Chapter 20: The Adrenal Medulla & Adrenal Cortex

After reading this chapter, you should be able to:

• Name the three catecholamines secreted by the adrenal medulla and summarize their biosynthesis, metabolism, and function.

• List the stimuli that increase adrenal medullary secretion.

• Differentiate between C₁₈, C₁₉, and C₂₁ steroids and give examples of each.

• Outline the steps involved in steroid biosynthesis in the adrenal cortex.

• Name the plasma proteins that bind adrenocortical steroids and discuss their physiologic role.

• Name the major site of adrenocortical hormone metabolism and the principal metabolites produced from glucocorticoids, adrenal androgens, and aldosterone.

• Describe the mechanisms by which glucocorticoids and aldosterone produce changes in cellular function.

• List and briefly describe the physiologic and pharmacologic effects of glucocorticoids.

• Contrast the physiologic and pathologic effects of adrenal androgens.

• Describe the mechanisms that regulate secretion of glucocorticoids and adrenal sex hormones.

• List the actions of aldosterone and describe the mechanisms that regulate aldosterone secretion.

• Describe the main features of the diseases caused by excess or deficiency of each of the hormones of the adrenal gland.

There are two endocrine organs in the adrenal gland, one surrounding the other. The main secretions of the inner adrenal medulla (Figure 20–1) are the catecholamines epinephrine, norepinephrine, and dopamine; the outer adrenal cortex secretes steroid hormones.

The adrenal medulla is in effect a sympathetic ganglion in which the postganglionic neurons have lost their axons and become secretory cells. The cells secrete when stimulated by the preganglionic nerve fibers that reach the gland via the splanchnic nerves. Adrenal medullary hormones work mostly to prepare the body for emergencies, the so-called “fight-or-flight” responses.

The adrenal cortex secretes glucocorticoids, steroids with widespread effects on the metabolism of carbohydrate and protein; and a mineralocorticoid essential to the maintenance of Na⁺ balance and extracellular fluid (ECF) volume. It is also a secondary site of androgen synthesis, secreting sex hormones such as testosterone, which can exert effects on reproductive function. Mineralocorticoids and the glucocorticoids are necessary for survival. Adrenocortical secretion is controlled primarily by adrenocorticotropic hormone (ACTH) from the anterior pituitary, but mineralocorticoid secretion is also subject to independent control by circulating factors, of which the most important is angiotensin II, a peptide formed in the bloodstream by the action of renin.

The adrenal medulla, which constitutes 28% of the mass of the adrenal gland, is made up of interlacing cords of densely innervated granule-containing cells that abut on venous sinuses. Two cell types can be distinguished morphologically: an epinephrine-secreting type that has larger, less dense granules; and a norepinephrine-secreting type in which smaller, very dense granules fail to fill the vesicles in which they are contained. In humans, 90% of the cells are the epinephrine-secreting type and 10% are the norepinephrine-secreting type. The type of cell that secretes dopamine is unknown. Paraganglia, small groups of cells resembling those in the adrenal medulla, are found near the thoracic and abdominal sympathetic ganglia (Figure 20–1).

In adult mammals, the adrenal cortex is divided into three zones (Figure 20–2). The outer zona glomerulosa is made up of whorls of cells that are continuous with the columns of cells that form the zona fasciculata. These columns are separated by venous sinuses. The inner portion of the zona fasciculata merges into the zona reticularis, where the cell columns become interlaced in a network. The zona glomerulosa makes up 15% of the mass of the adrenal gland; the zona fasciculata, 50%; and the zona reticularis, 7%. The adrenocortical cells contain abundant lipid, especially in the outer portion of the zona fasciculata. All three cortical zones secrete corticosterone, but the active enzymatic mechanism for aldosterone biosynthesis is limited to the zona glomerulosa, whereas the enzymatic mechanisms for forming cortisol and sex hormones are found in the two inner zones. Furthermore, subspecialization occurs within the inner two zones, with the zona fasciculata secreting mostly glucocorticoids and the zona reticularis secreting mainly sex hormones.

Arterial blood reaches the adrenal from many small branches of the phrenic and renal arteries and the aorta. From a plexus in the capsule, blood flows through the cortex to the sinusoids of the medulla. The medulla is also supplied by a few arterioles that pass directly to it from the capsule. In most species, including humans, blood from the medulla flows into a central adrenal vein. The blood flow through the adrenal is large, as it is in most endocrine glands.

During fetal life, the human adrenal is large and under pituitary control, but the three zones of the permanent cortex represent only 20% of the gland. The remaining 80% is the large fetal adrenal cortex, which undergoes rapid degeneration at the time of birth. A major function of this fetal adrenal is synthesis and secretion of sulfate conjugates of androgens that are converted in the placenta to estrogens (see Chapter 22). No structure is comparable to the human fetal adrenal in laboratory animals.

An important function of the zona glomerulosa, in addition to aldosterone synthesis, is the formation of new cortical cells. The adrenal medulla does not regenerate, but when the inner two zones of the cortex are removed, a new zona fasciculata and zona reticularis regenerate from glomerular cells attached to the capsule. Small capsular remnants regrow large pieces of adrenocortical tissue. Immediately after hypophysectomy, the zona fasciculata and zona reticularis begin to atrophy, whereas the zona glomerulosa is unchanged because of the action of angiotensin II on this zone. The ability to secrete aldosterone and conserve Na⁺ is normal for some time after hypophysectomy, but in long-standing hypopituitarism, aldosterone deficiency may develop, apparently because of the absence of a pituitary factor that maintains the responsiveness of the zona glomerulosa. Injections of ACTH and stimuli that cause endogenous ACTH secretion produce hypertrophy of the zona fasciculata and zona reticularis but actually decrease, rather than increase, the size of the zona glomerulosa.

The cells of the adrenal cortex contain large amounts of smooth endoplasmic reticulum, which is involved in the steroid-forming process. Other steps in steroid biosynthesis occur in the mitochondria. The structure of steroid-secreting cells is very similar throughout the body. The typical features of such cells are shown in Figure 20–3.

CATECHOLAMINES

Norepinephrine, epinephrine, and small amounts of dopamine are synthesized by the adrenal medulla. Cats and some other species secrete mainly norepinephrine, but in dogs and humans, most of the catecholamine output in the adrenal vein is epinephrine. Norepinephrine also enters the circulation from noradrenergic nerve endings.

The structures of norepinephrine, epinephrine, and dopamine and the pathways for their biosynthesis and metabolism are discussed in Chapter 7. Norepinephrine is formed by hydroxylation and decarboxylation of tyrosine, and epinephrine by methylation of norepinephrine. Phenylethanolamine-N-methyltransferase (PNMT), the enzyme that catalyzes the formation of epinephrine from norepinephrine, is found in appreciable quantities only in the brain and the adrenal medulla. Adrenal medullary PNMT is induced by glucocorticoids. Although relatively large amounts are required, the glucocorticoid concentration is high in the blood draining from the cortex to the medulla. After hypophysectomy, the glucocorticoid concentration of this blood falls and epinephrine synthesis is decreased. In addition, glucocorticoids are apparently necessary for the normal development of the adrenal medulla; in 21β-hydroxylase deficiency, glucocorticoid secretion is reduced during fetal life and the adrenal medulla is dysplastic. In untreated 21β-hydroxylase deficiency, circulating catecholamines are low after birth.

In plasma, about 95% of the dopamine and 70% of the norepinephrine and epinephrine are conjugated to sulfate. Sulfate conjugates are inactive and their function is unsettled. In recumbent humans, the normal plasma level of free norepinephrine is about 300 pg/mL (1.8 nmol/L). On standing, the level increases 50–100% (Figure 20–4). The plasma norepinephrine level is generally unchanged after adrenalectomy, but the free epinephrine level, which is normally about 30 pg/mL (0.16 nmol/L), falls to essentially zero. The epinephrine found in tissues other than the adrenal medulla and the brain is for the most part absorbed from the bloodstream rather than synthesized in situ. Interestingly, low levels of epinephrine reappear in the blood some time after bilateral adrenalectomy, and these levels are regulated like those secreted by the adrenal medulla. They may come from cells such as the intrinsic cardiac adrenergic (ICA) cells (see Chapter 13), but their exact source is unknown.

Plasma dopamine levels are normally very low, about 0.13 nmol/L. Most plasma dopamine is thought to be derived from sympathetic noradrenergic ganglia.

The catecholamines have a half-life of about 2 min in the circulation. For the most part, they are methoxylated and then oxidized to 3-methoxy-4-hydroxymandelic acid (vanillylmandelic acid [VMA]; see Chapter 7). About 50% of the secreted catecholamines appear in the urine as free or conjugated metanephrine and normetanephrine, and 35% as VMA. Only small amounts of free norepinephrine and epinephrine are excreted. In normal humans, about 30 μg of norepinephrine, 6 μg of epinephrine, and 700 μg of VMA are excreted per day.

OTHER SUBSTANCES SECRETED BY THE ADRENAL MEDULLA

In the medulla, norepinephrine and epinephrine are stored in granules with ATP. The granules also contain chromogranin A (see Chapter 7). Secretion is initiated by acetylcholine released from the preganglionic neurons that innervate the secretory cells. Acetylcholine activates cation channels allowing Ca²⁺ to enter the cells from the ECF and trigger the exocytosis of the granules. In this manner, catecholamines, ATP, and proteins from the granules are all released into the blood together.

Epinephrine-containing cells of the medulla also contain and secrete opioid peptides (see Chapter 7). The precursor molecule is preproenkephalin. Most of the circulating metenkephalin comes from the adrenal medulla. The circulating opioid peptides do not cross the blood–brain barrier.

Adrenomedullin, a vasodepressor polypeptide found in the adrenal medulla, is discussed in Chapter 32.

EFFECTS OF EPINEPHRINE & NOREPINEPHRINE

In addition to mimicking the effects of noradrenergic nervous discharge, norepinephrine and epinephrine exert metabolic effects that include glycogenolysis in liver and skeletal muscle, mobilization of free fatty acids (FFA), increased plasma lactate, and stimulation of the metabolic rate. The effects of norepinephrine and epinephrine are brought about by actions on two classes of receptors: α- and β-adrenergic receptors. α-Receptors are subdivided into two groups, α₁ and α₂ receptors, and β-receptors into three groups, β₁, β₂, and β₃ receptors (see Chapter 7). There are three subtypes of α₁-receptors and three subtypes of α₂-receptors (see Table 7–2).

Norepinephrine and epinephrine both increase the force and rate of contraction of the isolated heart. These responses are mediated by β₁-receptors. The catecholamines also increase myocardial excitability, causing extrasystoles and, occasionally, more serious cardiac arrhythmias. Norepinephrine produces vasoconstriction in most if not all organs via α₁-receptors, but epinephrine dilates the blood vessels in skeletal muscle and the liver via β₂-receptors. This usually overbalances the vasoconstriction produced by epinephrine elsewhere, and the total peripheral resistance drops. When norepinephrine is infused slowly in normal animals or humans, the systolic and diastolic blood pressures rise. The hypertension stimulates the carotid and aortic baroreceptors, producing reflex bradycardia that overrides the direct cardioacceleratory effect of norepinephrine. Consequently, cardiac output per minute falls. Epinephrine causes a widening of the pulse pressure but because baroreceptor stimulation is insufficient to obscure the direct effect of the hormone on the heart, cardiac rate and output increase. These changes are summarized in Figure 20–5.

Catecholamines increase alertness (see Chapter 14). Epinephrine and norepinephrine are equally potent in this regard, although in humans epinephrine usually evokes more anxiety and fear.

The catecholamines have several different actions that affect blood glucose. Epinephrine and norepinephrine both cause glycogenolysis. They produce this effect via β-adrenergic receptors that increase cyclic adenosine monophosphate (cAMP), with activation of phosphorylase, and via α-adrenergic receptors that increase intracellular Ca²⁺ (see Chapter 7). In addition, the catecholamines increase the secretion of insulin and glucagon via β-adrenergic mechanisms and inhibit the secretion of these hormones via α-adrenergic mechanisms.

Norepinephrine and epinephrine also produce a prompt rise in the metabolic rate that is independent of the liver and a smaller, delayed rise that is abolished by hepatectomy and coincides with the rise in blood lactate concentration. The initial rise in metabolic rate may be due to cutaneous vasoconstriction, which decreases heat loss and leads to a rise in body temperature, or to increased muscular activity, or both. The second rise is probably due to oxidation of lactate in the liver. Mice unable to make norepinephrine or epinephrine because their dopamine β-hydroxylase gene is knocked out are intolerant of cold, but surprisingly, their basal metabolic rate is elevated. The cause of this elevation is unknown.

When injected, epinephrine and norepinephrine cause an initial rise in plasma K⁺ because of release of K⁺ from the liver and then a prolonged fall in plasma K⁺ because of an increased entry of K⁺ into skeletal muscle that is mediated by β₂-adrenergic receptors. Some evidence suggests that activation of α-receptors opposes this effect.

The increases in plasma norepinephrine and epinephrine that are needed to produce the various effects listed above have been determined by infusion of catecholamines in resting humans. In general, the threshold for the cardiovascular and the metabolic effects of norepinephrine is about 1500 pg/mL, that is, about five times the resting value (Figure 20–4). Epinephrine, on the other hand, produces tachycardia when the plasma level is about 50 pg/mL, that is, about twice the resting value. The threshold for increased systolic blood pressure and lipolysis is about 75 pg/mL; the threshold for hyperglycemia, increased plasma lactate, and decreased diastolic blood pressure is about 150 pg/mL; and the threshold for the α-mediated decrease in insulin secretion is about 400 pg/mL. Plasma epinephrine often exceeds these thresholds. On the other hand, plasma norepinephrine rarely exceeds the threshold for its cardiovascular and metabolic effects, and most of its effects are due to its local release from postganglionic sympathetic neurons. Most adrenal medullary tumors (pheochromocytomas) secrete norepinephrine or epinephrine or both and produce sustained hypertension. However, 15% of epinephrine-secreting tumors secrete this catecholamine episodically, producing intermittent bouts of palpitations, headache, glycosuria, and extreme systolic hypertension. These same symptoms are produced by intravenous injection of a large dose of epinephrine.

EFFECTS OF DOPAMINE

The physiologic function of the dopamine in the circulation is unknown. However, injected dopamine produces renal vasodilation, probably by acting on a specific dopaminergic receptor. It also produces vasodilation in the mesentery. Elsewhere, it produces vasoconstriction, probably by releasing norepinephrine, and it has a positive inotropic effect on the heart by an action on β₁-adrenergic receptors. The net effect of moderate doses of dopamine is an increase in systolic pressure and no change in diastolic pressure. Because of these actions, dopamine is useful in the treatment of traumatic and cardiogenic shock (see Chapter 32).

Dopamine is made in the renal cortex. It causes natriuresis and may exert this effect by inhibiting renal Na, K, ATPase.

NEURAL CONTROL

Certain drugs act directly on the adrenal medulla, but physiologic stimuli affect medullary secretion through the nervous system. Catecholamine secretion is low in basal states, but the secretion of epinephrine and, to a lesser extent, that of norepinephrine is reduced even further during sleep.

Increased adrenal medullary secretion is part of the diffuse sympathetic discharge provoked in emergency situations, which Cannon called the “emergency function of the sympathoadrenal system.” The ways in which this discharge prepares the individual for flight or fight are described in Chapter 13, and the increases in plasma catecholamines under various conditions are shown in Figure 20–4.

The metabolic effects of circulating catecholamines are probably important, especially in certain situations. The calorigenic action of catecholamines in animals exposed to cold is an example, and so is the glycogenolytic effect (see Chapter 24) in combating hypoglycemia.

SELECTIVE SECRETION

When adrenal medullary secretion is increased, the ratio of norepinephrine to epinephrine in the adrenal effluent is generally unchanged. However, norepinephrine secretion tends to be selectively increased by emotional stresses with which the individual is familiar, whereas epinephrine secretion rises selectively in situations in which the individual does not know what to expect.

CLASSIFICATION & STRUCTURE

The hormones of the adrenal cortex are derivatives of cholesterol. Like cholesterol, bile acids, vitamin D, and ovarian and testicular steroids, they contain the cyclopentanoperhydrophenanthrene nucleus (Figure 20–6). Gonadal and adrenocortical steroids are of three types: C₂₁ steroids, which have a two-carbon side chain at position 17; C₁₉ steroids, which have a keto or hydroxyl group at position 17; and C₁₈ steroids, which, in addition to a 17-keto or hydroxyl group, have no angular methyl group attached to position 10. The adrenal cortex secretes primarily C₂₁ and C₁₉ steroids. Most of the C₁₉ steroids have a keto group at position 17 and are therefore called 17-ketosteroids. The C₂₁ steroids that have a hydroxyl group at the 17 position in addition to the side chain are often called 17-hydroxycorticoids or 17-hydroxycorticosteroids.

The C₁₉ steroids have androgenic activity. The C₂₁ steroids are classified, using Selye’s terminology, as mineralocorticoids or glucocorticoids. All secreted C₂₁ steroids have both mineralocorticoid and glucocorticoid activity; mineralocorticoids are those in which effects on Na⁺ and K⁺ excretion predominate and glucocorticoids are those in which effects on glucose and protein metabolism predominate.

The details of steroid nomenclature and isomerism can be found elsewhere. However, it is pertinent to mention that the Greek letter Δ indicates a double bond and that the groups that lie above the plane of each of the steroid rings are indicated by the Greek letter β and a solid line (—OH), whereas those that lie below the plane are indicated by α and a dashed line (- - -OH). Thus, the C₂₁ steroids secreted by the adrenal have a Δ⁴-3-keto configuration in the A ring. In most naturally occurring adrenal steroids, 17-hydroxy groups are in the α configuration, whereas 3-, 11-, and 21-hydroxy groups are in the β configuration. The 18-aldehyde configuration of naturally occurring aldosterone is the D form. L-aldosterone is physiologically inactive.

SECRETED STEROIDS

Innumerable steroids have been isolated from adrenal tissue, but the only steroids normally secreted in physiologically significant amounts are the mineralocorticoid aldosterone, the glucocorticoids cortisol and corticosterone, and the androgens dehydroepiandrosterone (DHEA) and androstenedione. The structures of these steroids are shown in Figure 20–7 and Figure 20–8. Deoxycorticosterone is a mineralocorticoid that is normally secreted in about the same amount as aldosterone (Table 20–1) but has only 3% of the mineralocorticoid activity of aldosterone. Its effect on mineral metabolism is usually negligible, but in diseases in which its secretion is increased, its effect can be appreciable. Most of the estrogens that are not formed in the ovaries are produced in the circulation from adrenal androstenedione. Almost all the dehydroepiandrosterone is secreted conjugated with sulfate, although most if not all of the other steroids are secreted in the free, unconjugated form (Clinical Box 20–1).

SPECIES DIFFERENCES

In all species from amphibia to humans, the major C₂₁ steroid hormones secreted by adrenocortical tissue appear to be aldosterone, cortisol, and corticosterone, although the ratio of cortisol to corticosterone varies. Birds, mice, and rats secrete corticosterone almost exclusively; dogs secrete approximately equal amounts of the two glucocorticoids; and cats, sheep, monkeys, and humans secrete predominantly cortisol. In humans, the ratio of secreted cortisol to corticosterone is approximately 7:1.

STEROID BIOSYNTHESIS

The major paths by which the naturally occurring adrenocortical hormones are synthesized in the body are summarized in Figures 20–7 and 20–8. The precursor of all steroids is cholesterol. Some of the cholesterol is synthesized from acetate, but most of it is taken up from LDL in the circulation. LDL receptors are especially abundant in adrenocortical cells. The cholesterol is esterified and stored in lipid droplets. Cholesterol ester hydrolase catalyzes the formation of free cholesterol in the lipid droplets (Figure 20–9). The cholesterol is transported to mitochondria by a sterol carrier protein. In the mitochondria, it is converted to pregnenolone in a reaction catalyzed by an enzyme known as cholesterol desmolase or side-chain cleavage enzyme. This enzyme, like most of the enzymes involved in steroid biosynthesis, is a member of the cytochrome P450 superfamily and is also known as P450scc or CYP11A1. For convenience, the various names of the enzymes involved in adrenocortical steroid biosynthesis are summarized in Table 20–3.

Pregnenolone moves to the smooth endoplasmic reticulum, where some of it is dehydrogenated to form progesterone in a reaction catalyzed by 3β-hydroxysteroid dehydrogenase. This enzyme has a molecular weight of 46,000 and is not a cytochrome P450. It also catalyzes the conversion of 17α-hydroxypregnenolone to 17α-hydroxyprogesterone, and dehydroepiandrosterone to androstenedione (Figure 22–7) in the smooth endoplasmic reticulum. The 17α-hydroxypregnenolone and the 17α-hydroxyprogesterone are formed from pregnenolone and progesterone, respectively (Figure 20–7) by the action of 17α-hydroxylase. This is another mitochondrial P450, and it is also known as P450c17 or CYP17. Located in another part of the same enzyme is 17,20-lyase activity that breaks the 17,20 bond, converting 17α-pregnenolone and 17α-progesterone to the C₁₉ steroids dehydroepiandrosterone and androstenedione.

Hydroxylation of progesterone to 11-deoxycorticosterone and of 17α-hydroxyprogesterone to 11-deoxycortisol occurs in the smooth endoplasmic reticulum. These reactions are catalyzed by 21β-hydroxylase, a cytochrome P450 that is also known as P450c21 or CYP21A2.

11-Deoxycorticosterone and the 11-deoxycortisol move back to the mitochondria, where they are 11-hydroxylated to form corticosterone and cortisol. These reactions occur in the zona fasciculata and zona reticularis and are catalyzed by 11β-hydroxylase, a cytochrome P450 also known as P450c11 or CYP11B1.

In the zona glomerulosa there is no 11β-hydroxylase, but a closely related enzyme called aldosterone synthase is present. This cytochrome P450 is 95% identical to 11β-hydroxylase and is also known as P450c11AS or CYP11B2. The genes that code CYP11B1 and CYP11B2 are both located on chromosome 8. However, aldosterone synthase is normally found only in the zona glomerulosa. The zona glomerulosa also lacks 17α-hydroxylase. This is why the zona glomerulosa makes aldosterone but fails to make cortisol or sex hormones.

Furthermore, subspecialization occurs within the inner two zones. The zona fasciculata has more 3β-hydroxysteroid dehydrogenase activity than the zona reticularis, and the zona reticularis has more of the cofactors required for the 17,20-lyase activity of 17α-hydroxylase. Therefore, the zona fasciculata makes more cortisol and corticosterone, and the zona reticularis makes more androgens. Most of the dehydroepiandrosterone that is formed is converted to dehydroepiandrosterone sulfate (DHEAS) by adrenal sulfokinase, and this enzyme is localized in the zona reticularis as well.

ACTION OF ACTH

ACTH binds to high-affinity receptors on the plasma membrane of adrenocortical cells. This activates adenylyl cyclase via G_s. The resulting reactions (Figure 20–9) lead to a prompt increase in the formation of pregnenolone and its derivatives, with secretion of the latter. Over longer periods, ACTH also increases the synthesis of the P450s involved in the synthesis of glucocorticoids.

ACTIONS OF ANGIOTENSIN II

Angiotensin II binds to AT₁ receptors (see Chapter 38) in the zona glomerulosa that act via a G-protein to activate phospholipase C. The resulting increase in protein kinase C fosters the conversion of cholesterol to pregnenolone (Figure 20–8) and facilitates the action of aldosterone synthase, resulting in increased secretion of aldosterone.

ENZYME DEFICIENCIES

The consequences of inhibiting any of the enzyme systems involved in steroid biosynthesis can be predicted from Figures 20–7 and 20–8. Congenital defects in the enzymes lead to deficient cortisol secretion and the syndrome of congenital adrenal hyperplasia. The hyperplasia is due to increased ACTH secretion. Cholesterol desmolase deficiency is fatal in utero because it prevents the placenta from making the progesterone necessary for pregnancy to continue. A cause of severe congenital adrenal hyperplasia in newborns is a loss of function mutation of the gene for the steroidogenic acute regulatory (StAR) protein. This protein is essential in the adrenals and gonads but not in the placenta for the normal movement of cholesterol into the mitochondria to reach cholesterol desmolase, which is located on the matrix space side of the internal mitochondrial membrane (see Chapter 16). In its absence, only small amounts of steroids are formed. The degree of ACTH stimulation is marked, resulting eventually in accumulation of large numbers of lipoid droplets in the adrenal. For this reason, the condition is called congenital lipoid adrenal hyperplasia. Because androgens are not formed, female genitalia develop regardless of genetic sex (see Chapter 22). In 3β hydroxysteroid dehydrogenase deficiency, another rare condition, DHEA secretion is increased. This steroid is a weak androgen that can cause some masculinization in females with the disease, but it is not adequate to produce full masculinization of the genitalia in genetic males. Consequently, hypospadias, a condition where the opening of the urethra is on the underside of the penis rather than its tip, is common. In fully developed 17α-hydroxylase deficiency, a third rare condition due to a mutated gene for CYP17, no sex hormones are produced, so female external genitalia are present. However, the pathway leading to corticosterone and aldosterone is intact, and elevated levels of 11-deoxycorticosterone and other mineralocorticoids produce hypertension and hypokalemia. Cortisol is deficient, but this is partially compensated by the glucocorticoid activity of corticosterone.

Unlike the defects discussed in the preceding paragraph, 21β-hydroxylase deficiency is common, accounting for 90% or more of the enzyme deficiency cases. The 21β-hydroxylase gene, which is in the HLA complex of genes on the short arm of chromosome 6 (see Chapter 3) is one of the most polymorphic in the human genome. Mutations occur at many different sites in the gene, and the abnormalities that are produced therefore range from mild to severe. Production of cortisol and aldosterone are generally reduced, so ACTH secretion and consequently production of precursor steroids are increased. These steroids are converted to androgens, producing virilization. The characteristic pattern that develops in females in the absence of treatment is the adrenogenital syndrome. Masculization may not be marked until later in life and mild cases can be detected only by laboratory tests. In 75% of the cases, aldosterone deficiency causes appreciable loss of Na⁺ (salt-losing form of adrenal hyperplasia). The resulting hypovolemia can be severe.

In 11β-hydroxylase deficiency, virilization plus excess secretion of 11-deoxycortisol and 11-deoxycorticosterone take place. Because the former is an active mineralocorticoid, patients with this condition also have salt and water retention and, in two-thirds of the cases, hypertension (hypertensive form of congenital adrenal hyperplasia).

Glucocorticoid treatment is indicated in all of the virilizing forms of congenital adrenal hyperplasia because it repairs the glucocorticoid deficit and inhibits ACTH secretion, reducing the abnormal secretion of androgens and other steroids.

Expression of the cytochrome P450 enzymes responsible for steroid hormone biosynthesis depends on steroid factor-1 (SF-1), an orphan nuclear receptor. If Ft2-F1, the gene for SF-1, is knocked out, the gonads as well as adrenals fail to develop and additional abnormalities are present at the pituitary and hypothalamic level.

GLUCOCORTICOID BINDING

Cortisol is bound in the circulation to an α globulin called transcortin or corticosteroid-binding globulin (CBG). A minor degree of binding to albumin also takes place. Corticosterone is similarly bound but to a lesser degree. The half-life of cortisol in the circulation is therefore longer (about 60–90 min) than that of corticosterone (50 min). Bound steroids are physiologically inactive (see Chapter 16). In addition, relatively little free cortisol and corticosterone are found in the urine because of protein binding.

The equilibrium between cortisol and its binding protein and the implications of binding in terms of tissue supplies and ACTH secretion are summarized in Figure 20–10. The bound cortisol functions as a circulating reservoir of hormone that keeps a supply of free cortisol available to the tissues. The relationship is similar to that of T₄ and its binding protein (see Chapter 19). At normal levels of total plasma cortisol (13.5 μg/dL or 375 nmol/L), very little free cortisol is present in the plasma, but the binding sites on CBG become saturated when the total plasma cortisol exceeds 20 μg/dL. At higher plasma levels, binding to albumin increases, but the main increase is in the unbound fraction.

CBG is synthesized in the liver and its production is increased by estrogen. CBG levels are elevated during pregnancy and depressed in cirrhosis, nephrosis, and multiple myeloma. When the CBG level rises, more cortisol is bound, and initially the free cortisol level drops. This stimulates ACTH secretion, and more cortisol is secreted until a new equilibrium is reached at which the bound cortisol is elevated but the free cortisol is normal. Changes in the opposite direction occur when the CBG level falls. This explains why pregnant women have high total plasma cortisol levels without symptoms of glucocorticoid excess and, conversely, why some patients with nephrosis have low total plasma cortisol without symptoms of glucocorticoid deficiency.

METABOLISM & EXCRETION OF GLUCOCORTICOIDS

Cortisol is metabolized in the liver, which is the principal site of glucocorticoid catabolism. Most of the cortisol is reduced to dihydrocortisol and then to tetrahydrocortisol, which is conjugated to glucuronic acid (Figure 20–11). The glucuronyl transferase system responsible for this conversion also catalyzes the formation of the glucuronides of bilirubin (see Chapter 28) and a number of hormones and drugs. Competitive inhibition takes place between these substrates for the enzyme system.

The liver and other tissues contain the enzyme 11β hydroxysteroid dehydrogenase. There are at least two forms of this enzyme. Type 1 catalyzes the conversion of cortisol to cortisone and the reverse reaction, though it functions primarily as a reductase, forming cortisol from corticosterone. Type 2 catalyzes almost exclusively the one-way conversion of cortisol to cortisone. Cortisone is an active glucocorticoid because it is converted to cortisol, and it is well known because of its extensive use in medicine. It is not secreted in appreciable quantities by the adrenal glands. Little, if any, of the cortisone formed in the liver enters the circulation, because it is promptly reduced and conjugated to form tetrahydrocortisone glucuronide. The tetrahydroglucuronide derivatives (“conjugates”) of cortisol and corticosterone are freely soluble. They enter the circulation, where they do not become bound to protein. They are rapidly excreted in the urine.

About 10% of the secreted cortisol is converted in the liver to the 17-ketosteroid derivatives of cortisol and cortisone. The ketosteroids are conjugated for the most part to sulfate and then excreted in the urine. Other metabolites, including 20-hydroxy derivatives, are formed. There is an enterohepatic circulation of glucocorticoids and about 15% of the secreted cortisol is excreted in the stool. The metabolism of corticosterone is similar to that of cortisol, except that it does not form a 17-ketosteroid derivative (Clinical Box 20–2).

ALDOSTERONE

Aldosterone is bound to protein to only a slight extent, and its half-life is short (about 20 min). The amount secreted is small (Table 20–1), and the total plasma aldosterone level in humans is normally about 0.006 μg/dL (0.17 nmol/L), compared with a cortisol level (bound and free) of about 13.5 μg/dL (375 nmol/L). Much of the aldosterone is converted in the liver to the tetrahydroglucuronide derivative, but some is changed in the liver and in the kidneys to an 18-glucuronide. This glucuronide, which is unlike the breakdown products of other steroids, is converted to free aldosterone by hydrolysis at pH 1.0, and it is therefore often referred to as the “acid-labile conjugate.” Less than 1% of the secreted aldosterone appears in the urine in the free form. Another 5% is in the form of the acid-labile conjugate, and up to 40% is in the form of the tetrahydroglucuronide.

17-KETOSTEROIDS

The major adrenal androgen is the 17-ketosteroid dehydroepiandrosterone, although androstenedione is also secreted. The 11-hydroxy derivative of androstenedione and the 17-ketosteroids formed from cortisol and cortisone by side chain cleavage in the liver are the only 17-ketosteroids that have an =O or an —OH group in the 11 position (“11-oxy-17-ketosteroids”). Testosterone is also converted to a 17-ketosteroid. Because the daily 17-ketosteroid excretion in normal adults is 15 mg in men and 10 mg in women, about two-thirds of the urinary ketosteroids in men are secreted by the adrenal or formed from cortisol in the liver and about one-third are of testicular origin.

Etiocholanolone, one of the metabolites of the adrenal androgens and testosterone, can cause fever when it is unconjugated (see Chapter 17). Certain individuals have episodic bouts of fever due to periodic accumulation in the blood of unconjugated etiocholanolone (“etiocholanolone fever”).

ANDROGENS

Androgens are the hormones that exert masculinizing effects and they promote protein anabolism and growth (see Chapter 23). Testosterone from the testes is the most active androgen and the adrenal androgens have less than 20% of its activity. Secretion of the adrenal androgens is controlled acutely by ACTH and not by gonadotropins. However, the concentration of DHEAS increases until it peaks at about 225 mg/dL in the early 20s, and then falls to very low values in old age (Figure 20–12). These long-term changes are not due to changes in ACTH secretion and appear to be due instead to a rise and then a gradual fall in the lyase activity of 17α-hydroxylase.

All but about 0.3% of the circulating DHEA is conjugated to sulfate (DHEAS). The secretion of adrenal androgens is nearly as great in castrated males and females as it is in normal males, so it is clear that these hormones exert very little masculinizing effect when secreted in normal amounts. However, they can produce appreciable masculinization when secreted in excessive amounts. In adult males, excess adrenal androgens merely accentuate existing characteristics, but in prepubertal boys they can cause precocious development of the secondary sex characteristics without testicular growth (precocious pseudopuberty). In females they cause female pseudo-hermaphroditism and the adrenogenital syndrome. Some health practitioners recommend injections of dehydroepiandrosterone to combat the effects of aging (see Chapter 1), but results to date are controversial at best.

ESTROGENS

The adrenal androgen androstenedione is converted to testosterone and to estrogens (aromatized) in fat and other peripheral tissues. This is an important source of estrogens in men and postmenopausal women (see Chapters 22 and 23).

ADRENAL INSUFFICIENCY

In untreated adrenal insufficiency, Na⁺ loss and shock occurs due to the lack of mineralocorticoid activity, as well as abnormalities of water, carbohydrate, protein, and fat metabolism due to the lack of glucocorticoids. These metabolic abnormalities are eventually fatal despite mineralocorticoid treatment. Small amounts of glucocorticoids correct the metabolic abnormalities, in part directly and in part by permitting other reactions to occur. It is important to separate these physiologic actions of glucocorticoids from the quite different effects produced by large amounts of the hormones.

MECHANISM OF ACTION

The multiple effects of glucocorticoids are triggered by binding to glucocorticoid receptors, and the steroid–receptor complexes act as transcription factors that promote the transcription of certain segments of DNA (see Chapter 1). This, in turn, leads via the appropriate mRNAs to synthesis of enzymes that alter cell function. In addition, it seems likely that glucocorticoids have nongenomic actions.

EFFECTS ON INTERMEDIARY METABOLISM

The actions of glucocorticoids on the intermediary metabolism of carbohydrate, protein, and fat are discussed in Chapter 24. They include increased protein catabolism and increased hepatic glycogenesis and gluconeogenesis. Glucose-6-phosphatase activity is increased, and the plasma glucose level rises. Glucocorticoids exert an anti-insulin action in peripheral tissues and make diabetes worse. However, the brain and the heart are spared, so the increase in plasma glucose provides extra glucose to these vital organs. In diabetics, glucocorticoids raise plasma lipid levels and increase ketone body formation, but in normal individuals, the increase in insulin secretion provoked by the rise in plasma glucose obscures these actions. In adrenal insufficiency, the plasma glucose level is normal as long as an adequate caloric intake is maintained, but fasting causes hypoglycemia that can be fatal. The adrenal cortex is not essential for the ketogenic response to fasting.

PERMISSIVE ACTION

Small amounts of glucocorticoids must be present for a number of metabolic reactions to occur, although the glucocorticoids do not produce the reactions by themselves. This effect is called their permissive action. Permissive effects include the requirement for glucocorticoids to be present for glucagon and catecholamines to exert their calorigenic effects (see above and Chapter 24), for catecholamines to exert their lipolytic effects, and for catecholamines to produce pressor responses and bronchodilation.

EFFECTS ON ACTH SECRETION

Glucocorticoids inhibit ACTH secretion, which represents a negative feedback response on the pituitary. ACTH secretion is increased in adrenalectomized animals. The consequences of the negative feedback action of cortisol on ACTH secretion are discussed below in the section on regulation of glucocorticoid secretion.

VASCULAR REACTIVITY

In adrenally insufficient animals, vascular smooth muscle becomes unresponsive to norepinephrine and epinephrine. The capillaries dilate and, terminally, become permeable to colloidal dyes. Failure to respond to the norepinephrine liberated at noradrenergic nerve endings probably impairs vascular compensation for the hypovolemia of adrenal insufficiency and promotes vascular collapse. Glucocorticoids restore vascular reactivity.

EFFECTS ON THE NERVOUS SYSTEM

Changes in the nervous system in adrenal insufficiency that are reversed only by glucocorticoids include the appearance of electroencephalographic waves slower than the normal β rhythm, and personality changes. The latter, which are mild, include irritability, apprehension, and inability to concentrate.

EFFECTS ON WATER METABOLISM

Adrenal insufficiency is characterized by an inability to excrete a water load, causing the possibility of water intoxication. Only glucocorticoids repair this deficit. In patients with adrenal insufficiency who have not received glucocorticoids, glucose infusion may cause high fever (“glucose fever”) followed by collapse and death. Presumably, the glucose is metabolized, the water dilutes the plasma, and the resultant osmotic gradient between the plasma and the cells causes the cells of the thermoregulatory centers in the hypothalamus to swell to such an extent that their function is disrupted.

The cause of defective water excretion in adrenal insufficiency is unsettled. Plasma vasopressin levels are elevated in adrenal insufficiency and reduced by glucocorticoid treatment. The glomerular filtration rate is low, and this probably contributes to the reduction in water excretion. The selective effect of glucocorticoids on the abnormal water excretion is consistent with this possibility, because even though the mineralocorticoids improve filtration by restoring plasma volume, the glucocorticoids raise the glomerular filtration rate to a much greater degree.

EFFECTS ON THE BLOOD CELLS & LYMPHATIC ORGANS

Glucocorticoids decrease the number of circulating eosinophils by increasing their sequestration in the spleen and lungs. Glucocorticoids also lower the number of basophils in the circulation and increase the number of neutrophils, platelets, and red blood cells (Table 20–4).

Glucocorticoids decrease the circulating lymphocyte count and the size of the lymph nodes and thymus by inhibiting lymphocyte mitotic activity. They reduce secretion of cytokines by inhibiting the effect of NF-κB on the nucleus. The reduced secretion of the cytokine IL-2 leads to reduced proliferation of lymphocytes (see Chapter 3), and these cells undergo apoptosis.

RESISTANCE TO STRESS

The term stress as used in biology has been defined as any change in the environment that changes or threatens to change an existing optimal steady state. Most, if not all, of these stresses activate processes at the molecular, cellular, or systemic level that tend to restore the previous state, that is, they are homeostatic reactions. Some, but not all, of the stresses stimulate ACTH secretion. The increase in ACTH secretion is essential for survival when the stress is severe. If animals are then hypophysectomized, or adrenalectomized but treated with maintenance doses of glucocorticoids, they die when exposed to the same stress.

The reason an elevated circulating ACTH, and hence glucocorticoid level, is essential for resisting stress remains for the most part unknown. Most of the stressful stimuli that increase ACTH secretion also activate the sympathetic nervous system, and part of the function of circulating glucocorticoids may be maintenance of vascular reactivity to catecholamines. Glucocorticoids are also necessary for the catecholamines to exert their full FFA-mobilizing action, and the FFAs are an important emergency energy supply. However, sympathectomized animals tolerate a variety of stresses with relative impunity. Another theory holds that glucocorticoids prevent other stress-induced changes from becoming excessive. At present, all that can be said is that stress causes increases in plasma glucocorticoids to high “pharmacologic” levels that in the short run are life-saving.

It should also be noted that the increase in ACTH, which is beneficial in the short term, becomes harmful and disruptive in the long term, causing among other things, the abnormalities of Cushing syndrome.

CUSHING SYNDROME

The clinical picture produced by prolonged increases in plasma glucocorticoids was described by Harvey Cushing and is called Cushing syndrome (Figure 20–13). It may be ACTH-independent or ACTH-dependent. The causes of ACTH-independent Cushing syndrome include glucocorticoid-secreting adrenal tumors, adrenal hyperplasia, and prolonged administration of exogenous glucocorticoids for diseases such as rheumatoid arthritis. Rare but interesting ACTH-independent cases have been reported in which adrenocortical cells abnormally express receptors for gastric inhibitory polypeptide (GIP) (see Chapter 25), vasopressin (see Chapter 38), β-adrenergic agonists, IL-1, or gonadotropin-releasing hormone (GnRH; see Chapter 22), causing these peptides to increase glucocorticoid secretion. The causes of ACTH-dependent Cushing syndrome include ACTH-secreting tumors of the anterior pituitary gland and tumors of other organs, usually the lungs, that secrete ACTH (ectopic ACTH syndrome) or corticotropin releasing hormone (CRH). Cushing syndrome due to anterior pituitary tumors is often called Cushing disease because these tumors were the cause of the cases described by Cushing. However, it is confusing to speak of Cushing disease as a subtype of Cushing syndrome, and the distinction seems to be of little more than historical value.

Patients with Cushing syndrome are protein-depleted as a result of excess protein catabolism. The skin and subcutaneous tissues are therefore thin and the muscles are poorly developed. Wounds heal poorly, and minor injuries cause bruises and ecchymoses. The hair is thin and scraggly. Many patients with the disease have some increase in facial hair and acne, but this is caused by the increased secretion of adrenal androgens and often accompanies the increase in glucocorticoid secretion.

Body fat is redistributed in a characteristic way. The extremities are thin, but fat collects in the abdominal wall, face, and upper back, where it produces a “buffalo hump.” As the thin skin of the abdomen is stretched by the increased subcutaneous fat depots, the subdermal tissues rupture to form prominent reddish purple striae. These scars are seen normally whenever a rapid stretching of skin occurs, but in normal individuals the striae are usually inconspicuous and lack the intense purplish color.

Many of the amino acids liberated from catabolized proteins are converted into glucose in the liver and the resultant hyperglycemia and decreased peripheral utilization of glucose may be sufficient to precipitate insulin-resistant diabetes mellitus, especially in patients genetically predisposed to diabetes. Hyperlipidemia and ketosis are associated with the diabetes, but acidosis is usually not severe.

The glucocorticoids are present in such large amounts in Cushing syndrome that they may exert a significant mineralocorticoid action. Deoxycorticosterone secretion is also elevated in cases due to ACTH hypersecretion. The salt and water retention plus the facial obesity cause the characteristic plethoric, rounded “moon-faced” appearance, and there may be significant K⁺ depletion and weakness. About 85% of patients with Cushing syndrome are hypertensive. The hypertension may be due to increased deoxycorticosterone secretion, increased angiotensinogen secretion, or a direct glucocorticoid effect on blood vessels (see Chapter 32).

Glucocorticoid excess leads to bone dissolution by decreasing bone formation and increasing bone resorption. This leads to osteoporosis, a loss of bone mass that leads eventually to collapse of vertebral bodies and other fractures. The mechanisms by which glucocorticoids produce their effects on bone are discussed in Chapter 21.

Glucocorticoids in excess accelerate the basic electroencephalographic rhythms and produce mental aberrations ranging from increased appetite, insomnia, and euphoria to frank toxic psychoses. As noted above, glucocorticoid deficiency is also associated with mental symptoms, but the symptoms produced by glucocorticoid excess are more severe.

ANTI-INFLAMMATORY & ANTI-ALLERGIC EFFECTS OF GLUCOCORTICOIDS

Glucocorticoids inhibit the inflammatory response to tissue injury. The glucocorticoids also suppress manifestations of allergic disease that are due to the release of histamine from mast cells and basophils. Both of these effects require high levels of circulating glucocorticoids and cannot be produced by administering steroids without producing the other manifestations of glucocorticoid excess. Furthermore, large doses of exogenous glucocorticoids inhibit ACTH secretion to the point that severe adrenal insufficiency can be a dangerous problem when therapy is stopped. However, local administration of glucocorticoids, for example, by injection into an inflamed joint or near an irritated nerve, produces a high local concentration of the steroid, often without enough systemic absorption to cause serious side effects.

The actions of glucocorticoids in patients with bacterial infections are dramatic but dangerous. For example, in pneumococcal pneumonia or active tuberculosis, the febrile reaction, the toxicity, and the lung symptoms disappear, but unless antibiotics are given at the same time, the bacteria spread throughout the body. It is important to remember that the symptoms are the warning that disease is present; when these symptoms are masked by treatment with glucocorticoids, there may be serious and even fatal delays in diagnosis and the institution of treatment with antimicrobial drugs.

The role of NF-κB in the anti-inflammatory and anti-allergic effects of glucocorticoids has been mentioned above and is discussed in Chapter 3. An additional action that combats local inflammation is inhibition of phospholipase A₂. This reduces the release of arachidonic acid from tissue phospholipids and consequently reduces the formation of leukotrienes, thromboxanes, prostaglandins, and prostacyclin (see Chapter 32).

OTHER EFFECTS

Large doses of glucocorticoids inhibit growth, decrease growth hormone secretion (see Chapter 18), induce PNMT, and decrease thyroid-stimulating hormone secretion. During fetal life, glucocorticoids accelerate the maturation of surfactant in the lungs (see Chapter 34).

ROLE OF ACTH

Both basal secretion of glucocorticoids and the increased secretion provoked by stress depend on ACTH from the anterior pituitary. Angiotensin II also stimulates the adrenal cortex, but its effect is mainly on aldosterone secretion. Large doses of a number of other naturally occurring substances, including vasopressin, serotonin, and vasoactive intestinal polypeptide (VIP), are capable of stimulating the adrenal directly, but there is no evidence that these agents play any role in the physiologic regulation of glucocorticoid secretion.

CHEMISTRY & METABOLISM OF ACTH

ACTH is a single-chain polypeptide containing 39 amino acids. Its origin from proopiomelanocortin (POMC) in the pituitary is discussed in Chapter 18. The first 23 amino acids in the chain generally constitute the active “core” of the molecule. Amino acids 24–39 constitute a “tail” that stabilizes the molecule and varies slightly in composition from species to species. The ACTHs that have been isolated are generally active in all species but antigenic in heterologous species.

ACTH is inactivated in blood in vitro more slowly than in vivo; its half-life in the circulation in humans is about 10 min. A large part of an injected dose of ACTH is found in the kidneys, but neither nephrectomy nor evisceration appreciably enhances its in vivo activity, and the site of its inactivation is not known.

EFFECT OF ACTH ON THE ADRENAL

After hypophysectomy, glucocorticoid synthesis and output decline within 1 h to very low levels, although some hormone is still secreted. Within a short time after an injection of ACTH (in dogs, less than 2 min), glucocorticoid output is increased. With low doses of ACTH, the relationship between the log of the dose and the increase in glucocorticoid secretion is linear. However, the maximal rate at which glucocorticoids can be secreted is rapidly reached, and this “ceiling on output” also exists in humans. The effects of ACTH on adrenal morphology and the mechanism by which it increases steroid secretion have been discussed above.

ADRENAL RESPONSIVENESS

ACTH not only produces prompt increases in glucocorticoid secretion but also increases the sensitivity of the adrenal to subsequent doses of ACTH. Conversely, single doses of ACTH do not increase glucocorticoid secretion in chronically hypophysectomized animals and patients with hypopituitarism, and repeated injections or prolonged infusions of ACTH are necessary to restore normal adrenal responses to ACTH. Decreased responsiveness is also produced by doses of glucocorticoids that inhibit ACTH secretion. The decreased adrenal responsiveness to ACTH is detectable within 24 h after hypophysectomy and increases progressively with time (Figure 20–14). It is marked when the adrenal is atrophic but develops before visible changes occur in adrenal size or morphology.

CIRCADIAN RHYTHM

ACTH is secreted in irregular bursts throughout the day and plasma cortisol tends to rise and fall in response to these bursts (Figure 20–15). In humans, the bursts are most frequent in the early morning, and about 75% of the daily production of cortisol occurs between 4:00 AM and 10:00 AM. The bursts are least frequent in the evening. This diurnal (circadian) rhythm in ACTH secretion is present in patients with adrenal insufficiency receiving constant doses of glucocorticoids. It is not due to the stress of getting up in the morning, traumatic as that may be, because the increased ACTH secretion occurs before waking up. If the “day” is lengthened experimentally to more than 24 h, that is, if the individual is isolated and the day’s activities are spread over more than 24 h, the adrenal cycle also lengthens, but the increase in ACTH secretion still occurs during the period of sleep. The biologic clock responsible for the diurnal ACTH rhythm is located in the suprachiasmatic nuclei of the hypothalamus (see Chapter 14).

THE RESPONSE TO STRESS

The morning plasma ACTH concentration in a healthy resting human is about 25 pg/mL (5.5 pmol/L). ACTH and cortisol values in various abnormal conditions are summarized in Figure 20–16. During severe stress, the amount of ACTH secreted exceeds the amount necessary to produce maximal glucocorticoid output. However, prolonged exposure to ACTH in conditions such as the ectopic ACTH syndrome increases the adrenal maximum.

Increases in ACTH secretion to meet emergency situations are mediated almost exclusively through the hypothalamus via release of CRH. This polypeptide is produced by neurons in the paraventricular nuclei. It is secreted in the median eminence and transported in the portal-hypophysial vessels to the anterior pituitary, where it stimulates ACTH secretion (see Chapter 18). If the median eminence is destroyed, increased secretion in response to many different stresses is blocked. Afferent nerve pathways from many parts of the brain converge on the paraventricular nuclei. Fibers from the amygdaloid nuclei mediate responses to emotional stresses, and fear, anxiety, and apprehension cause marked increases in ACTH secretion. Input from the suprachiasmatic nuclei provides the drive for the diurnal rhythm. Impulses ascending to the hypothalamus via the nociceptive pathways and the reticular formation trigger increased ACTH secretion in response to injury (Figure 20–16). The baroreceptors exert an inhibitory input via the nucleus of the tractus solitarius.

GLUCOCORTICOID FEEDBACK

Free glucocorticoids inhibit ACTH secretion, and the degree of pituitary inhibition is proportional to the circulating glucocorticoid level. The inhibitory effect is exerted at both the pituitary and the hypothalamic levels. The inhibition is due primarily to an action on DNA, and maximal inhibition takes several hours to develop, although more rapid “fast feedback” also occurs. The ACTH-inhibiting activity of the various steroids parallels their glucocorticoid potency. A drop in resting corticoid levels stimulates ACTH secretion, and in chronic adrenal insufficiency the rate of ACTH synthesis and secretion is markedly increased.

Thus, the rate of ACTH secretion is determined by two opposing forces: the sum of the neural and possibly other stimuli converging through the hypothalamus to increase ACTH secretion, and the magnitude of the braking action of glucocorticoids on ACTH secretion, which is proportional to their level in the circulating blood (Figure 20–17).

The dangers involved when prolonged treatment with anti-inflammatory doses of glucocorticoids is stopped deserve emphasis. Not only is the adrenal atrophic and unresponsive after such treatment, but even if its responsiveness is restored by injecting ACTH, the pituitary may be unable to secrete normal amounts of ACTH for as long as a month. The cause of the deficiency is presumably diminished ACTH synthesis. Thereafter, ACTH secretion slowly increases to supranormal levels. These in turn stimulate the adrenal, and glucocorticoid output rises, with feedback inhibition gradually reducing the elevated ACTH levels to normal (Figure 20–18). The complications of sudden cessation of steroid therapy can usually be avoided by slowly decreasing the steroid dose over a long period of time.

ACTIONS

Aldosterone and other steroids with mineralocorticoid activity increase the reabsorption of Na⁺ from the urine, sweat, saliva, and the contents of the colon. Thus, mineralocorticoids cause retention of Na⁺ in the ECF. This expands ECF volume. In the kidneys, they act primarily on the principal cells (P cells) of the collecting ducts (see Chapter 37). Under the influence of aldosterone, increased amounts of Na⁺ are in effect exchanged for K⁺ and H⁺ in the renal tubules, producing a K⁺ diuresis (Figure 20–19) and an increase in urine acidity.

MECHANISM OF ACTION

Like many other steroids, aldosterone binds to a cytoplasmic receptor, and the receptor–hormone complex moves to the nucleus where it alters the transcription of mRNAs. This in turn increases the production of proteins that alter cell function. The aldosterone-stimulated proteins have two effects—a rapid effect, to increase the activity of epithelial sodium channels (ENaCs) by increasing the insertion of these channels into the cell membrane from a cytoplasmic pool; and a slower effect to increase the synthesis of ENaCs. Among the genes activated by aldosterone is the gene for serum-and glucocorticoid regulated kinase (sgk), a serine-threonine protein kinase. The gene for sgk is an early response gene, and sgk increases ENaC activity. Aldosterone also increases the mRNAs for the three subunits that make up ENaCs. The fact that sgk is activated by glucocorticoids as well as aldosterone is not a problem because glucocorticoids are inactivated at mineralocorticoid receptor sites. However, aldosterone activates the genes for other proteins in addition to sgk and ENaCs and inhibits others. Therefore, the exact mechanism by which aldosterone-induced proteins increase Na⁺ reabsorption is still unsettled.

Evidence is accumulating that aldosterone also binds to the cell membrane and by a rapid, nongenomic action increases the activity of membrane Na⁺–K⁺ exchangers. This produces an increase in intracellular Na⁺, and the second messenger involved is probably IP₃. In any case, the principal effect of aldosterone on Na⁺ transport takes 10–30 min to develop and peaks even later (Figure 20–19), indicating that it depends on the synthesis of new proteins by a genomic mechanism.

RELATION OF MINERALOCORTICOID TO GLUCOCORTICOID RECEPTORS

It is intriguing that in vitro, the mineralocorticoid receptor (MR) has an appreciably higher affinity for glucocorticoids than the glucocorticoid receptor does, and glucocorticoids are present in large amounts in vivo. This raises the question of why glucocorticoids do not bind to the mineralocorticoid receptors in the kidneys and other locations and produce mineralocorticoid effects. At least in part, the answer is that the kidneys and other mineralocorticoid-sensitive tissues also contain the enzyme 11β-hydroxysteroid dehydrogenase type 2. This enzyme leaves aldosterone untouched, but it converts cortisol to cortisone (Figure 20–11) and corticosterone to its 11-oxy derivative. These 11-oxy derivatives do not bind to the receptor (Clinical Box 20–3).

OTHER STEROIDS THAT AFFECT NA⁺ EXCRETION

Aldosterone is the principal mineralocorticoid secreted by the adrenals, although corticosterone is secreted in sufficient amounts to exert a minor mineralocorticoid effect (Tables 20–1 and 20–2). Deoxycorticosterone, which is secreted in appreciable amounts only in abnormal situations, has about 3% of the activity of aldosterone. Large amounts of progesterone and some other steroids cause natriuresis, but there is little evidence that they play any normal role in the control of Na⁺ excretion.

EFFECT OF ADRENALECTOMY

In adrenal insufficiency, Na⁺ is lost in the urine; K⁺ is retained, and the plasma K⁺ rises. When adrenal insufficiency develops rapidly, the amount of Na⁺ lost from the ECF exceeds the amount excreted in the urine, indicating that Na⁺ also must be entering cells. When the posterior pituitary is intact, salt loss exceeds water loss, and the plasma Na⁺ falls (Table 20–5). However, the plasma volume is also reduced, resulting in hypotension, circulatory insufficiency and, eventually, fatal shock. These changes can be prevented to a degree by increasing dietary NaCl intake. Rats survive indefinitely on extra salt alone, but in dogs and most humans, the amount of supplementary salt needed is so large that it is almost impossible to prevent eventual collapse and death unless mineralocorticoid treatment is also instituted (see Clinical Box 20–4).

STIMULI

The principal conditions that increase aldosterone secretion are summarized in Table 20–6. Some of them also increase glucocorticoid secretion; others selectively affect the output of aldosterone. The primary regulatory factors involved are ACTH from the pituitary, renin from the kidney via angiotensin II, and a direct stimulatory effect on the adrenal cortex of a rise in plasma K⁺ concentration.

EFFECT OF ACTH

When first administered, ACTH stimulates the output of aldosterone as well as that of glucocorticoids and sex hormones. Although the amount of ACTH required to increase aldosterone output is somewhat greater than the amount that stimulates maximal glucocorticoid secretion (Figure 20–21), it is well within the range of endogenous ACTH secretion. The effect is transient, and even if ACTH secretion remains elevated, aldosterone output declines in 1 or 2 days. On the other hand, the output of the mineralocorticoid deoxycorticosterone remains elevated. The decline in aldosterone output is partly due to decreased renin secretion secondary to hypervolemia, but it is possible that some other factor also decreases the conversion of corticosterone to aldosterone. After hypophysectomy, the basal rate of aldosterone secretion is normal. The increase normally produced by surgical and other stresses is absent, but the increase produced by dietary salt restriction is unaffected for some time. Later on, atrophy of the zona glomerulosa complicates the picture in long-standing hypopituitarism, and this may lead to salt loss and hypoaldosteronism.

Normally, glucocorticoid treatment does not suppress aldosterone secretion. However, an interesting recently described syndrome is glucocorticoid-remediable aldosteronism (GRA). This is an autosomal dominant disorder in which the increase in aldosterone secretion produced by ACTH is no longer transient. The hypersecretion of aldosterone and the accompanying hypertension are remedied when ACTH secretion is suppressed by administering glucocorticoids. The genes encoding aldosterone synthase and 11β-hydroxylase are 95% identical and are close together on chromosome 8. In individuals with GRA, there is unequal crossing over so that the 5′regulatory region of the 11β-hydroxylase gene is fused to the coding region of the aldosterone synthase gene. The product of this hybrid gene is an ACTH-sensitive aldosterone synthase.

EFFECTS OF ANGIOTENSIN II & RENIN

The octapeptide angiotensin II is formed in the body from angiotensin I, which is liberated by the action of renin on circulating angiotensinogen (see Chapter 38). Injections of angiotensin II stimulate adrenocortical secretion and, in small doses, affect primarily the secretion of aldosterone. The sites of action of angiotensin II are both early and late in the steroid biosynthetic pathway. The early action is on the conversion of cholesterol to pregnenolone, and the late action is on the conversion of corticosterone to aldosterone (Figure 20–8). Angiotensin II does not increase the secretion of deoxycorticosterone, which is controlled by ACTH.

Renin is secreted from the juxtaglomerular cells that surround the renal afferent arterioles as they enter the glomeruli (see Chapter 38). Aldosterone secretion is regulated via the renin–angiotensin system in a feedback manner (Figure 20–22). A drop in ECF volume or intra-arterial vascular volume leads to a reflex increase in renal nerve discharge and decreases renal arterial pressure. Both changes increase renin secretion, and the angiotensin II formed by the action of renin increases the rate of secretion of aldosterone. The aldosterone causes Na⁺ and, secondarily, water retention, expanding ECF volume, and shutting off the stimulus that initiated increased renin secretion.

Hemorrhage stimulates ACTH and renin secretion. Like hemorrhage, standing and constriction of the thoracic inferior vena cava decrease intrarenal arterial pressure. Dietary sodium restriction also increases aldosterone secretion via the renin–angiotensin system (Figure 20–23). Such restriction reduces ECF volume, but aldosterone and renin secretion are increased before any consistent decrease in blood pressure takes place. Consequently, the initial increase in renin secretion produced by dietary sodium restriction is probably due to a reflex increase in the activity of the renal nerves. The increase in circulating angiotensin II produced by salt depletion upregulates the angiotensin II receptors in the adrenal cortex and hence increases the response to angiotensin II, whereas it down-regulates the angiotensin II receptors in the blood vessels.

ELECTROLYTES & OTHER FACTORS

An acute decline in plasma Na⁺ of about 20 mEq/L stimulates aldosterone secretion, but changes of this magnitude are rare. However, the plasma K⁺ level need increase only 1 mEq/L to stimulate aldosterone secretion, and transient increases of this magnitude may occur after a meal, particularly if it is rich in K⁺. Like angiotensin II, K⁺ stimulates the conversion of cholesterol to pregnenolone and the conversion of deoxycorticosterone to aldosterone. It appears to act by depolarizing the cell, which opens voltage-gated Ca²⁺ channels, increasing intracellular Ca²⁺. The sensitivity of the zona glomerulosa to angiotensin II and consequently to a low-sodium diet is decreased by a low-potassium diet.

In normal individuals, plasma aldosterone concentrations increase during the portion of the day that the individual is carrying on activities in the upright position. This increase is due to a decrease in the rate of removal of aldosterone from the circulation by the liver and an increase in aldosterone secretion due to a postural increase in renin secretion. Individuals who are confined to bed show a circadian rhythm of aldosterone and renin secretion, with the highest values in the early morning before awakening. Atrial natriuretic peptide (ANP) inhibits renin secretion and decreases the responsiveness of the zona glomerulosa to angiotensin II (see Chapter 38). The mechanisms by which ACTH, angiotensin II, and K⁺ stimulate aldosterone secretion are summarized in Table 20–7.

Variations in aldosterone secretion is only one of many factors affecting Na⁺ excretion. Other major factors include the glomerular filtration rate, ANP, the presence or absence of osmotic diuresis, and changes in tubular reabsorption of Na⁺ independent of aldosterone. It takes some time for aldosterone to act. When one rises from the supine to the standing position, aldosterone secretion increases and Na⁺ is retained from the urine. However, the decrease in Na⁺ excretion develops too rapidly to be explained solely by increased aldosterone secretion. The primary function of the aldosterone-secreting mechanism is the defense of intravascular volume, but it is only one of the homeostatic mechanisms involved in this regulation.

Recapitulating the manifestations of excess and deficiency of the adrenocortical hormones in humans is a convenient way to summarize the multiple and complex actions of these steroids. A characteristic clinical syndrome is associated with excess secretion of each of the types of hormones.

Excess androgen secretion causes masculinization (adrenogenital syndrome) and precocious pseudopuberty or female pseudohermaphroditism.

Excess glucocorticoid secretion produces a moon-faced, plethoric appearance, with trunk obesity, purple abdominal striae, hypertension, osteoporosis, protein depletion, mental abnormalities and, frequently, diabetes mellitus (Cushing syndrome). Excess mineralocorticoid secretion leads to K⁺ depletion and Na⁺ retention, usually without edema but with weakness, hypertension, tetany, polyuria, and hypokalemic alkalosis (hyperaldosteronism). This condition may be due to primary adrenal disease (primary hyperaldosteronism; Conn syndrome) such as an adenoma of the zona glomerulosa, unilateral or bilateral adrenal hyperplasia, adrenal carcinoma, or by GRA. In patients with primary hyperaldosteronism, renin secretion is depressed. Secondary hyperaldosteronism with high plasma renin activity is caused by cirrhosis, heart failure, and nephrosis. Increased renin secretion is also found in individuals with the salt-losing form of the adrenogenital syndrome (see above), because their ECF volume is low. In patients with elevated renin secretion due to renal artery constriction, aldosterone secretion is increased; in those in whom renin secretion is not elevated, aldosterone secretion is normal. The relationship of aldosterone to hypertension is discussed in Chapter 32.

Primary adrenal insufficiency due to disease processes that destroy the adrenal cortex is called Addison disease. The condition used to be a relatively common complication of tuberculosis, but now it is usually due to autoimmune inflammation of the adrenal. Patients lose weight, are tired, and become chronically hypotensive. They have small hearts, probably because the hypotension decreases the work of the heart. Eventually, severe hypotension and shock (addisonian crisis) develop. This is due not only to mineralocorticoid deficiency but to glucocorticoid deficiency as well. Fasting causes fatal hypoglycemia, and any stress causes collapse. Water is retained, and there is always the danger of water intoxication. Circulating ACTH levels are elevated. The diffuse tanning of the skin and the spotty pigmentation characteristic of chronic glucocorticoid deficiency are due, at least in part, to the melanocyte-stimulating hormone (MSH) activity of the ACTH in the blood. Pigmentation of skin creases on the hands and the gums are common. Minor menstrual abnormalities occur in women, but the deficiency of adrenal sex hormones usually has little effect in the presence of normal testes or ovaries.

Secondary adrenal insufficiency is caused by pituitary diseases that decrease ACTH secretion, and tertiary adrenal insufficiency is caused by hypothalamic disorders disrupting CRH secretion. Both are usually milder than primary adrenal insufficiency because electrolyte metabolism is affected to a lesser degree. In addition, there is no pigmentation because in both of these conditions, plasma ACTH is low, not high.

Cases of isolated aldosterone deficiency have also been reported in patients with renal disease and a low circulating renin level (hyporeninemic hypoaldosteronism). In addition, pseudohypoaldosteronism is produced when there is resistance to the action of aldosterone. Patients with these syndromes have marked hyperkalemia, salt wasting, and hypotension, and they may develop metabolic acidosis.

• The adrenal gland consists of the adrenal medulla that secretes dopamine and the catecholamines epinephrine and norepinephrine, and the adrenal cortex that secretes steroid hormones.

• Norepinephrine and epinephrine act on two classes of receptors, α- and β-adrenergic receptors, and exert metabolic effects that include glycogenolysis in liver and skeletal muscle, mobilization of FFA, increased plasma lactate, and stimulation of the metabolic rate.

• The hormones of the adrenal cortex are derivatives of cholesterol and include the mineralocorticoid aldosterone, the glucocorticoids cortisol and corticosterone, and the androgens dehydroepiandrosterone (DHEA) and androstenedione.

• Androgens are the hormones that exert masculinizing effects, and they promote protein anabolism and growth. The adrenal androgen androstenedione is converted to testosterone and to estrogens (aromatized) in fat and other peripheral tissues. This is an important source of estrogens in men and postmenopausal women.

• The mineralocorticoid aldosterone has effects on Na⁺ and K⁺ excretion and glucocorticoids affect glucose and protein metabolism.

• Glucocorticoid secretion is dependent on ACTH from the anterior pituitary and is increased by stress. Angiotensin II increases the secretion of aldosterone.