMP as a second messenger signal system. The most important of all the ACTH-stimulated steps for controlling adrenocortical secretion is acti- vation of the enzyme protein kinase A, which causes initial conversion of cholesterol to pregnenolone. This initial conversion is the “rate-limiting” step for all the adrenocortical hormones, which explains why ACTH is normally necessary for any adrenocortical hormones to be formed. Long-term stimulation of the adrenal cor- tex by ACTH not only increases secretory activity but also causes hypertrophy and proliferation of the adre- nocortical cells, especially in the zona fasciculata and zona reticularis, where cortisol and the androgens are secreted. Physiological Stress Increases ACTH and Adrenocorti- cal Secretion. As pointed out earlier in the chapter, al- most any type of physical or mental stress can lead within minutes to greatly enhanced secretion of ACTH and con- sequently cortisol as well, often increasing cortisol secre- tion as much as 20-fold. This effect was demonstrated by the rapid and strong adrenocortical secretory responses after trauma shown in Figure 78-6. Pain stimuli caused by physical stress or tissue dam- age are transmitted first upward through the brain stem to neurons of the paraventricular nucleus, and eventually to the median eminence of the hypothalamus, as shown in Figure 78-8. Here CRF is secreted into the hypophysial portal system. Within minutes the entire control sequence leads to large quantities of cortisol in the blood. Mental stress can cause an equally rapid increase in ACTH secretion. This increase is believed to result from increased activity in the limbic system, especially in the region of the amygdala and hippocampus, both of which then transmit signals to the posterior medial hypothalamus. Inhibitory Effect of Cortisol on the Hypothalamus and Anterior Pituitary to Decrease ACTH Secre- tion. Cortisol has direct negative feedback effects on (1) the hypothalamus to decrease formation of CRF and (2) the anterior pituitary gland to decrease forma- tion of ACTH. Both of these feedbacks help regulate the plasma concentration of cortisol. That is, whenever the cortisol concentration becomes too great, the feedbacks automatically reduce the ACTH toward a normal con- trol level. Summary of the Cortisol Control System Figure 78-8 shows the overall system for control of cor- tisol secretion. The key to this control is the excitation of the hypothalamus by different types of stress. Stress stimuli activate the entire system to cause rapid release of cortisol, and cortisol in turn initiates a series of metabolic effects directed toward relieving the damaging nature of the stressful state. UNIT XIV Endocrinology and Reproduction 968 Direct feedback of cortisol to both the hypothala- mus and the anterior pituitary gland also occurs to decrease the concentration of cortisol in the plasma at times when the body is not experiencing stress. How- ever, the stress stimuli are the most potent ones; they can always break through this direct inhibitory feed- back of cortisol, causing either periodic exacerbations of cortisol secretion at multiple times during the day (Figure 78-9) or prolonged cortisol secretion in times of chronic stress. Circadian Rhythm of Glucocorticoid Secretion. The se- cretory rates of CRF, ACTH, and cortisol are high in the early morning but low in the late evening, as shown in Fig- ure 78-9; plasma cortisol level ranges between a high of about 20 μg/dl an hour before arising in the morning and a low of about 5 μg/dl around midnight. This effect results from a 24-hour cyclical alteration in the signals from the hypothalamus that cause cortisol secretion. When a person changes his or her daily sleeping habits, the cycle changes correspondingly. Therefore, measurements of blood corti- sol levels are meaningful only when expressed in terms of the time in the cycle at which the measurements are made. Synthesis and Secretion of ACTH in Association With Melanocyte-Stimulating Hormone, Lipotropin, and Endorphin When ACTH is secreted by the anterior pituitary gland, several other hormones that have similar chemical struc- tures are secreted simultaneously. The gene that is tran- scribed to form the RNA molecule that causes ACTH synthesis initially causes formation of a considerably larger protein, a preprohormone called pro-opiomelanocortin (POMC), which is the precursor of ACTH and several other peptides, including melanocyte-stimulating hor- mone (MSH), β-lipotropin, β-endorphin, and a few others (Figure 78-10). Under normal conditions, most of these hormones are not secreted in enough quantity by the pitu- itary to have a major effect on the human body, but when the rate of secretion of ACTH is high, as may occur in persons with Addison’s disease, formation of some of the other POMC-derived hormones may also be increased. The POMC gene is actively transcribed in several tissues, including the corticotroph cells of the anterior pituitary, POMC neurons in the arcuate nucleus of the hypothalamus, cells of the dermis, and lymphoid tissue. In all of these cell types, POMC is processed to form a series of smaller peptides. The precise type of POMC- derived products from a particular tissue depends on the type of processing enzymes present in the tissue. Thus, pituitary corticotroph cells express prohormone conver- tase 1 (PC1), resulting in the production of N-terminal peptide, joining peptide, ACTH, and β-lipotropin. In the hypothalamus, the expression of PC2 leads to production of α-MSH, β-MSH, γ-MSH, and β-endorphin, but not ACTH. As discussed in Chapter 72, α-MSH formed by neurons of the hypothalamus plays a major role in appe- tite regulation. In melanocytes located in abundance between the der- mis and epidermis of the skin, MSH stimulates formation of the black pigment melanin and disperses it to the epi- dermis. Injection of MSH into a person over 8 to 10 days can greatly increase darkening of the skin. The effect is Figure 78-10. Pro-opiomelanocortin process- ing by prohormone convertase 1 (PC1; red ar- rows) and PC2 (blue arrows). Tissue-specific expression of these two enzymes results in different peptides produced in various tissues. ACTH, Adrenocorticotropic hormone; CLIP, corticotropin-like intermediate peptide; MSH, melanocyte-stimulating hormone. Proopiomelanocortin NH2 COOH Joining ACTH protein N-Terminal protein γ-MSH α-MSH β-MSH CLIP γ-Lipotropin PCI PC2 β-Lipotropin β-Endorphin 0 20 15 10 5 12:00 4:00 8:00 12:00 4:00 8:00 12:00 Cortisol concentration (µg/100 ml) AM PM Noon Figure 78-9. Typical pattern of cortisol concentration during the day. Note the oscillations in secretion, as well as a daily secretory surge an hour or so after waking in the morning. Chapter 78 Adrenocortical Hormones 969 UNIT XIV much greater in people who have genetically dark skins than in light-skinned people. In some animals, an intermediate “lobe” of the pitu- itary gland, called the pars intermedia, is highly devel- oped, lying between the anterior and posterior pituitary lobes. This lobe secretes an especially large amount of MSH. Furthermore, this secretion is independently con- trolled by the hypothalamus in response to the amount of light to which the animal is exposed or in response to other environmental factors. For instance, some arctic animals develop darkened fur in the summer and yet have entirely white fur in the winter. ACTH, because it contains an MSH sequence, has about 1 ⁄30 as much melanocyte-stimulating effect as MSH. Fur- thermore, because the quantities of pure MSH secreted in humans are extremely small, whereas those of ACTH are large, it is likely that ACTH is normally more important than MSH in determining the amount of melanin in the skin. Adrenal Androgens Several moderately active male sex hormones called adre- nal androgens (the most important of which is dehydroe- piandrosterone) are continually secreted by the adrenal cortex, especially during fetal life, as discussed in Chapter 84. Also, progesterone and estrogens, which are female sex hormones, are secreted in minute quantities. Normally, the adrenal androgens have only weak effects in humans. It is possible that part of the early development of the male sex organs results from childhood secretion of adrenal androgens. The adrenal androgens also exert mild effects in the female, not only before puberty but also throughout life. Much of the growth of the pubic and axillary hair in the female results from the action of these hormones. In extra-adrenal tissues, some of the adrenal androgens are converted to testosterone, the primary male sex hor- mone, which probably accounts for much of their andro- genic activity. The physiological effects of androgens are discussed in Chapter 81 in relation to male sexual function. Abnormalities of Adrenocortical Secretion Hypoadrenalism (Adrenal Insufficiency)— Addison’s Disease Addison’s disease results from an inability of the adrenal cortices to produce sufficient adrenocortical hormones, and this in turn is most frequently caused by primary atro- phy or injury of the adrenal cortices. In about 80% of cases, the atrophy is caused by autoimmunity against the cortices. Adrenal gland hypofunction may also be caused by tuber- culous destruction of the adrenal glands or invasion of the adrenal cortices by cancer. In some cases, adrenal insufficiency is secondary to im- paired function of the pituitary gland, which fails to pro- duce sufficient ACTH. When ACTH output is too low, cor- tisol and aldosterone production decrease, and eventually the adrenal glands may atrophy because of a lack of ACTH stimulation. Secondary adrenal insufficiency is much more common than Addison's disease, which is sometimes called primary adrenal insufficiency. Disturbances in severe ad- renal insufficiency are described in the following sections. Mineralocorticoid Deficiency. Lack of aldosterone se- cretion greatly decreases renal tubular sodium reabsorp- tion and consequently allows sodium ions, chloride ions, and water to be lost into urine in great profusion. The net result is a greatly decreased extracellular fluid volume and hyponatremia. Furthermore, hyperkalemia and mild acido- sis develop because of failure of potassium and hydrogen ions to be secreted in exchange for sodium reabsorption. As the extracellular fluid becomes depleted, plasma volume falls, red blood cell concentration rises markedly, cardiac out- put and blood pressure decrease, and the patient may in shock, with death usually occurring in the untreated patient 4 days to 2 weeks after complete cessation of mineralocorticoid secretion. Glucocorticoid Deficiency. Loss of cortisol secretion makes it impossible for a person with Addison’s disease to maintain normal blood glucose concentration between meals because he or she cannot synthesize significant quan- tities of glucose by gluconeogenesis. Furthermore, lack of cortisol reduces the mobilization of proteins and fats from the tissues, thereby depressing many other metabolic func- tions of the body. This sluggishness of energy mobilization when cortisol is not available is one of the major detrimen- tal effects of glucocorticoid deficiency. Even when excess quantities of glucose and other nutrients are available, the person’s muscles are weak, indicating that glucocorticoids are necessary to maintain other metabolic functions of the tissues in addition to energy metabolism. Lack of adequate glucocorticoid secretion also makes a person with Addison’s disease highly susceptible to the deteriorating effects of different types of stress, and even a mild respiratory infection can cause death. Melanin Pigmentation. Another characteristic of most people with Addison’s disease is melanin pigmentation of the mucous membranes and skin. This melanin is not always de- posited evenly but occasionally is deposited in blotches, and it is deposited especially in the thin skin areas, such as the mu- cous membranes of the lips and the thin skin of the nipples. When cortisol secretion is depressed, the normal nega- tive feedback to the hypothalamus and anterior pituitary gland is also depressed, therefore allowing tremendous rates of ACTH secretion, as well as simultaneous secretion of increased amounts of MSH. The large amounts of ACTH probably cause most of the pigmenting effect because they can stimulate formation of melanin by the melanocytes in the same way that MSH does. Treatment of People With Addison's Disease. An un- treated person with total adrenal destruction dies within a few days to a few weeks because of weakness and, usually, circulatory shock. Yet, such a person can live for years if small quantities of mineralocorticoids and glucocorticoids are administered daily. Adrenal Crisis. As noted earlier in the chapter, large quantities of glucocorticoids are occasionally secreted in response to different types of physical or mental stress. In a person with Addison’s disease, the output of glucocorti- coids does not increase during stress. Yet, during different types of trauma, disease, or other stresses, such as surgi- cal operations, a person is likely to have an acute need for increased amounts of glucocorticoids and often must be given 10 or more times the normal quantities of glucocorti- coids to prevent death. UNIT XIV Endocrinology and Reproduction 970 This critical need for extra glucocorticoids and the as- sociated severe debility in times of acute stress is called an adrenal (or Addisonian) crisis. Hyperadrenalism—Cushing’s Syndrome Hypersecretion by the adrenal cortex causes a complex cas- cade of hormone effects called Cushing's syndrome. Many of the abnormalities of Cushing’s syndrome can be ascribed to abnormal amounts of cortisol, but excess secretion of andro- gens may also cause important effects. Hypercortisolism can occur from multiple causes, including (1) adenomas of the anterior pituitary that secrete large amounts of ACTH, which then causes adrenal hyperplasia and excess cortisol secretion; (2) abnormal function of the hypothalamus that causes high levels of corticotropin-releasing hormone, which stimulates excess ACTH release; (3) “ectopic secretion” of ACTH by a tu- mor elsewhere in the body, such as an abdominal carcinoma; and (4) adenomas of the adrenal cortex. When Cushing’s syn- drome is secondary to excess secretion of ACTH by the ante- rior pituitary, this condition is referred to as Cushing's disease. Excess ACTH secretion is the most common cause of Cushing’s syndrome and is characterized by high plasma levels of ACTH and cortisol. Primary overproduction of cortisol by the adrenal glands accounts for about 20% to 25% of clinical cases of Cushing’s syndrome and is usually associ- ated with reduced ACTH levels due to cortisol feedback in- hibition of ACTH secretion by the anterior pituitary gland. Administration of large doses of dexamethasone, a synthetic glucocorticoid, can be used to distinguish be- tween ACTH-dependent and ACTH-independent Cush- ing’s syndrome. In patients who have overproduction of ACTH due to an ACTH-secreting pituitary adenoma or to hypothalamic-pituitary dysfunction, low doses of dexamethasone usually do not suppress ACTH secretion normally. By increasing the dose of dexamethasone to very high levels, ACTH eventually can be suppressed in most patients with Cushing’s disease. In contrast, patients with primary adrenal overproduction of cortisol (ACTH- independent Cushing’s syndrome) usually have low or un- detectable levels of ACTH. The dexamethasone test, although widely used, can sometimes result in an incorrect diagnosis because some ACTH-secreting pituitary tumors do respond to dexa- methasone with suppressed ACTH secretion. Also, non- pituitary malignant tumors that produce ACTH ectopi- cally, such as some lung carcinomas, are not responsive to glucocorticoid-negative feedback. Therefore, the dexa- methasone test is usually considered to be a first step in the differential diagnosis of Cushing’s syndrome. Cushing’s syndrome can also occur when large amounts of glucocorticoids are administered over prolonged peri- ods for therapeutic purposes. For example, patients with chronic inflammation associated with diseases such as rheumatoid arthritis are often treated with glucocorti- coids and may experience some of the clinical symptoms of Cushing syndrome. A special characteristic of Cushing’s syndrome is mo- bilization of fat from the lower part of the body, with con- comitant extra deposition of fat in the thoracic and upper abdominal regions, giving rise to a buffalo-like torso. The excess secretion of steroids also leads to an edematous ap- pearance of the face, and the androgenic potency of some of the hormones sometimes causes acne and hirsutism (ex- cess growth of facial hair). The appearance of the face is frequently described as a “moon face,” as demonstrated in the untreated patient with Cushing’s syndrome to the left in Figure 78-11. About 80% of patients have hypertension, presumably because of the mineralocorticoid effects of cor- tisol. Effects of Cushing’s Syndrome on Carbohydrate and Protein Metabolism. The abundance of cortisol secreted in Cushing’s syndrome can increase blood glucose con- centration, sometimes to values as high as 200 mg/dl af- ter meals—as much as twice normal. This increase results mainly from enhanced gluconeogenesis and decreased glu- cose utilization by the tissues. Figure 78-11. A person with Cushing's syndrome before (left) and after (right) a subtotal adrenalectomy. (Courtesy Dr. Leonard Posey.) Chapter 78 Adrenocortical Hormones 971 UNIT XIV The effects of glucocorticoids on protein catabolism are of- ten profound in Cushing’s syndrome, causing greatly decreased tissue proteins almost everywhere in the body with the excep- tion of the liver; the plasma proteins also remain unaffected. The loss of protein from the muscles in particular causes severe weakness. The loss of protein synthesis in the lymphoid tissues leads to a suppressed immune system, and thus these patients are highly susceptible to infections. Even the protein collagen fibers in the subcutaneous tissue are diminished so that the subcutaneous tissues tear easily, resulting in development of large purplish striae where they have torn apart. In addition, se- verely diminished protein deposition in the bones often causes severe osteoporosis with consequent weakness of the bones. Treatment of People With Cushing’s Syndrome. Treat- ment of people with Cushing’s syndrome consists of remov- ing an adrenal tumor if this is the cause or decreasing the se- cretion of ACTH, if possible. Hypertrophied pituitary glands or even small tumors in the pituitary that oversecrete ACTH can sometimes be surgically removed or destroyed by radia- tion. Drugs that block steroidogenesis, such as metyrapone, ketoconazole, and aminoglutethimide, or that inhibit ACTH secretion, such as serotonin antagonists and GABA- transaminase inhibitors, can also be used when surgery is not feasible. If ACTH secretion cannot easily be decreased, the only satisfactory treatment is usually bilateral partial (or even total) adrenalectomy, followed by administration of adrenal steroids to make up for any insufficiency that develops. Primary Aldosteronism (Conn’s Syndrome) Occasionally a small tumor of the zona glomerulosa cells occurs and secretes large amounts of aldosterone; the re- sulting condition is called primary aldosteronism or Conn’s syndrome. Also, in a few instances, hyperplastic adrenal cortices secrete aldosterone rather than cortisol. The effects of the excess aldosterone are discussed in detail earlier in the chapter. The most important effects are hypokalemia, mild metabolic alkalosis, a slight increase in extracellular fluid volume and blood volume, a modest increase in plas- ma sodium concentration (usually <4–6-mEq/L increase) and, almost always, hypertension. Especially interesting in persons with primary aldosteronism are occasional periods of muscle paralysis caused by the hypokalemia. The paraly- sis is caused by a depressant effect of low extracellular po- tassium concentration on action potential transmission by the nerve fibers, as explained in Chapter 5. One of the diagnostic criteria of primary aldosteron- ism is a decreased plasma renin concentration. This de- crease results from feedback suppression of renin secretion caused by the excess aldosterone or by the excess extracel- lular fluid volume and arterial pressure resulting from the aldosteronism. Treatment of primary aldosteronism may include surgical removal of the tumor or of most of the ad- renal tissue when hyperplasia is the cause. Another option for treatment is pharmacological antagonism of the min- eralocorticoid receptor with spironolactone or eplerenone. Adrenogenital Syndrome Occasionally an adrenocortical tumor secretes excessive quantities of androgens that cause intense masculinizing effects throughout the body. If this phenomenon occurs in a female, virile characteristics develop, including growth of a beard, a much deeper voice, occasionally baldness if she also has the genetic trait for baldness, masculine distribu- tion of hair on the body and the pubis, growth of the clito- ris to resemble a penis, and deposition of proteins in the skin and especially in the muscles to give typical masculine characteristics. In the prepubertal male, a virilizing adrenal tumor causes the same characteristics as in the female plus rapid development of the male sexual organs, as shown in Figure 78-12, which depicts a 4-year-old boy with adrenogenital syndrome. In the adult male, the virilizing characteristics of adrenogenital syndrome are usually obscured by the nor- mal virilizing characteristics of the testosterone secreted by the testes. It is often difficult to make a diagnosis of adreno- genital syndrome in the adult male. In adrenogenital syn- drome, the excretion of 17-ketosteroids (which are derived from androgens) in the urine may be 10 to 15 times normal. This finding can be used in diagnosing the disease. Prepare 40 clinical based MCqs

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