Physiology 5th Ed.


The adrenal glands are located in the retroperitoneal cavity above each kidney. The adrenal glands are actually two separate glands, the adrenal medulla and the adrenal cortex, whose secretions are essential for life. When corrected for weight, these glands receive among the highest blood flow of any organ in the body.

The adrenal medulla, which is in the inner zone of the gland, composes approximately 20% of the tissue. The adrenal medulla is of neuroectodermal origin and secretes the catecholamines epinephrine and norepinephrine (see Chapter 2).

The adrenal cortex, which is in the outer zone of the gland, is of mesodermal origin and has three distinct layers. It composes 80% of the adrenal tissue and secretes adrenocortical steroid hormones. The adrenal cortex differentiates by gestational week 8 and is responsible for the production of fetal adrenal steroids throughout intrauterine life (see Chapter 10). Soon after birth, the fetal adrenal cortex begins to involute, eventually disappears, and is replaced by the three-layered adult adrenal cortex.

Synthesis of Adrenocortical Steroid Hormones

The adrenal cortex secretes three classes of steroid hormones: glucocorticoids, mineralocorticoids, and androgens. Figure 9-21 shows the three layers of the adrenal cortex in relation to the adrenal medulla. The innermost zone of the cortex, called the zona reticularis, and the middle (and widest) zone, called the zona fasciculata, synthesize and secrete glucocorticoids and adrenal androgens. The outermost zone, called the zona glomerulosa, secretes mineralocorticoids.


Figure 9–21 Secretions of the adrenal medulla and adrenal cortex. The zonae fasciculata and reticularis secrete glucocorticoids and androgens; the zona glomerulosa secretes mineralocorticoids.

Structures of Adrenocortical Steroids

The structures of the major adrenocortical steroids are shown in Figure 9-22, which should be used as a reference throughout this section. All of the steroids of the adrenal cortex are chemical modifications of a basic steroid nucleus, which is illustrated in the structure of cholesterol. The basic nucleus is a carbon skeleton, with carbons numbered from 1 through 21 and four labeled rings: A, B, C, and D. (Cholesterol is called, therefore, a 21-carbon steroid.) The glucocorticoids, represented by cortisol, have a ketone group at carbon 3 (C3) and hydroxyl groups at C11 and C21. The mineralocorticoids,represented by aldosterone, have a double-bond oxygen at C18. The androgens,represented in the adrenal cortex by dehydroepiandrosterone (DHEA) and androstenedione, have a double-bond oxygen at C17; androgens do not have the C20,21 side chain that is present in glucocorticoids and mineralocorticoids. Another androgen, testosterone (not shown in Fig. 9-22), is produced primarily in the testes. Estrogens (not shown), which are aromatized in the A ring and are lacking C19, are produced primarily in the ovaries.


Figure 9–22 Structures of adrenocortical steroids. In the structure of cholesterol, the four rings of the steroid molecules are labeled A, B, C, and D, and the carbon atoms are numbered.

In summary, cholesterol, progesterone, the glucocorticoids, and the mineralocorticoids are 21-carbon steroids; androgens are 19-carbon steroids; and estrogens (produced primarily in the ovaries) are 18-carbon steroids.

Biosynthetic Pathways in the Adrenal Cortex

Figure 9-23 is a schematic diagram of the biosynthetic pathways of the adrenocortical steroids. As noted earlier, the layers of the adrenal cortex are specialized to synthesize and secrete particular steroid hormones: either glucocorticoids and androgens or mineralocorticoids. The basis for this specialization is the presence or absence of the enzymes that catalyze various modifications of the steroid nucleus. For example, the zonae reticularis/fasciculata produce androgenic steroids because they contain 17,20-lyase; on the other hand, the zona glomerulosa produces aldosterone because it contains aldosterone synthase.


Figure 9–23 Biosynthetic pathways for glucocorticoids, mineralocorticoids, and androgens in the adrenal cortex. ACTH, Adrenocorticotropic hormone. The major secretory products of the adrenal cortex are shown in colored boxes.

The precursor for all adrenocortical steroids is cholesterol. Most of the cholesterol is provided to the adrenal cortex via the circulation, and small amounts are synthesized de novo within the adrenal cortical cells. Cholesterol circulates bound to low-density lipoproteins. There are receptors for these lipoproteins in the membranes of adrenocortical cells; the lipoprotein-cholesterol complex binds and is transferred into the cell by endocytosis. Inside the cells, cholesterol is esterified and stored in cytoplasmic vesicles until it is needed for synthesis of steroid hormones.

The enzymes catalyzing the conversion of cholesterol to active steroid hormones require cytochrome P-450, molecular oxygen, and NADPH, which serves as the hydrogen donor for the reducing steps. A flavoprotein enzyme called adrenodoxin reductase and an iron-containing protein called adrenodoxin are intermediates in the transfer of hydrogen from NADPH to the cytochrome P-450 enzymes.

For purposes of illustration, all of the biosynthetic pathways in the adrenal cortex are shown in Figure 9-23. Remember, however, that not all layers of the cortex contain all of the steps in the pathway: Each layer has that portion of the pathway necessary to produce its primary hormones (i.e., glucocorticoids and androgens or mineralocorticoids).

The first step in each pathway is the conversion of cholesterol to pregnenolone, catalyzed by cholesterol desmolase. Thus, all layers of the adrenal cortex contain cholesterol desmolase. Cholesterol desmolase is the rate-limiting enzyme in the pathway, and it is stimulated by ACTH (see further discussion concerning regulation of cortisol secretion). Follow the pathways for the synthesis of cortisol, aldosterone, and DHEA and androstenedione:

image Glucocorticoids (cortisol). The major glucocorticoid produced in humans is cortisol (hydrocortisone), which is synthesized n the zonae fasciculata/reticularis. Thus, the zona fasciculata contains all of the enzymes required to convert cholesterol to cortisol: cholesterol desmolase, which converts cholesterol to pregnenolone; 17α-hydroxylase, which hydroxylates pregnenolone to form 17-hydroxypregnenolone; 3β-hydroxysteroid dehydrogenase, which converts 17-hydroxypregnenolone to 17-hydroxyprogesterone; and 21β-hydroxylase and 11β-hydroxylase, which hydroxylate at C11 and C21 to produce the final product, cortisol. Interestingly, some steps in the cortisol biosynthetic pathway can occur in a different order; for example, hydroxylation at C17 can occur before or after the action of 3β-hydroxysteroid dehydrogenase.

  Cortisol is not the only steroid in the pathway with glucocorticoid activity; corticosterone is also a glucocorticoid. For example, if the 17α-hydroxylase step is blocked, the zona fasciculata still can produce corticosterone without deleterious effect. Thus, cortisol is not absolutely necessary to sustain life as long as corticosterone is being synthesized. Blocks at the cholesterol desmolase, 3β-hydroxysteroid dehydrogenase, 21β-hydroxylase, or 11β-hydroxylase steps are devastating because they prevent the production of cortisol and corticosterone; in these cases, death will ensue without appropriate hormone replacement therapy.

  Metyrapone and ketoconazole are drugs that inhibit glucocorticoid biosynthesis. Metyrapone inhibits 11β-hydroxylase, the last step in cortisol synthesis. Ketoconazole inhibits several steps in the pathway including cholesterol desmolase, the first step.

image Adrenal androgens (DHEA and androstenedione). DHEA and androstenedione are androgenic steroids produced by the zonae fasciculata/reticularis. These compounds have weak androgenic activity, but in the testes, they are converted to testosterone, a more potent androgen. The precursors for the adrenal androgens are 17-hydroxypregnenolone and 17-hydroxyprogesterone, which are converted to androgens by removal of the C20,21 side chain. In males, adrenal androgens are of little significance; the testes produce their own testosterone from cholesterol and do not require the adrenal precursors (seeChapter 10). In females, however, the adrenal cortex is the major source of androgenic compounds.

  Adrenal androgens have a ketone group at C17 that distinguishes them from cortisol, aldosterone, and testosterone. (Cortisol and aldosterone have side chains at C17. Testosterone has a hydroxyl group at C17.) Thus, the major adrenal androgens are called 17-ketosteroids, which can be measured in the urine.

  The zonae fasciculata/reticularis also produce small amounts of testosterone and 17β-estradiol, although the major sources for these hormones are the testes and ovaries, respectively (see Chapter 10).

image Mineralocorticoids (aldosterone). The major mineralocorticoid in the body is aldosterone, which is synthesized only in the zona glomerulosa. The steps required to convert cholesterol to corticosterone are identical to those in the zona fasciculata, and the addition of aldosterone synthase in the zona glomerulosa converts corticosterone to aldosterone. The zona glomerulosa does not produce glucocorticoids for two reasons: (1) Corticosterone, a glucocorticoid, is converted to aldosterone because this zone contains aldosterone synthase, and (2) the zona glomerulosa lacks 17α-hydroxylase and, therefore, is unable to produce cortisol from progesterone.

  Aldosterone is not the only steroid with mineralocorticoid activity; 11-deoxycorticosterone (DOC) and corticosterone also have mineralocorticoid activity. Thus, if the mineralocorticoid pathway is blockedbelow the level of DOC (e.g., absence of 11β-hydroxylase or aldosterone synthase), mineralocorticoids will continue to be produced. However, if the pathway is blocked above the level of DOC (e.g., absence of 21β-hydroxylase), then no mineralocorticoids will be produced.

Regulation of Secretion of Adrenocortical Steroids

As discussed previously, the synthesis and secretion of steroid hormones by the adrenal cortex depend on the stimulation of cholesterol desmolase (the first step) by ACTH. In the absence of ACTH, biosynthesis of adrenocortical steroid hormones ceases. Two questions arise, therefore: What regulates the secretion of ACTH? What special regulatory factors control the functions of the zonae reticularis, fasciculata, and glomerulosa?

image The zonae fasciculata/reticularis, which secrete glucocorticoids and androgens, is under the exclusive control of the hypothalamic-pituitary axis. The hypothalamic hormone is corticotropin-releasing hormone (CRH), and the anterior pituitary hormone is ACTH.

image The zona glomerulosa, which secretes mineralocorticoids, depends on ACTH for the first step in steroid biosynthesis, but otherwise it is controlled separately via the renin-angiotensin-aldosterone system.

Control of the zonae fasciculata and reticularis will be discussed together, and control of the zona glomerulosa will be discussed separately.

Regulation of Glucocorticoid and Adrenal Androgen Secretion

An impressive feature of the regulation of cortisol secretion is its pulsatile nature and its diurnal (daily) pattern (Fig. 9-24). The daily profile of blood cortisol levels is characterized by an average of 10 secretory bursts during a 24-hour period. The lowest secretory rates occur during the evening hours and just after falling asleep (e.g., midnight), and the highest secretory rates occur just before awakening in the morning (e.g., 8 AM). The major burst of cortisol secretion before awakening accounts for one half of the total daily cortisol secretion. Other adrenal steroids (e.g., adrenal androgens) are secreted in similar bursting diurnal patterns. ACTH secretion also exhibits the same diurnal pattern; in fact, it is the pattern of ACTH secretion that drives the diurnal pattern of steroid hormone secretion.


Figure 9–24 Diurnal pattern of cortisol secretion.

The secretion of glucocorticoids by the zonae fasciculata/reticularis is regulated exclusively by the hypothalamic-pituitary axis (Fig. 9-25). CRH is secreted by the hypothalamus and acts on the corticotrophs of the anterior pituitary to cause secretion of ACTH. In turn, ACTH acts on the cells of the adrenal cortex to stimulate the synthesis and secretion of adrenocortical hormones.


Figure 9–25 Regulation of cortisol secretion. ACTH, Adrenocorticotropic hormone; CRH, corticotropin-releasing hormone.

image CRH is a polypeptide containing 41 amino acids. It is secreted by cells of the paraventricular nuclei of the hypothalamus. Like other hypothalamic hormones that act on the anterior pituitary, CRH travels to the pituitary in the hypothalamic-hypophysial portal blood. In the anterior lobe, it acts on the corticotrophs by an adenylyl cyclase/cAMP mechanism to cause secretion of ACTH into the bloodstream.

image ACTH, the anterior pituitary hormone, has several effects on the adrenal cortex. The immediate effects of ACTH are to stimulate transfer of stored cholesterol to the mitochondria, to stimulate binding of cholesterol to cytochrome P-450, and to activate cholesterol desmolase. Long-term effects of ACTH include stimulation of transcription of the genes for cytochrome P-450 and adrenodoxin and up-regulation of ACTH receptors. Chronic effects of elevated ACTH levels include hypertrophy and hyperplasia of the adrenal cortical cells, mediated by local growth factors (e.g., IGF-2).

  As noted, ACTH has a pulsatile and diurnal secretory pattern that drives a parallel pattern of cortisol secretion. The nocturnal peak of ACTH (i.e., preceding awakening) is driven, in turn, by a burst of CRH secretion. The “internal clock” that drives the diurnal pattern can be shifted by alternating the sleep-wake cycle (e.g., varying the time of going to sleep and awakening). The diurnal pattern is abolished by coma, blindness, or constant exposure to either light or dark.

image Negative feedback is exerted by cortisol at three points in the hypothalamic-pituitary axis. (1) Cortisol directly inhibits secretion of CRH from the hypothalamus. (2) Cortisol indirectly inhibits CRH secretion by effects on hippocampal neurons, which synapse on the hypothalamus. (3) Cortisol inhibits the action of CRH on the anterior pituitary, resulting in inhibition of ACTH secretion. Thus, chronicdeficiency of cortisol leads to stimulation of the CRH-ACTH axis and to increased ACTH levels; chronic excess of cortisol leads to inhibition (suppression) of the CRH-ACTH axis and decreased ACTH levels.

image The dexamethasone suppression test is based on the negative feedback effects of cortisol on the CRH-ACTH axis. Dexamethasone is a synthetic glucocorticoid that has all of the actions of cortisol including the negative feedback effect on ACTH secretion. When a low dose of dexamethasone is given to a healthy person, it inhibits (or “suppresses”) ACTH secretion, just as cortisol, the natural glucocorticoid, does. The decreased level of ACTH then causes decreased cortisol secretion, which is measured in the test. The major use of the dexamethasone suppression test is in persons withhypercortisolism (high levels of cortisol). The test is used to determine whether the hypercortisolism is due to an ACTH-secreting tumor or a cortisol-secreting tumor of the adrenal cortex. If the cause of hypercortisolism is an ACTH-secreting tumor of the anterior pituitary, a low dose of dexamethasone does not suppress cortisol secretion but a high dose of dexamethasone does. (The tumor’s ACTH secretion is less sensitive to negative feedback by glucocorticoids than is normal anterior pituitary tissue.) If the cause of hypercortisolism is an adrenal cortical tumor, then neither low-dose nor high-dose dexamethasone suppresses cortisol secretion. (The tumor’s secretion of cortisol is autonomous and is not affected by changes in the ACTH level.)

In addition to negative feedback control by the CRH-ACTH axis, other factors alter ACTH and cortisol secretion (Table 9-10). Many of these factors alter ACTH secretion via effects of higher brain centers on the hypothalamus.

Table 9–10 Factors Affecting ACTH Secretion

Stimulatory Factors

Inhibitory Factors

Decreased blood cortisol levels

Sleep-wake transition

Stress; hypoglycemia; surgery; trauma

Psychiatric disturbances


α-Adrenergic agonists

β-Adrenergic antagonists


Increased blood cortisol levels



ADH, Antidiuretic hormone.

Regulation of Aldosterone Secretion

The regulation of aldosterone secretion by the zona glomerulosa is different from the regulation of the secretion of cortisol and adrenal androgens. Naturally, ACTH remains essential in this process because it stimulates cholesterol desmolase, the first step in the biosynthetic pathway. (Thus, ACTH has a tonic effect on aldosterone secretion.) Like the other adrenal steroid hormones, aldosterone exhibits a diurnal pattern, with the lowest levels occurring at midnight and the highest levels occurring just before awakening. However, the primary regulation of aldosterone secretion occurs not by ACTH, but through changes in ECF volume via the renin–angiotensin II–aldosterone system and through changes in serum potassium (K+) levels.

image Reninangiotensin IIaldosterone. The major control of aldosterone secretion is via the renin–angiotensin II–aldosterone system. The mediator of this regulation is angiotensin II, which increases the synthesis and secretion of aldosterone by stimulating cholesterol desmolase and aldosterone synthase, the first and last steps in the pathway (see Fig. 9-23). In the zona glomerulosa, angiotensin II binds to AT1receptors that are coupled to phospholipase C via a Gq protein. Thus, the second messengers for the action of angiotensin II are IP3/Ca2+.

  Regulation of the renin–angiotensin II–aldosterone axis is described in Chapter 4. Briefly, a decrease in ECF volume (e.g., due to hemorrhage or Na+ depletion) causes a decrease in renal perfusion pressure, which increases renin secretion by the juxtaglomerular cells of the kidney. Renin, an enzyme, catalyzes the conversion of angiotensinogen to angiotensin I, which is inactive. Angiotensin-converting enzyme(ACE) catalyzes the conversion of angiotensin I to angiotensin II, which then acts on the zona glomerulosa to stimulate aldosterone synthesis.

  In light of the role that aldosterone plays in maintaining ECF volume, the control of aldosterone secretion by the renin–angiotensin II–aldosterone system is logical. For example, decreases in ECF volume stimulate aldosterone secretion, and aldosterone stimulates Na+ reabsorption by the kidney to help restore ECF Na+ content and ECF volume.

image Serum K+. The other factor that controls aldosterone secretion is the serum K+ concentration. Increases in serum K+ concentration increase aldosterone secretion, and decreases in serum K+ concentration decrease aldosterone secretion. For example, an increase in serum K+ concentration acts on adrenal cells by depolarizing them and opening voltage-sensitive Ca2+ channels. When Ca2+ channels open, intracellular Ca2+ concentration increases and stimulates aldosterone secretion. In light of the major role that aldosterone plays in maintaining K+ balance, the control of aldosterone secretion by serum K+concentration also is logical. For example, increases in serum K+stimulate aldosterone secretion, and aldosterone increases K+ secretion by the kidney, thereby decreasing serum K+ toward normal.

Actions of Adrenocortical Steroids

Adrenocortical steroids have diverse actions, and the actions are classified as glucocorticoid (cortisol), mineralocorticoid (aldosterone), or androgenic (DHEA and androstenedione). As steroid hormones, these actions first require transcription of DNA, synthesis of specific mRNAs, and induction of new protein synthesis. These new proteins confer specificity to the steroid hormone actions in target tissues (Table 9-11).

Table 9–11 Actions of Adrenocortical Steroids

Actions of Glucocorticoids

Actions of Mineralocorticoids

Actions of Adrenal Androgens

Increase gluconeogenesis

Increase proteolysis (catabolic)

Increase lipolysis

Decrease glucose utilization

Decrease insulin sensitivity

Inhibit inflammatory response

Suppress immune response

Enhance vascular responsiveness to catecholamines

Inhibit bone formation

Increase GFR

Decrease REM sleep

Increase Na+ reabsorption

Increase K+ secretion

Increase H+ secretion

Females: stimulate growth of pubic and axillary hair; stimulate libido

Males: same as testosterone

GFR, Glomerular filtration rate; REM, rapid eye movement.

Actions of Glucocorticoids

Glucocorticoids are essential for life. If the adrenal cortex is removed or is not functioning, exogenous glucocorticoids must be administered or death will ensue. The actions of glucocorticoids (e.g., cortisol) are essential for gluconeogenesis, vascular responsiveness to catecholamines, suppression of inflammatory and immune responses, and modulation of CNS function.

image Stimulation of gluconeogenesis. A major action of cortisol is to promote gluconeogenesis and storage of glycogen. Overall, the effects of cortisol are catabolic and diabetogenic. Cortisol affects protein, fat, and carbohydrate metabolism in a coordinated fashion to increase glucose synthesis as follows: Cortisol increases protein catabolism in muscle and decreases new protein synthesis, thereby providing additional amino acids to the liver for gluconeogenesis. Cortisol increases lipolysis, which provides additional glycerol to the liver for gluconeogenesis. Finally, cortisol decreases glucose utilization by tissues and decreases the insulin sensitivity of adipose tissue. Glucocorticoids are essential for survival during fasting because they stimulate these gluconeogenic routes. In hypocortisolism (e.g., primary adrenal insufficiency, Addison disease), there is hypoglycemia. In hypercortisolism (e.g., Cushing syndrome), there is hyperglycemia.

image Anti-inflammatory effects. Cortisol has three actions that interfere with the body’s inflammatory response to trauma and irritants. (1) Cortisol induces the synthesis of lipocortin, an inhibitor of the enzyme phospholipase A2. Phospholipase A2 liberates arachidonic acid from membrane phospholipids and provides the precursor for the prostaglandins and leukotrienes that mediate the inflammatory response. Therefore, this component of the antiinflammatory effect of cortisol is based on inhibiting the synthesis of the precursor to prostaglandins and leukotrienes. (2) Cortisol inhibits the production of interleukin-2(IL-2) and the proliferation of T lymphocytes. (3) Cortisol inhibits the release of histamine and serotonin from mast cells and platelets.

image Suppression of immune response. As previously noted, cortisol inhibits the production of IL-2 and the proliferation of T lymphocytes, which also are critical for cellular immunity. Exogenous glucocorticoids can be administered therapeutically to suppress the immune response and prevent the rejection of transplanted organs.

image Maintenance of vascular responsiveness to catecholamines. Cortisol is necessary for the maintenance of normal blood pressure and plays a permissive role in the arterioles by up-regulating α1-adrenergic receptors. In this way, cortisol is required for the vasoconstrictive response of the arterioles to catecholamines. In hypocortisolism, there is hypotension; in hypercortisolism, there is hypertension.

image Inhibition of bone formation. Cortisol inhibits bone formation by decreasing the synthesis of type I collagen, the major component of bone matrix; by decreasing formation of new bone by osteoblasts; and by decreasing intestinal Ca2+ absorption.

image Increases in glomerular filtration rate (GFR). Cortisol increases GFR by causing vasodilation of afferent arterioles, thereby increasing renal blood flow and GFR.

image Effects on CNS. Glucocorticoid receptors are found in the brain, particularly in the limbic system. Cortisol decreases REM sleep, increases slow-wave sleep, and increases awake time. (Recall that the largest bursts of ACTH and cortisol occur just before awakening.)

Actions of Mineralocorticoids

The actions of mineralocorticoids (e.g., aldosterone) are described in detail in Chapter 6. Briefly, aldosterone has three actions on the late distal tubule and collecting ducts of the kidney: It increases Na+reabsorption, it increases K+secretion, and it increases H+ secretion. Its effects on Na+ reabsorption and K+ secretion are on the principal cells, and its effect on H+ secretion is on the α-intercalated cells. Thus, when aldosterone levels are increased (e.g., due to an aldosterone-secreting tumor), Na+ reabsorption, K+ secretion, and H+ secretion all are increased. These changes in renal transport result in ECF volume expansion and hypertension, hypokalemia, and metabolic alkalosis. Conversely, when aldosterone levels are decreased (e.g., due to adrenal insufficiency), Na+ reabsorption, K+ secretion, and H+secretion all are decreased. These changes produce ECF volume contraction and hypotension, hyperkalemia, and metabolic acidosis.

An interesting “problem” arises with respect to the actions of mineralocorticoids in their target tissues (i.e., late distal tubule and collecting ducts of the kidney). That is, the affinity of mineralocorticoid receptors for cortisol is, surprisingly, just as high as their affinity for aldosterone. Because circulating levels of cortisol are much higher than circulating levels of aldosterone, it seems that cortisol would overwhelm and dominate the mineralocorticoid receptors. How would the kidneys know that a change in aldosterone concentration had occurred and that mineralocorticoid actions are desired? The “problem” is solved by the renal cells themselves. They contain the enzyme 11β-hydroxysteroid dehydrogenase, which converts cortisol to cortisone; in contrast to cortisol, cortisone has a low affinity for mineralocorticoid receptors. In this way, cortisol is effectively inactivated in mineralocorticoid target tissues. This unique solution allows changes in blood levels of aldosterone to be “seen” by the renal cells and not be overshadowed by the high circulating levels of cortisol. This inactivation of cortisol in mineralocorticoid target tissues also explains why, when circulating levels of cortisol are high, the cortisol has only weak mineralocorticoid activity (despite its high affinity for mineralocorticoid receptors).

Actions of Adrenal Androgens

The adrenal cortex produces the androgenic compounds, DHEA and androstenedione, which are converted to testosterone primarily in the testes. In males, adrenal androgens play only a minor role because de novo synthesis of testosterone from cholesterol in the testes is much greater than testosterone synthesis from adrenal androgenic precursors. In females, however, adrenal androgens are the major androgens, and they are responsible for the development of pubic and axillary hair and for libido.

In conditions such as adrenogenital syndrome, in which there is increased synthesis of adrenal androgens, the high levels of DHEA and androstenedione lead to masculinization in females, early development of axillary and pubic hair, and suppression of gonadal function in both males and females. Also, in the adrenogenital syndromes, due to the overproduction of adrenal androgens, there will be increased urinary levels of 17-ketosteroids.

Pathophysiology of the Adrenal Cortex

Disorders involving the adrenal cortex are characterized by either an excess or a deficiency of adrenocortical hormones. When evaluating the pathophysiology of these disorders, it is helpful to consider the following issues:

1.          What are the symptoms and signs? Are the signs and symptoms consistent with an excess or a deficiency of one or more of the adrenocortical hormones? The normal physiologic effects of each of the adrenocortical hormones can be used to predict the effects of hormonal excess or deficiency (see Table 9-11). A few examples are cited here.

  Cortisol promotes gluconeogenesis, and therefore, excess levels of cortisol will produce hyperglycemia; deficits of cortisol will produce hypoglycemia upon fasting. Aldosterone causes increased K+secretion by the renal principal cells; thus excess aldosterone will cause increased K+ secretion and hypokalemia, and deficiency of aldosterone will cause decreased K+ secretion and hyperkalemia. Aldosterone also causes increased Na+reabsorption by the principal cells; thus, excess aldosterone causes ECF volume expansion and hypertension, and deficiency of aldosterone causes ECF volume contraction and hypotension. Because adrenal androgens have testosterone-like effects, overproduction causes masculinization in females (e.g., hirsutism); deficits of adrenal androgens result in loss of pubic and axillary hair and decreased libido in females.

2.          What is the etiology of the disorder? Disorders of the adrenal cortex can be caused by a primary defect in the adrenal cortex or by a primary defect in the hypothalamic-pituitary axis. Or, in the case of aldosterone, the defect may be in the renin-angiotensin II axis. For example, symptoms consistent with overproduction of an adrenocortical hormone (e.g., hypercortisolism) may be caused by a primary defect in the adrenal cortex. Or, the symptoms may be caused by a primary defect in the anterior pituitary or the hypothalamus, which then produces a secondary effect on the adrenal cortex. The etiology of the disorder may not be deduced until circulating levels of CRH and ACTH are measured and the feedback regulation of the CRH-ACTH axis is evaluated.

  For disorders caused by enzyme deficiencies in the steroid hormone biosynthetic pathway, the pathways can be visualized to predict the effects of a given enzyme block (see Fig. 9-23). For example, a woman with masculinization also has symptoms consistent with aldosterone deficiency (e.g., hyperkalemia) and cortisol deficiency (e.g., hypoglycemia). This constellation of symptoms suggests that there is an enzyme block preventing the synthesis of all mineralocorticoids and all glucocorticoids (e.g., deficiency of 21β-hydroxylase). Because of the block, steroid intermediates are “shunted” toward androgen production and the increased adrenal androgen levels cause masculinization. To understand the pathophysiology of the adrenal cortex, use the biosynthetic pathway shown in Figure 9-23 in combination with the actions of the steroid hormones summarized in Table 9-11. The features of each disorder are summarized in Table 9-12.

Table 9–12 Pathophysiology of the Adrenal Cortex


Addison Disease

Addison disease, or primary adrenocortical insufficiency, is commonly caused by autoimmune destruction of all zones of the adrenal cortex (Box 9-2). In this disease, there is decreased synthesis of all adrenocortical hormones, resulting in decreased circulating levels of cortisol, aldosterone, and adrenal androgens. The symptoms of Addison disease can be predicted on the basis of the known physiologic effects of these hormones. The loss of glucocorticoids (cortisol) produces hypoglycemia, anorexia, weight loss, nausea and vomiting, and weakness. The loss of mineralocorticoids (aldosterone) produces hyperkalemia, metabolic acidosis, and hypotension (due to decreased ECF volume). In women, the loss of the adrenal androgens, DHEA and androstenedione, results in decreased pubic and axillary hair and decreased libido.

BOX 9–2 Clinical Physiology: Addison Disease

DESCRIPTION OF CASE. A 45-year-old woman is admitted to the hospital with a history of progressive weakness and weight loss, occasional nausea, and darkening skin pigmentation. On physical examination, she is thin, has dark skin creases, and has diminished axillary and pubic hair. Her blood pressure is 120/80 when supine and 106/50 when standing. Her pulse rate is 100/minute when supine and 120/minute when standing. Laboratory studies yield the following values:



[Na+] 120 mEq/L

Na+, increased

[K+], 5.8 mEq/L

K+, decreased

[HCO3], 120 mEq/L

pH, increased

Osmolarity, 254 mOsm/L

Osmolarity, 450 mOsm/L

Arterial blood gases are consistent with metabolic acidosis. Blood urea nitrogen (BUN) and serum creatinine are increased. Her blood glucose concentration is low-normal, and she becomes hypoglycemic upon fasting. Serum levels of ACTH are elevated. An ACTH stimulation test shows a “flat” cortisol response (i.e., the adrenal cortex did not respond to ACTH).

The woman is treated with cortisol, taken twice daily, early morning and late afternoon, and fludrocortisone, a synthetic mineralocorticoid.

EXPLANATION OF CASE. The woman has primary adrenocortical insufficiency (Addison disease), in which all layers of the adrenal cortex are destroyed. None of the adrenocortical hormones, glucocorticoids, mineralocorticoids, and adrenal androgens are secreted in adequate amounts. Decreased blood levels of cortisol, via negative feedback mechanisms, then cause increased secretion of ACTH by the anterior lobe of the pituitary. The woman’s abnormal serum and urine values, orthostatic hypotension, hypoglycemia, decreased body hair, and hyperpigmentation can be explained by decreased circulating levels of adrenocortical steroids as follows:

The woman has increased serum [K+] (hyperkalemia) and metabolic acidosis. Simultaneously, urinary excretion of K+ is decreased, and urine pH is increased. These disturbances of K+ and acid-base balance are caused by the loss of the adrenocortical hormone aldosterone. Normally, aldosterone stimulates K+ and H+ secretion in the renal distal tubule and collecting duct. Therefore, when there is a deficiency of aldosterone, the kidney secretes inadequate amounts of K+ and H+, elevating their respective blood levels and causing hyperkalemia and metabolic acidosis. (Accordingly, the excretion of K+ and H+ in urine is decreased.)

When the woman moves from a supine to a standing position, her blood pressure decreases and her pulse rate increases. Orthostatic hypotension, the decrease in blood pressure upon standing, is explained by a deficiency of aldosterone and a deficiency of cortisol. In addition to its effects on K+ and H+ secretion, aldosterone stimulates renal Na+ reabsorption. When aldosterone is deficient, there is inadequate renal Na+ reabsorption, which results in decreased body Na+ content, decreased ECF volume and blood volume, and decreased arterial blood pressure (especially when standing). Lack of cortisol contributes to her hypotension by reducing vascular responsiveness to catecholamines. The increased pulse rate upon standing reflects the response of the baroreceptor reflex to this orthostatic decrease in blood pressure. A component of the baroreceptor reflex response is increased heart rate, which attempts to restore blood pressure back to normal. The woman’s elevated BUN and serum creatinine reflect a decreased GFR, which is consistent with decreased ECF volume (i.e., prerenal azotemia).

The woman’s decreased serum [Na+] and serum osmolarity are secondary to the ECF volume contraction. When ECF volume decreases by 10% or more, ADH secretion is stimulated. ADH then circulates to the kidney, stimulating water reabsorption, as reflected in the hyperosmotic urine. The reabsorbed water is added to the body fluids, diluting them, as reflected in the decreased [Na+] and osmolarity. ADH secreted under such hypovolemic conditions is quite appropriate for her volume status but inappropriate for her serum osmolarity.

Hypoglycemia, nausea, weight loss, and weakness are caused by a deficiency of glucocorticoids. The decreased body Na+ content and decreased ECF volume also contribute to weight loss because a large percentage of body weight is water.

Hyperpigmentation resulted from negative feedback on the anterior pituitary by the low circulating cortisol levels. The decreased levels of cortisol stimulate secretion of ACTH, which contains the α-MSH fragment. When circulating levels of ACTH are elevated, as in Addison disease, the α-MSH component of the molecule produces darkening skin pigmentation.

The woman has decreased pubic and axillary hair from the loss of the adrenal androgens, DHEA and androstenedione. (In females, adrenal androgens are the major source of androgens.)

TREATMENT. Treatment of this patient consists of replacing the missing adrenocortical steroid hormones, which are necessary for life. She is given a synthetic mineralocorticoid (fludrocortisone) and a glucocorticoid (cortisol). Cortisol is administered twice daily, a large dose in early morning and a smaller dose in late afternoon, to simulate the normal diurnal pattern of cortisol secretion.

Addison disease also is characterized by hyperpigmentation of the skin, particularly of the elbows, knees, nail beds, nipples, areolae, and on recent scars. Hyperpigmentation is a result of increased levels of ACTH (which contains the α-MSH fragment). Hyperpigmentation, therefore, provides an important clue about the etiology of Addison disease: ACTH levels must be high, not low, and the cause of the hypocortisolism must not be a primary defect in ACTH secretion from the anterior pituitary. Rather, the hypocortisolism of Addison disease must be due to a primary defect in the adrenal cortex itself (i.e., primary adrenal insufficiency), with low levels of cortisol then causing an increase in ACTH secretion by negative feedback (see Fig. 9-25).

Treatment of Addison disease includes glucocorticoid and mineralocorticoid replacement.

Secondary Adrenocortical Insufficiency

Conditions of secondary adrenocortical insufficiency occur when there is insufficient CRH (uncommon) or insufficient ACTH (resulting from failure of corticotrophs in the anterior pituitary to secrete ACTH). In either case, there is decreased ACTH, which then decreases cortisol secretion by the adrenal cortex. The cortisol deficiency then produces many of the symptoms that occur in primary adrenocortical insufficiency (e.g., hypoglycemia). There are, however, several distinctions between primary and secondary adrenocortical insufficiency. (1) In secondary adrenocortical insufficiency, ACTH levels are low, not high. (2) In secondary adrenocortical insufficiency, aldosterone levels usually are normal because aldosterone synthesis by the zona glomerulosa requires only tonic levels of ACTH. If aldosterone levels are normal, hyperkalemia, metabolic acidosis, and ECF volume contraction are not present. (3) In secondary adrenocortical insufficiency, hyperpigmentation does not occur because levels of ACTH (containing the α-MSH fragment) are low, not high as occurs in Addison disease.

Cushing Syndrome

Cushing syndrome is the result of chronic excess of glucocorticoids. It can be caused by spontaneous overproduction of cortisol by the adrenal cortex or from the administration of pharmacologic doses of exogenous glucocorticoids. Cushing disease is a separate entity, also characterized by excess glucocorticoids, in which the cause is hypersecretion of ACTH from a pituitary adenoma (which then drives the adrenal cortex to secrete excess cortisol).

The symptoms of either Cushing syndrome or Cushing disease are the result of excessive glucocorticoids and adrenal androgens (Fig. 9-26). Excess cortisol causes hyperglycemia, increased proteolysis and muscle wasting, increased lipolysis and thin extremities, central obesity, round face, supraclavicular fat, buffalo hump, poor wound healing, osteoporosis, and striae (caused by a loss of connective tissue). Hypertension occurs because cortisol has weak mineralocorticoid activity and because cortisol increases the responsiveness of arterioles to catecholamines (by up-regulating α1 receptors). Excess androgens cause virilization and menstrual disorders in females.


Figure 9–26 Drawing of a woman with Cushing disease. Note the central obesity, buffalo hump, muscle wasting, and striae.

Cushing syndrome and Cushing disease exhibit similar clinical features, but they differ in the circulating levels of ACTH. In Cushing syndrome, the primary defect is in the adrenal cortex, which is overproducing cortisol. Accordingly, ACTH levels are low because the high cortisol levels feed back on the anterior pituitary and inhibit ACTH secretion. In Cushing disease, the primary defect is in the anterior pituitary, which is overproducing ACTH; ACTH levels are elevated. As already described, the dexamethasone suppression test, in which a synthetic glucocorticoid is administered, can distinguish between the two disorders. In Cushing syndrome (primary adrenal defect with a normal CRH-ACTH axis), because the adrenal tumor functions autonomously, cortisol secretion is not suppressed by either low- or high-dose dexamethasone. In Cushing disease, ACTH and cortisol secretion are suppressed by high-dose dexamethasone but not by low-dose dexamethasone.

Treatment of Cushing syndrome includes administration of drugs such as ketoconazole or metyrapone, which block steroid hormone biosynthesis. If drug treatment is ineffective, then bilateral adrenalectomy coupled with steroid hormone replacement may be required. Because of its different etiology, treatment of Cushing disease involves surgical removal of the ACTH-secreting tumor.

Conn Syndrome

Conn syndrome, or primary hyperaldosteronism, is caused by an aldosterone-secreting tumor. The symptoms of Conn syndrome are explainable by the known physiologic actions of aldosterone: Na+reabsorption, K+ secretion, and H+ secretion. The effects of excess aldosterone are increased ECF volume and hypertension (due to increased Na+ reabsorption), hypokalemia (due to increased K+ secretion), and metabolic alkalosis (due to increased H+ secretion). In Conn syndrome, circulating renin levels are decreased because the increased ECF volume (caused by high levels of aldosterone) increases renal perfusion pressure, which inhibits renin secretion. Treatment of Conn syndrome consists of administration of an aldosterone antagonist such as spironolactone, followed by surgical removal of the aldosterone-secreting tumor.

21β-Hydroxylase Deficiency

Several congenital abnormalities are associated with enzyme defects in the steroid hormone biosynthetic pathways. The most common enzymatic defect is deficiency of 21β-hydroxylase, which belongs to a group of disorders called adrenogenital syndrome. Review Figure 9-23 to understand the consequences of this enzyme deficiency. Without 21β-hydroxylase, the adrenal cortex is unable to convert progesterone to 11-deoxycorticosterone (DOC) or to convert 17-hydroxyprogesterone to 11-deoxycortisol. In other words, the adrenal cortex does not synthesize mineralocorticoids or glucocorticoids, resulting in predictable symptoms (as previously discussed). Steroid intermediates will accumulate above the enzyme block and be shunted toward production of the adrenal androgens, DHEA and androstenedione, which then cause virilization in females. There will be increased urinary levels of 17-ketosteroids. If the defect is present in utero in a female fetus, the excess androgens cause masculinization of the external genitalia, with a penis-like clitoris and scrotum-like labia. If untreated in childhood, the androgen excess will cause an acceleration of linear growth, the early appearance of pubic and axillary hair, and suppression of gonadal function. ACTH levels will be elevated because of negative feedback on the anterior pituitary by the low cortisol levels, and these high ACTH levels will have a trophic effect on the adrenal cortex and cause adrenocortical hyperplasia. (Thus, the other name for this group of disorders is congenital adrenal hyperplasia.) Treatment of 21β-hydroxylase deficiency consists of replacement of both glucocorticoids and mineralocorticoids.

17α-Hydroxylase Deficiency

A less-common congenital abnormality of the steroid hormone biosynthetic pathway is deficiency of 17α-hydroxylase. The consequences of this defect differ from those of 21β-hydroxylase deficiency. Examination of Figure 9-23shows that without 17α-hydroxylase, pregnenolone cannot be converted to 17-hydroxypregnenolone and progesterone cannot be converted to 17-hydroxyprogesterone. As a result, neither glucocorticoids nor adrenal androgens will be produced by the adrenal cortex. The absence of cortisol will cause predictable effects (e.g., hypoglycemia), and the absence of adrenal androgens will result in the lack of pubic and axillary hair in females. In this disorder, steroid intermediates accumulate to the left of the enzyme block and will be shunted toward mineralocorticoids; there will be overproduction of 11-deoxycorticosterone and corticosterone, both of which have mineralocorticoid activity. The resulting high levels of mineralocorticoids then cause hypertension, hypokalemia, and metabolic alkalosis.

Interestingly, the levels of aldosterone itself are actually decreased in 17α-hydroxylase deficiency. Why would this be so, if steroid intermediates are shunted toward the production of mineralocorticoids? The answer lies in the feedback regulation of the renin–angiotensin II–aldosterone system. The increased levels of 11-deoxycorticosterone and corticosterone cause symptoms of mineralocorticoid excess: hypertension, metabolic alkalosis, and hypokalemia. Hypertension inhibits renin secretion, thus leading to decreased levels of angiotensin II and aldosterone; hypokalemia also inhibits aldosterone secretion directly.