Guyton and Hall Textbook of Medical Physiology, 12th Ed

CHAPTER 77

Adrenocortical Hormones

imageThe two adrenal glands, each of which weighs about 4 grams, lie at the superior poles of the two kidneys. As shown in Figure 77-1, each gland is composed of two distinct parts, the adrenal medulla and the adrenal cortex. The adrenal medulla, the central 20 percent 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 hormones 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 60 in relation to the sympathetic nervous system.

image

Figure 77-1 Secretion of adrenocortical hormones by the different zones of the adrenal cortex and secretion of catecholamines by the adrenal medulla.

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 differences in their molecular structures give them several different but very important functions.

Corticosteroids: Mineralocorticoids, Glucocorticoids, and Androgens

Two major types of adrenocortical hormones, the mineralocorticoids and the glucocorticoids, are secreted by the adrenal cortex. In addition to these, small amounts of sex hormones are secreted, especially androgenic 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 have gained this name because they especially affect the electrolytes (the “minerals”) of the extracellular fluids, especially sodium and potassium. The glucocorticoids have gained their name because they exhibit important effects that increase blood glucose concentration. They have additional effects on both 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: aldosterone, which is the principal mineralocorticoid, and cortisol, which is the principal glucocorticoid.

Synthesis and Secretion of Adrenocortical Hormones

The Adrenal Cortex Has Three Distinct Layers

Figure 77-1 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 percent 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 is controlled mainly by the extracellular fluid concentrations of angiotensin II and potassium, both of which stimulate aldosterone secretion.

2. The zona fasciculata, the middle and widest layer, constitutes about 75 percent of the adrenal cortex and secretes the glucocorticoids cortisol and corticosterone, as well as small amounts of adrenal androgens and estrogens. The secretion of these cells is controlled in large part by the hypothalamic-pituitary axis via adrenocorticotropic hormone (ACTH).

3. The zona reticularis, the deep layer of the cortex, secretes the adrenal androgens dehydroepiandrosterone (DHEA) and androstenedione, as well as small amounts of estrogens and some glucocorticoids. ACTH also regulates secretion of these cells, although other factors such as cortical androgen-stimulating hormone, released from the pituitary, may also be involved. The mechanisms for controlling adrenal androgen production, 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 cholesterol. Although the cells of the adrenal cortex can synthesize de novo small amounts of cholesterol from acetate, approximately 80 percent of the cholesterol used for steroid synthesis is provided by low-density lipoproteins (LDL) in the circulating 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 regulated 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 77-2). In all three zones of the adrenal cortex, this initial step in steroid 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 the conversion of cholesterol to pregnenolone.

image

Figure 77-2 Pathways for synthesis of steroid hormones by the adrenal cortex. The enzymes are shown in italics.

Synthetic Pathways for Adrenal Steroids

Figure 77-2 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 endoplasmic reticulum, 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 proportions 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 most important mineralocorticoid and glucocorticoid hormones, respectively, are shown in Figure 77-2. Cortisol has a keto-oxygen on carbon number 3 and is hydroxylated at carbon numbers 11 and 21. The mineralocorticoid aldosterone 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. And several additional potent steroid hormones 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, including the synthetic ones, are the following, as summarized in Table 77-1.

Table 77-1 Adrenal Steroid Hormones in Adults; Synthetic Steroids and Their Relative Glucocorticoid and Mineralocorticoid Activities

image

Mineralocorticoids

• Aldosterone (very potent, accounts for about 90 percent of all mineralocorticoid activity)

• Deoxycorticosterone (1/30 as potent as aldosterone, but very small quantities secreted)

• Corticosterone (slight mineralocorticoid activity)

• 9α-Fluorocortisol (synthetic, slightly more potent than aldosterone)

• Cortisol (very slight mineralocorticoid activity, but large quantity secreted)

• Cortisone (slight mineralocorticoid activity)

Glucocorticoids

• Cortisol (very potent, accounts for about 95 percent of all glucocorticoid activity)

• Corticosterone (provides about 4 percent of total glucocorticoid activity, but 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 cortisol)

• Dexamethasone (synthetic, 30 times as potent as cortisol)

It is clear from this list that some of these hormones have both glucocorticoid and mineralocorticoid activities. It is especially significant that cortisol 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 hormone dexamethasone, which has almost zero mineralocorticoid activity, makes this an especially important drug for stimulating specific glucocorticoid activity.

Adrenocortical Hormones Are Bound to Plasma Proteins

Approximately 90 to 95 percent of the cortisol in the plasma 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 percent of circulating aldosterone combines with the plasma proteins, so about 40 percent 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 hormone concentrations, as would occur, for example, with cortisol during brief periods of stress and episodic secretion of ACTH. This reservoir function may also help to ensure a relatively uniform distribution of the adrenal hormones to the tissues.

Adrenocortical Hormones Are Metabolized in the Liver

The adrenal steroids are degraded mainly in the liver and conjugated especially to glucuronic acid and, to a lesser extent, sulfates. These substances are inactive and do not have mineralocorticoid or glucocorticoid activity. About 25 percent 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 proteins, 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 inactivation of adrenocortical hormones, and kidney diseases reduce the excretion of the inactive conjugates.

The normal concentration of aldosterone in blood is about 6 nanograms (6 billionths of a gram) per 100 milliliters, 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 dietary 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 cortisol fluctuate throughout the day, rising in the early morning and declining in the evening, as discussed later.

Functions of the Mineralocorticoids—Aldosterone

Mineralocorticoid Deficiency Causes Severe Renal Sodium Chloride Wasting and Hyperkalemia

Total loss of adrenocortical secretion usually causes death within 3 days to 2 weeks unless the person receives extensive salt therapy or injection of mineralocorticoids.

Without mineralocorticoids, potassium ion concentration 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. The person soon develops diminished cardiac output, which progresses to a shocklike state, followed by death. This entire sequence can be prevented by the administration 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, allowing the person to resist the destructive effects of life’s intermittent physical and mental “stresses,” as discussed later in the chapter.

Aldosterone Is the Major Mineralocorticoid Secreted by the Adrenals

Aldosterone exerts nearly 90 percent of the mineralocorticoid activity of the adrenocortical secretions, but cortisol, the major glucocorticoid secreted by the adrenal cortex, also provides a significant amount of mineralocorticoid activity. Aldosterone’s mineralocorticoid activity is about 3000 times greater than that of cortisol, but the plasma concentration of cortisol is nearly 2000 times that of aldosterone.

Cortisol can also bind to mineralocorticoid receptors with high affinity. However, the renal epithelial cells also contain the enzyme 11β-hydroxysteroid dehydrogenase type 2, which converts cortisol to cortisone. Because cortisone does not avidly bind mineralocorticoid receptors, cortisol does not normally exert significant mineralocorticoid effects. However, in patients with genetic deficiency of 11β-hydroxysteroid dehydrogenase type 2 activity, cortisol may have substantial mineralocorticoid effects. This condition is called apparent mineralocorticoid excess syndrome (AME) because the patient has essentially the same pathophysiological changes as a patient with excess aldosterone secretion, except that plasma aldosterone levels are very low. Ingestion of large amounts of licorice, which contains glycyrrhetinic acid, may also cause AME due to its ability to block 11β-hydroxysteroid dehydrogenase type 2 enzyme activity.

Renal and Circulatory Effects of Aldosterone

Aldosterone Increases Renal Tubular Reabsorption of Sodium and Secretion of Potassium

It will be recalled from Chapter 27 that 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 tubulesand, 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 a day. At the same time, potassium loss into the urine transiently increases severalfold. 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

Although aldosterone has a potent effect in decreasing the rate of sodium ion excretion 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, there is simultaneous osmotic absorption of almost equivalent amounts of water. Also, small increases in extracellular fluid sodium concentration stimulate thirst and increased water intake, if water is available. 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 powerful sodium-retaining hormones, only transient sodium retention occurs when excess amounts are secreted. An aldosterone-mediated increase in extracellular fluid volume 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 salt and water, called pressure natriuresis and pressure diuresis, respectively. Thus, after the extracellular fluid volume increases 5 to 15 percent above normal, arterial pressure also increases 15 to 25 mm Hg, and this elevated blood pressure returns the renal output of salt and water to normal despite the excess aldosterone (Figure 77-3).

image

Figure 77-3 Effect of aldosterone infusion on arterial pressure, extracellular fluid volume, and sodium excretion in dogs. Although aldosterone 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.

(Drawn from data in Hall JE, Granger JP, Smith MJ Jr, et al: Role of hemodynamics and arterial pressure in aldosterone “escape.” Hypertension 6 (suppl I):I183-192, 1984.)

This return to normal of salt and water excretion by the kidneys as a result of pressure natriuresis and diuresis is called aldosterone escape. Thereafter, the rate of gain of salt and water by the body is zero, and balance is maintained between salt and water intake and output by the kidneys despite continued excess aldosterone. In the meantime, however, the person has developed hypertension, which lasts as long as the person remains exposed to high levels of aldosterone.

Conversely, when aldosterone secretion becomes zero, large amounts of salt are lost in the urine, not only diminishing the amount of sodium chloride in the extracellular fluid but also decreasing the extracellular fluid volume. The result is severe extracellular fluid dehydration 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; Too Little Aldosterone Causes Hyperkalemia and Cardiac Toxicity

Excess aldosterone not only causes loss of potassium ions from the extracellular fluid into the urine but also stimulates transport of potassium 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, sometimes from the normal value of 4.5 mEq/L to as low as 2 mEq/L. This condition is called hypokalemia. When the potassium ion concentration falls below about one-half normal, severe muscle weakness often develops. This 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 extracellular fluid potassium ion concentration can rise far above normal. When it rises to 60 to 100 percent above normal, serious cardiac toxicity, including weakness of heart contraction and development of arrhythmia, becomes evident; 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 exchange for sodium reabsorption in the principal cells of the renal collecting tubules but also causes secretion of hydrogen ions in exchange for sodium in the intercalated cells of the cortical collecting tubules. This decreases the hydrogen ion concentration in the extracellular fluid, causing a 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, on 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 conserve body salt in hot environments, 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 aldosterone’s actions on the tubular 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 be the following.

First, because of its lipid solubility in the cellular membranes, aldosterone diffuses readily to the interior of the tubular epithelial cells.

Second, in the cytoplasm of the tubular cells, aldosterone combines with a highly specific cytoplasmic mineralocorticoid receptor (MR) protein (Figure 77-4), a protein that 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-hydroxysteroid dehydrogenase type 2 normally converts most of the cortisol to cortisone, which does not readily bind to MR receptors, as discussed previously.

image

Figure 77-4 Aldosterone-responsive epithelial cell signaling pathways. ENaC, epithelial sodium channel proteins; MR, mineralocorticoid receptor. Activation of the MR by aldosterone can be antagonized with spironolactone. Amiloride is a drug that can be used to block ENaC.

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 related to the process of sodium and potassium transport.

Fourth, the messenger RNA 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 77-4). One of the enzymes especially increased is sodium-potassium adenosine triphosphatase, which serves as the principal part of the pump for sodium and potassium exchange at the basolateral membranes of the renal tubular cells. Additional proteins, perhaps equally important, are epithelial sodium channel(ENaC) proteins inserted into the luminal membrane of the same tubular cells that allow rapid diffusion of sodium ions from the tubular lumen into the cell; then the sodium is pumped the rest of the way by the sodium-potassium pump located in the basolateral membranes of the cell.

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 rate of sodium transport begins to increase; the effect reaches maximum only after several hours.

Possible Nongenomic Actions of Aldosterone and Other Steroid Hormones

Recent studies suggest that many steroids, including aldosterone, elicit not only slowly developing genomic effects that have a latency of 60 to 90 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 mediated 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 formation of cAMP in vascular smooth muscle cells and in epithelial cells of the renal collecting tubules in less than 2 minutes, a time 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 second messenger system. However, the precise structure of receptors responsible for the rapid effects of aldosterone has not been determined, nor is the physiological significance of these nongenomic actions of steroids well understood.

Regulation of Aldosterone Secretion

The regulation of aldosterone secretion is so deeply intertwined with the regulation of extracellular fluid electrolyte concentrations, extracellular fluid volume, blood volume, arterial pressure, and many special aspects of renal function that it is difficult to discuss the regulation of aldosterone secretion independently of all these other factors. This subject is presented in detail in Chapters 28 and 29, to which the reader is referred. However, it is important to list here some of the more important points of aldosterone secretion control.

The regulation of aldosterone secretion by the zona glomerulosa cells is almost entirely independent of the regulation of cortisol and androgens by the zona fasciculata and zona reticularis.

Four factors are known to play essential roles in the regulation of aldosterone. In the probable order of their importance, they are as follows:

1. Increased potassium ion concentration in the extracellular fluid greatly increases aldosterone secretion.

2. Increased angiotensin II concentration in the extracellular fluid also greatly increases aldosterone secretion.

3. Increased sodium ion concentration in the extracellular fluid very slightly decreases aldosterone secretion.

4. ACTH from the anterior pituitary gland is necessary for aldosterone secretion but has little effect in controlling the rate of secretion in most physiological conditions.

Of these factors, potassium ion concentration and the renin-angiotensin system are by far the most potent in regulating aldosterone secretion. A small percentage increase in potassium concentration can cause a severalfold increase in aldosterone secretion. Likewise, activation of the renin-angiotensin system, usually in response to diminished blood flow to the kidneys or to sodium loss, can increase in aldosterone secretion severalfold. In turn, the aldosterone acts on the kidneys (1) to help them excrete the excess potassium ions and (2) to increase the blood volume and arterial pressure, thus returning the renin-angiotensin system toward its normal level of activity. These feedback control mechanisms are essential for maintaining life, and the reader is referred again to Chapters 27 and 29 for a more complete description of their functions.

Figure 77-5 shows the effects on plasma aldosterone concentration caused by blocking the formation of angiotensin II with an angiotensin-converting enzyme inhibitor after several weeks of a low-sodium diet that increases plasma aldosterone concentration. Note that blocking angiotensin II formation markedly decreases plasma aldosterone concentration without significantly changing cortisol concentration; this indicates the important role of angiotensin II in stimulating aldosterone secretion when sodium intake and extracellular fluid volume are reduced.

image

Figure 77-5 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 blocking 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.

(Drawn from data in Hall JE, Guyton AC, Smith MJ Jr, et al: Chronic blockade of angiotensin II formation during sodium deprivation. Am J Physiol 237:F424, 1979.)

By contrast, the effects of sodium ion concentration per se and of ACTH in controlling aldosterone secretion are usually minor. Nevertheless, a 10 to 20 percent decrease in extracellular fluid sodium ion concentration, which occurs on rare occasions, can perhaps increase aldosterone secretion by about 50 percent. In the case of ACTH, if there is even a small amount of ACTH 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 the Glucocorticoids

Even though mineralocorticoids can save the life of an acutely adrenalectomized animal, the animal still is far from normal. Instead, its metabolic systems for utilization of proteins, carbohydrates, and fats remain considerably deranged. Furthermore, the animal cannot resist different types of physical or even mental stress, and minor illnesses such as respiratory tract infections can lead to death. Therefore, the glucocorticoids have functions just as important to the long-continued life of the animal as those of the mineralocorticoids. They are explained in the following sections.

At least 95 percent of the glucocorticoid activity of the adrenocortical secretions results from the secretion of cortisol, known also as hydrocortisone. In addition to this, a small but significant amount of glucocorticoid activity is provided by corticosterone.

Effects of Cortisol on Carbohydrate Metabolism

Stimulation of Gluconeogenesis

By far the best-known metabolic effect of cortisol and other glucocorticoids on metabolism is the ability to stimulate gluconeogenesis (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 results mainly from two effects of cortisol.

1. Cortisol increases the enzymes required to convert amino acids into glucose in the liver cells. This results from the effect of the glucocorticoids to activate DNA transcription in the liver cell nuclei in the same way that aldosterone functions in the renal tubular cells, with formation of messenger RNAs that in turn lead to the array of enzymes required for gluconeogenesis.

2. Cortisol causes mobilization of amino acids from the extrahepatic 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 the formation of glucose.

One of the effects of increased gluconeogenesis is a marked increase in glycogen storage in the liver cells. This effect of cortisol allows other glycolytic hormones, such as epinephrine and glucagon, to mobilize glucose in times of need, such as between meals.

Decreased Glucose Utilization by Cells

Cortisol also causes a moderate decrease in the rate of glucose utilization by most cells in the body. Although the cause of this decrease is unknown, most physiologists believe that somewhere between the point of entry of glucose into the cells and its final degradation, cortisol directly delays the rate of glucose utilization. A suggested mechanism is based on the observation that glucocorticoids depress the oxidation of nicotinamide-adenine dinucleotide (NADH) to form NAD+. Because NADH must be oxidized to allow glycolysis, this effect could account for the diminished utilization of glucose by the cells.

Elevated Blood Glucose Concentration and “Adrenal Diabetes.”

Both the increased rate of gluconeogenesis and the moderate reduction in the rate of glucose utilization by the cells cause the blood glucose concentrations to rise. The rise in blood glucose in turn stimulates secretion of insulin. The increased plasma levels of insulin, however, are not as effective in maintaining plasma glucose as they are under normal conditions. For reasons that are not entirely clear, high levels of glucocorticoid reduce the sensitivity of many tissues, especially skeletal muscle and adipose tissue, to the stimulatory effects of insulin on glucose uptake and utilization. One possible explanation is that high levels of fatty acids, caused by the effect of glucocorticoids to mobilize lipids from fat depots, may impair insulin’s actions on the tissues. In this way, excess secretion of glucocorticoids may produce disturbances of carbohydrate metabolism similar to those found in patients with excess levels of growth hormone.

The increase in blood glucose concentration is occasionally great enough (50 percent or more above 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 pancreatic 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 effects of cortisol on the metabolic systems of the body is reduction of the protein stores in essentially all body cells except those of the liver. This is caused by both decreased protein synthesis and increased catabolism of protein already in the cells. Both these effects may result partly from decreased amino acid transport into extrahepatic tissues, as discussed later; this is probably not the major cause because cortisol also depresses the formation of RNA and subsequent protein synthesis in many extrahepatic tissues, especially in muscle and lymphoid tissue.

In the presence of great excesses of cortisol, the muscles can become so weak that the person cannot rise from the squatting position. And the immunity functions of the lymphoid tissue can be decreased to a small fraction of normal.

Cortisol Increases Liver and Plasma Proteins

Coincidentally with the reduced proteins elsewhere in the body, the liver proteins become enhanced. Furthermore, the plasma proteins (which are produced by the liver and then released into the blood) are also increased. 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 extrahepatic cells.

The decreased transport of amino acids into extrahepatic cells decreases their intracellular amino acid concentrations and consequently decreases the synthesis of protein. Yet catabolism of proteins in the cells continues to release amino acids from the already existing proteins, and these diffuse out of the cells to increase the plasma amino acid concentration. Therefore, cortisol mobilizes amino acids from the nonhepatic tissues and in doing so diminishes the tissue stores of protein.

The increased plasma concentration of amino acids and enhanced transport of amino acids into the hepatic cells by cortisol could also account for enhanced utilization 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 manner that cortisol promotes amino acid mobilization from muscle, it also promotes mobilization of fatty acids from adipose tissue. This increases the concentration 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 deposition 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, combined with increased oxidation of fatty acids in the cells, helps shift the metabolic systems of the cells from utilization of glucose for energy to utilization of fatty acids in times of starvation or other stresses. This cortisol mechanism, 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 78. Nevertheless, the increased use of fatty acids for metabolic energy is an important factor for long-term conservation of body glucose and glycogen.

Obesity Caused by Excess Cortisol

Despite the fact that cortisol can cause a moderate degree of fatty acid mobilization from adipose tissue, many people with excess cortisol secretion develop a peculiar type of obesity, with excess deposition 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 unknown, it has been suggested that this obesity results from excess stimulation of food intake, with fat being 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 neurogenic, causes an immediate and marked increase in ACTH secretion by the anterior pituitary gland, followed within minutes by greatly increased adrenocortical secretion of cortisol. This is demonstrated dramatically by the experiment shown in Figure 77-6, in which corticosteroid formation and secretion increased sixfold in a rat within 4 to 20 minutes after fracture of two leg bones.

image

Figure 77-6 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.)

(Courtesy Drs. Guillemin, Dear, and Lipscomb.)

Some of the different types of stress that increase cortisol release are the following:

1. Trauma of almost any type

2. Infection

3. Intense heat or cold

4. Injection of norepinephrine and other sympathomimetic drugs

5. Surgery

6. Injection of necrotizing substances beneath the skin

7. Restraining an animal so that it cannot move

8. Almost any debilitating disease

Even though we know that cortisol secretion often increases greatly in stressful situations, we are not sure why this is of significant benefit to the animal. One possibility is that the glucocorticoids cause rapid mobilization of amino acids and fats from their cellular stores, making them immediately available both for energy and for synthesis of other compounds, including glucose, needed by the different tissues of the body. Indeed, it has been shown in a few instances that damaged tissues that are momentarily depleted of proteins 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 essential intracellular substances, such as purines, pyrimidines, and creatine phosphate, which are necessary for maintenance of cellular life and reproduction of new cells.

But all this is mainly supposition. It is supported only by the fact that cortisol usually does not mobilize the basic functional proteins of the cells, such as the muscle contractile 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 substances 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. The 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 to block inflammation, let us review the basic steps in the inflammation process, discussed in more detail in Chapter 33.

Five main stages of inflammation occur: (1) release from the damaged tissue cells of chemical substances that activate the inflammation process—chemicals such as histamine, bradykinin, proteolytic enzymes, prostaglandins, and leukotrienes; (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 cortisol has two basic anti-inflammatory effects: (1) it can block the early stages of the inflammation process before 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 as follows.

Cortisol Prevents the Development of Inflammation by Stabilizing Lysosomes and by Other Effects

Cortisol has the following effects in preventing inflammation:

1. Cortisol stabilizes the lysosomal membranes. This 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, most of the proteolytic enzymes that are released by damaged cells to cause inflammation, which are mainly stored in the lysosomes, are released in greatly decreased quantity.

2. Cortisol decreases the permeability of the capillaries, probably as a secondary effect of the reduced release of proteolytic enzymes. This prevents loss of plasma into the tissues.

3. Cortisol decreases both 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 the formation of prostaglandins and leukotrienes that otherwise would increase vasodilation, capillary 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 the tissue reactions that would otherwise promote the inflammation process.

5. Cortisol attenuates fever mainly because it reduces the release of interleukin-1 from the white blood cells, which is one of the principal excitants to the hypothalamic temperature control system. The decreased temperature in turn reduces the degree of vasodilation.

Thus, cortisol has an almost global effect in reducing all aspects of the inflammatory process. How much of this results from the simple effect of cortisol in stabilizing lysosomal and cell membranes versus its effect to reduce the formation of prostaglandins and leukotrienes from arachidonic acid in damaged cell membranes and other effects of cortisol is unclear.

Cortisol Causes Resolution of Inflammation

Even after inflammation has become well established, the administration of cortisol can often reduce inflammation within hours to a few days. The immediate effect is to block most of the factors that promote the inflammation. But in addition, the rate of healing is enhanced. This probably results from the same, mainly undefined, factors that allow the body to resist many other types of physical stress when large quantities of cortisol are secreted. Perhaps this results from the mobilization of amino acids and use of these to repair the damaged tissues; perhaps it results from the increased glucogenesis that makes extra glucose available in critical metabolic systems; perhaps it results from increased amounts of fatty acids available for cellular energy; or perhaps it depends on 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 glomerulonephritis. All these diseases are characterized by severe local inflammation, and the harmful effects on the body are caused mainly by the inflammation itself and not by other aspects of the disease.

When cortisol or other glucocorticoids are administered to patients with these diseases, almost invariably the inflammation begins to subside within 24 hours. And even though the cortisol does not correct the basic disease condition, merely preventing the damaging effects of the inflammatory response, this alone 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. However, 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 the release of inflammatory products, can be lifesaving. For instance, cortisol effectively prevents shock or death in anaphylaxis, which otherwise kills many people, as explained in Chapter 34.

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 the 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.

Likewise, the administration of large doses of cortisol causes significant atrophy of all the lymphoid tissue throughout the body, which in turn decreases the output of both 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 occasionally can lead to fulminating infection and death from diseases that would otherwise not be lethal, such as fulminating tuberculosis in a person whose disease had previously been arrested. Conversely, this ability of cortisol and other glucocorticoids to suppress immunity makes them useful drugs in preventing immunological rejection of transplanted hearts, kidneys, and other tissues.

Cortisol increases the production of red blood cells by mechanisms that are unclear. When excess cortisol is secreted 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 immediate but require 45 to 60 minutes for proteins to be synthesized, and up to several hours or days to fully develop. Recent evidence suggests that glucocorticoids, especially at high concentrations, may also have some rapid nongenomic effectson cell membrane ion transport that may contribute to their therapeutic benefits.

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 acting directly on the adrenocortical cells, secretion of cortisol is controlled almost entirely by ACTH secreted by the anterior pituitary gland. This hormone, also called corticotropin or adrenocorticotropin, also enhances the production of adrenal androgens.

Chemistry of ACTH

ACTH has been isolated in pure form from the anterior pituitary. It is a large polypeptide, having a chain length of 39 amino acids. A smaller polypeptide, a digested product of ACTH having a chain 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 releasing factors from the hypothalamus, an important releasing factor also controls ACTH secretion. This 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 carried 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 Steroids by Increasing Cyclic Adenosine Monophosphate (cAMP)

The principal effect of ACTH on the adrenocortical cells is to activate adenylyl cyclase in the cell membrane. This then induces the formation 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 adrenocortical hormones. This 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 activation 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 cortex by ACTH not only increases secretory activity but also causes hypertrophy and proliferation of the adrenocortical cells, especially in the zona fasciculata and zona reticularis, where cortisol and the androgens are secreted.

Physiological Stress Increases ACTH and Adrenocortical Secretion

As pointed out earlier in the chapter, almost any type of physical or mental stress can lead within minutes to greatly enhanced secretion of ACTH and consequently cortisol as well, often increasing cortisol secretion as much as 20-fold. This effect was demonstrated by the rapid and strong adrenocortical secretory responses after trauma shown in Figure 77-6.

Pain stimuli caused by physical stress or tissue damage are transmitted first upward through the brain stem and eventually to the median eminence of the hypothalamus, as shown in Figure 77-7. Here CRF is secreted into the hypophysial portal system. Within minutes the entire control sequence leads to large quantities of cortisol in the blood.

image

Figure 77-7 Mechanism for regulation of glucocorticoid secretion. ACTH, adrenocorticotropic hormone; CRF, corticotropin-releasing factor.

Mental stress can cause an equally rapid increase in ACTH secretion. This 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 on the Anterior Pituitary to Decrease ACTH Secretion

Cortisol has direct negative feedback effects on (1) the hypothalamus to decrease the formation of CRF and (2) the anterior pituitary gland to decrease the formation 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 control level.

Summary of the Cortisol Control System

Figure 77-7 shows the overall system for control of cortisol 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 the cortisol in turn initiates a series of metabolic effects directed toward relieving the damaging nature of the stressful state.

There is also direct feedback of the cortisol to both the hypothalamus and the anterior pituitary gland to decrease the concentration of cortisol in the plasma at times when the body is not experiencing stress. However, the stress stimuli are the prepotent ones; they can always break through this direct inhibitory feedback of cortisol, causing either periodic exacerbations of cortisol secretion at multiple times during the day (Figure 77-8) or prolonged cortisol secretion in times of chronic stress.

image

Figure 77-8 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 awaking in the morning.

Circadian Rhythm of Glucocorticoid Secretion

The secretory rates of CRF, ACTH, and cortisol are high in the early morning but low in the late evening, as shown in Figure 77-8; the 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 daily sleeping habits, the cycle changes correspondingly. Therefore, measurements of blood cortisol 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 structures are secreted simultaneously. The reason for this is that the gene that is transcribed to form the RNA molecule that causes ACTH synthesis initially causes the formation of a considerably larger protein, a preprohormone called proopiomelanocortin (POMC), which is the precursor of ACTH and several other peptides, including melanocyte-stimulating hormone (MSH), β-lipotropin, β-endorphin, and a few others (Figure 77-9). Under normal conditions, none of these hormones is secreted in enough quantity by the pituitary to have a significant effect on the human body, but when the rate of secretion of ACTH is high, as may occur in Addison’s disease, formation of some of the other POMC-derived hormones may also be increased.

image

Figure 77-9 Proopiomelanocortin (POMC) processing by prohormone convertase 1 (PC1, red arrows) and PC 2 (blue arrows). Tissue-specific expression of these two enzymes results in different peptides produced in various tissues. The anterior pituitary expresses PC1, resulting in formation of N-terminal peptide, joining peptide, ACTH, and β-lipotropin. Expression of PC2 within the hypothalamus leads to the production of α-, β-, and γ-melanocyte stimulating hormone (MSH), but not ACTH. CLIP, corticotropin-like intermediate peptide.

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 convertase 1 (PC1), but not PC2, resulting in the production of N-terminal peptide, joining peptide, ACTH, and β-lipotropin. In the hypothalamus, the expression of PC2 leads to the production of α-, β-, and γ-MSH and β-endorphin but not ACTH. As discussed in Chapter 71, α-MSH formed by neurons of the hypothalamus plays a major role in appetite regulation.

In melanocytes located in abundance between the dermis and epidermis of the skin, MSH stimulates formation of the black pigment melanin and disperses it to the epidermis. Injection of MSH into a person over 8 to 10 days can greatly increase darkening of the skin. The effect is much greater in people who have genetically dark skins than in light-skinned people.

In some lower animals, an intermediate “lobe” of the pituitary gland, called the pars intermedia, is highly developed, lying between the anterior and posterior pituitary lobes. This lobe secretes an especially large amount of MSH. Furthermore, this secretion is independently controlled 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. Furthermore, because the quantities of pure MSH secreted in the human being 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 adrenal androgens (the most important of which is dehydroepiandrosterone) are continually secreted by the adrenal cortex, especially during fetal life, as discussed more fully in Chapter 83. 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 hormone, which probably accounts for much of their androgenic activity. The physiological effects of androgens are discussed in Chapter 80 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 atrophy or injury of the adrenal cortices. In about 80 percent of the cases, the atrophy is caused by autoimmunity against the cortices. Adrenal gland hypofunction is also frequently caused by tuberculous destruction of the adrenal glands or invasion of the adrenal cortices by cancer.

In some cases, adrenal insufficiency is secondary to impaired function of the pituitary gland, which fails to produce sufficient ACTH. When ACTH output is too low, cortisol and aldosterone production decrease and eventually, the adrenal glands may atrophy due to 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 adrenal insufficiency are as follows.

Mineralocorticoid Deficiency

Lack of aldosterone secretion greatly decreases renal tubular sodium reabsorption 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. Furthermore, hyponatremia, hyperkalemia, and mild acidosis 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 output and blood pressure decrease, and the patient dies in shock, 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 quantities of glucose by gluconeogenesis. Furthermore, lack of cortisol reduces the mobilization of both proteins and fats from the tissues, thereby depressing many other metabolic functions of the body. This sluggishness of energy mobilization when cortisol is not available is one of the major detrimental effects of glucocorticoid lack. 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 deposited evenly but occasionally is deposited in blotches, and it is deposited especially in the thin skin areas, such as the mucous membranes of the lips and the thin skin of the nipples.

The cause of the melanin deposition is believed to be the following: When cortisol secretion is depressed, the normal negative 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. Probably the tremendous amounts of ACTH 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 untreated 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.

Addisonian Crisis

As noted earlier in the chapter, great 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 glucocorticoids does not increase during stress. Yet whenever different types of trauma, disease, or other stresses, such as surgical operations, supervene, a person is likely to have an acute need for excessive amounts of glucocorticoids and often must be given 10 or more times the normal quantities of glucocorticoids to prevent death.

This critical need for extra glucocorticoids and the associated severe debility in times of stress is called an addisonian crisis.

Hyperadrenalism—Cushing’s Syndrome

Hypersecretion by the adrenal cortex causes a complex cascade of hormone effects called Cushing’s syndrome. Many of the abnormalities of Cushing’s syndrome are ascribable to abnormal amounts of cortisol, but excess secretion of androgens 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 (CRH), which stimulates excess ACTH release; (3) “ectopic secretion” of ACTH by a tumor elsewhere in the body, such as an abdominal carcinoma; and (4) adenomas of the adrenal cortex. When Cushing’s syndrome is secondary to excess secretion of ACTH by the anterior pituitary, this 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 percent of clinical cases of Cushing’s syndrome and is usually associated with reduced ACTH levels due to cortisol feedback inhibition of ACTH secretion by the anterior pituitary gland.

Administration of large doses of dexamethasone, a synthetic glucocorticoid, can be used to distinguish between ACTH-dependent and ACTH-independent Cushing’s syndrome. In patients who have overproduction of ACTH due to an ACTH-secreting pituitary adenoma or to hypothalamic-pituitary dysfunction, even large doses of dexamethasone usually do not suppress ACTH secretion. In contrast, patients with primary adrenal overproduction of cortisol (ACTH-independent) usually have low or undetectable levels of ACTH. The dexamethasone test, although widely used, can sometimes give an incorrect diagnosis because some ACTH-secreting pituitary tumors respond to dexamethasone with suppressed ACTH secretion. Therefore, it 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 periods for therapeutic purposes. For example, patients with chronic inflammation associated with diseases such as rheumatoid arthritis are often treated with glucocorticoids and may develop some of the clinical symptoms of Cushing’s syndrome.

A special characteristic of Cushing’s syndrome is mobilization of fat from the lower part of the body, with concomitant extra deposition of fat in the thoracic and upper abdominal regions, giving rise to a buffalo torso. The excess secretion of steroids also leads to an edematous appearance of the face, and the androgenic potency of some of the hormones sometimes causes acne and hirsutism (excess 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 77-10. About 80 percent of patients have hypertension, presumably because of the mineralocorticoid effects of cortisol.

image

Figure 77-10 A person with Cushing’s syndrome before (left) and after (right) subtotal adrenalectomy.

(Courtesy Dr. Leonard Posey.)

Effects on Carbohydrate and Protein Metabolism

The abundance of cortisol secreted in Cushing’s syndrome can cause increased blood glucose concentration, sometimes to values as high as 200 mg/dl after meals—as much as twice normal. This results mainly from enhanced gluconeogenesis and decreased glucose utilization by the tissues.

The effects of glucocorticoids on protein catabolism are often profound in Cushing’s syndrome, causing greatly decreased tissue proteins almost everywhere in the body with the exception 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, so many of these patients die of 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, severely diminished protein deposition in the bones often causes severe osteoporosis with consequent weakness of the bones.

Treatment of Cushing’s Syndrome

Treatment of Cushing’s syndrome consists of removing an adrenal tumor if this is the cause or decreasing the secretion of ACTH, if this is possible. Hypertrophied pituitary glands or even small tumors in the pituitary that oversecrete ACTH can sometimes be surgically removed or destroyed by radiation. 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 resulting 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, slight increase in extracellular fluid volume and blood volume, very slight increase in plasma sodium concentration (usually > 4 to 6 mEq/L increase), and, almost always, hypertension. Especially interesting in primary aldosteronism are occasional periods of muscle paralysis caused by the hypokalemia. The paralysis is caused by a depressant effect of low extracellular potassium concentration on action potential transmission by the nerve fibers, as explained in Chapter 5.

One of the diagnostic criteria of primary aldosteronism is a decreased plasma renin concentration. This results from feedback suppression of renin secretion caused by the excess aldosterone or by the excess extracellular 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 adrenal tissue when hyperplasia is the cause. Another option for treatment is pharmacological antagonism of the mineralocorticoid receptor with spironolactone or eplerenone.

Adrenogenital Syndrome

An occasional adrenocortical tumor secretes excessive quantities of androgens that cause intense masculinizing effects throughout the body. If this occurs in a female, she develops virile characteristics, including growth of a beard, a much deeper voice, occasionally baldness if she also has the genetic trait for baldness, masculine distribution of hair on the body and the pubis, growth of the clitoris 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 77-11, 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 normal virilizing characteristics of the testosterone secreted by the testes. It is often difficult to make a diagnosis of adrenogenital syndrome in the adult male. In adrenogenital syndrome, 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.

image

Figure 77-11 Adrenogenital syndrome in a 4-year-old boy.

(Courtesy Dr. Leonard Posey.)

Bibliography

Adcock I.M., Barnes P.J. Molecular mechanisms of corticosteroid resistance. Chest. 2008;134:394.

Biller B.M., Grossman A.B., Stewart P.M., et al. Treatment of adrenocorticotropin-dependent Cushing’s syndrome: a consensus statement. J Clin Endocrinol Metab. 2008;93:2454.

Boldyreff B., Wehling M. Aldosterone: refreshing a slow hormone by swift action. News Physiol Sci. 2004;19:97.

Bornstein S.R. Predisposing factors for adrenal insufficiency. N Engl J Med. 2009;360:2328.

Boscaro M., Arnaldi G. Approach to the patient with possible Cushing’s syndrome. J Clin Endocrinol Metab.. 2009;94:3121.

Boscaro M., Barzon L., Fallo F., et al. Cushing’s syndrome. Lancet. 2001;357:783.

de Paula R.B., da Silva A.A., Hall J.E. Aldosterone antagonism attenuates obesity-induced hypertension and glomerular hyperfiltration. Hypertension. 2004;43:41.

Fuller P.J., Young M.J. Mechanisms of mineralocorticoid action. Hypertension. 2005;46:1227.

Funder J.W. Reconsidering the roles of the mineralocorticoid receptor. Hypertension. 2009;53:286.

Funder J.W. Aldosterone and the cardiovascular system: genomic and nongenomic effects. Endocrinology. 2006;147:5564.

Hall J.E., Granger J.P., Smith M.J.Jr, et al. Role of renal hemodynamics and arterial pressure in aldosterone “escape”. Hypertension. 1984;6:I183.

Larsen P.R., Kronenberg H.M., Melmed S., et al. Williams Textbook of Endocrinology, ed 10. Philadelphia: WB Saunders Co, 2003.

Levin E.R. Rapid signaling by steroid receptors. Am J Physiol Regul Integr Comp Physiol. 2008;295:R1425.

Lösel R.M., Falkenstein E., Feuring M., et al. Nongenomic steroid action: Controversies, questions, and answers. Physiol Rev. 2003;83:965.

Oberleithner H. Unorthodox sites and modes of aldosterone action. News Physiol Sci. 2004;19:51.

O’shaughnessy K.M., Karet F.E. Salt handling and hypertension. J Clin Invest. 2004;113:1075.

Pippal J.B., Fuller P.J. Structure-function relationships in the mineralocorticoid receptor. J Mol Endocrinol. 2008;41:405.

Raff H. Utility of salivary cortisol measurements in Cushing’s syndrome and adrenal insufficiency. J Clin Endocrinol Metab. 2009;94:3647.

Rickard A.J., Young M.J. Corticosteroid receptors, macrophages and cardiovascular disease. J Mol Endocrinol. 2009;42:449.

Spat A., Hunyady L. Control of aldosterone secretion: a model for convergence in cellular signaling pathways. Physiol Rev. 2004;84:489.

Speiser P.W., White P.C. Congenital adrenal hyperplasia. N Engl J Med. 2003;349:776.

Sowers J.R., Whaley-Connell A., Epstein M. Narrative review: the emerging clinical implications of the role of aldosterone in the metabolic syndrome and resistant hypertension. Ann Intern Med. 2009;150:776.

Stockand J.D. New ideas about aldosterone signaling in epithelia. Am J Physiol Renal Physiol. 2002;282:F559.

Vinson G.P. The adrenal cortex and life. Mol Cell Endocrinol. 2009;300:2.

 



If you find an error or have any questions, please email us at admin@doctorlib.info. Thank you!