ADRENAL

DEVELOPMENT OF THE ADRENAL GLANDS

The detailed anatomy of the adrenal glands was first described by Bartholomeo Eustacius in 1563. Each adrenal gland consists of two parts—the cortex and medulla—that are enveloped in a common capsule. The cortex is derived from mesenchymal tissue and the medulla from ectodermal tissue. From the fifth to sixth week of embryogenesis, the cortical portion of each adrenal gland begins as a proliferation of cells, which originate from the coelomic cavity lining adjacent to the urogenital ridge. The cells proliferate rapidly and penetrate the retroperitoneal mesenchyme to form the primitive cortex. The primitive cortex soon becomes enveloped by a thin layer of more compactly arranged cells that become the permanent cortex, the cells being derived from the same source as those of the primitive cortex. By the eighth week, the cortical tissue has an intimate relationship with the cranial pole of the kidney. Toward the end of the eighth week, the cortical mass attains a considerable size, separates from its peritoneal mesothelial cell layer of origin, and becomes invested in the capsule of connective tissue. At this time, the developing adrenal gland is much larger than the developing kidney.

The primitive, or fetal, cortex constitutes the chief bulk of the adrenal glands at birth. By the second week after birth, the adrenal glands lose one-third of their weight; this is a result of the degeneration of the bulky primitive cortex, which disappears by the end of the first year of life. The outer permanent cortex, which is thin at birth, begins to differentiate as the inner primitive cortex undergoes involution. However, full differentiation of the permanent cortex into the three zones of the adult gland (glomerulosa, fasciculata, and reticularis) is not completed until about the third year after birth. The differentiation of the adrenal cortex is dependent on the temporal expression of transcription factors (e.g., steroidogenic factor 1, zona glomerulosa–specific protein, and inner zone antigen).

Certain ectodermal cells arise from the neural crest and migrate from their source of origin to differentiate into sympathetic neurons of the autonomic nervous system. However, not all of the cells of the primitive autonomic ganglia differentiate into neurons. Some become endocrine cells, designated as chromaffin cells because they stain brown with chromium salts. Cytoplasmic granules turn dark when stained with chromic acid because of the oxidation of epinephrine and norepinephrine to melanin. Certain chromaffin cells migrate from the primitive autonomic ganglia adjacent to the developing cortex to give rise eventually to the medulla of the adrenal glands. When the cortex of the adrenal gland has become a prominent structure (during the seventh week of embryogenesis), masses of these migrating chromaffin cells come into contact with the cortex and begin to invade it on its medial side. By the middle of fetal life, some of the chromaffin cells have migrated to the central position within the cortex. Some chromaffin cells also migrate to form paraganglia, collections of chromaffin cells on both sides of the aorta. The largest cluster of chromaffin cells outside the adrenal medulla is near the level of the inferior mesenteric artery and is referred to as the organ of Zuckerkandl , which is quite prominent in fetuses and is a major source of catecholamines in the first year of life.

True accessory adrenal glands, consisting of both cortex and medulla, are rarely found in adults. When they are present, they may be within the celiac plexus or embedded in the cortex of the kidney. Adrenal rests, composed of only cortical tissue, occur frequently and are usually located near the adrenal glands. In adults, accessory separate cortical or medullary tissue may be present in the spleen, in the retroperitoneal area below the kidneys, along the aorta, or in the pelvis. Because the adrenal glands are situated close to the gonads during their early development, accessory tissue may also be present in the spermatic cord, attached to the testis in the scrotum, attached to the ovary, or in the broad ligament of the uterus. Although one adrenal gland may be absent occasionally, complete absence of the adrenal glands is extremely rare.

ANATOMY AND BLOOD SUPPLY OF THE ADRENAL GLANDS

The adrenal glands are two small triangular structures located retroperitoneally at the upper poles of the kidneys. They are found on the posterior parietal wall, on each side of the vertebral column, at the level of the 11th thoracic rib and lateral to the first lumbar vertebra. The typical weight of each adrenal gland is 3.5 to 6.0 g. The surface of the gland is corrugated or nodular to a variable extent. Each gland measures 2 to 3 cm in width, 4 to 6 cm in length, and 0.3 to 0.6 cm in thickness. They are surrounded by areolar tissue, containing much fat and covered by a thin, fibrous capsule attached to the gland by many fibrous bands. The adrenal glands have their own fascial supports so they do not descend with the kidneys when these are displaced. The glands appear golden-yellow, distinct from the paler surrounding fat. The cut section demonstrates a golden cortical layer and a flattened mass of darker (reddish-brown) medullary tissue.

The right adrenal gland is pyramidal or triangular in shape. It occupies a somewhat higher and more lateral position than does the left one. Its posterior surface is in close apposition to the right diaphragmatic crus. The gland is located retroperitoneally in the recess, bounded superiorly by the posteroinferior border of the right lobe of the liver and medially by the right border of the inferior vena cava. The base of the pyramid is in close apposition to the anteromedial aspect of the upper pole of the right kidney.

The left adrenal gland is generally elongated or semilunar in shape and is a little larger than the right one. It is more centrally located, its medial border frequently overlapping the lateral border of the abdominal aorta. Its posterior surface is in close relationship to the diaphragm and to the splanchnic nerves. The upper two-thirds of the gland lie behind the posterior peritoneal wall of the lesser sac. The lower third is in close relationship to the posterior surface of the body of the pancreas and to the splenic vessels.

The adrenal glands have a very rich vascular supply, characterized by the following features:

• 1.

  Unlike those in other organs, the arteries and veins do not usually run together.

• 2.

  The arterial supply is abundant, with as many as 12 small arteries.

• 3.

  The venous blood is channeled almost completely through a large, single venous trunk that is easily identified.

Arterial blood reaches the adrenal glands through a variable number of slender, short, twiglike arteries, encompassing the gland in an arterial circle (see Plate 3-5 ). Three types must be distinguished: short capsular arterioles, intermediate cortical ones, and long branches that go through the cortex to the medulla and its sinusoids. These small arteries are terminal branches of the inferior phrenic artery superiorly forming the superior adrenal artery (located along the superior medial margin of the gland). The middle adrenal artery arises from the aorta; the inferior adrenal artery on the inferomedial margin of the adrenal gland arises from the renal artery. This general pattern is occasionally supplemented by additional branches from vessels adjacent to the gland, such as the ovarian artery in females or the internal spermatic artery in males (on the left side).

Venous blood from the right adrenal gland empties into the vena cava through the right adrenal vein. This vein is short, generally measuring only 4 to 5 mm, and is located in an indentation on the anteromedial aspect of the right adrenal gland at the junction of the upper and middle thirds. On the left side, the left adrenal vein is situated inferomedially and empties directly into the left renal vein. The left adrenal vein is often joined by the left inferior phrenic vein before it empties into the left renal vein.

Arterial and venous capillaries within the adrenal gland help to integrate the function of the cortex and medulla. For example, cortisol-enriched blood flows from the cortex to the medulla, where cortisol enhances the activity of phenylethanolamine- N -methyltransferase that converts norepinephrine to epinephrine. Extra-adrenal chromaffin tissues lack these high levels of cortisol and produce norepinephrine almost exclusively.

SURGICAL APPROACHES TO THE ADRENAL GLANDS

The pathologic process, tumor size, patient size, and previous operations are all factors that help determine the surgical approach to the adrenal glands. No one particular approach can be considered suitable for all cases, and the removal of a diseased gland or an adrenal tumor may, at times, present formidable difficulties.

Open Transabdominal Adrenalectomy

The patient is in the supine position, and the incision is typically in an extended subcostal location. A midline incision may be used if the patient has a narrow costal angle or bilateral adrenal disease is present. The approach to the left adrenal gland is typically through the gastrocolic ligament into the lesser sac. The left adrenal is exposed by lifting the inferior surface of the pancreas upward, Gerota fascia is opened, and the upper pole of the kidney is retracted inferiorly. The approach to the right adrenal gland involves mobilizing the hepatic flexure of the colon inferiorly and retracting the right lobe of the liver upward.

Open Posterior Adrenalectomy

Compared with the open anterior approach, the open posterior approach causes less pain, ileus, and other complications. The patient is in the prone position and the incision is either curvilinear extending from the 10th rib (4 cm from the midvertebral line) to the iliac crest (8 cm from the midvertebral line) or a single straight incision over the 12th rib with a small vertical paravertebral upward extension. The 12th rib is resected, the pleura is reflected upward, and Gerota fascia is incised.

Laparoscopic Transabdominal Adrenalectomy

Since its description in 1992, laparoscopic adrenalectomy has rapidly become the procedure of choice for unilateral adrenalectomy when the adrenal mass is smaller than 8 cm and there are no frank signs of malignancy (e.g., invasion of contiguous structures). The postoperative recovery time and long-term morbidity associated with laparoscopic adrenalectomy are significantly reduced compared with open adrenalectomy. The patient is placed in the lateral decubitus position with the side to be operated facing upward. Four trocars are placed in a straight line, 1 to 2 cm below the subcostal margin. On the right side, the liver with the gallbladder is retracted upward, and the retroperitoneum is incised. On the left side, the left colonic flexure and the descending colon are mobilized inferiorly and medially to expose the upper pole of the left kidney, and the retroperitoneum is incised.

Posterior Retroperitoneoscopic Adrenalectomy

A minimally invasive posterior approach to the adrenal is favored by some endocrine surgeons and is advantageous in patients who have had previous anterior upper abdominal operations. The patient is in the prone position, and three trocars are used. A gas pressure of 20 to 25 mm Hg allows the creation of sufficient space in the retroperitoneum to facilitate the operation.

Keys to Successful Adrenal Surgery

The keys to successful adrenal surgery are appropriate patient selection, knowledge of anatomy, delicate tissue handling, meticulous hemostasis, and experience with the approach used. Familiarity with the vascular anomalies of the blood supply of the adrenal glands is indispensable. Finally, the gland should be handled gently because it fractures easily when traumatized, jeopardizing its complete removal.

INNERVATION OF THE ADRENAL GLANDS

Relative to their size, the adrenal glands have a richer innervation than other viscera. The sympathetic preganglionic fibers for these glands are the axons of cells located in the intermediolateral columns of the lowest two or three thoracic and highest one or two lumbar segments of the spinal cord. They emerge in the anterior rootlets of the corresponding spinal nerves; pass in the white rami communicantes to the homolateral sympathetic trunks; and leave them in the greater, lesser, and least thoracic and first lumbar splanchnic nerves, which run to the celiac, aorticorenal, and renal ganglia. Some fibers end in these ganglia, but most pass through them without relaying and enter numerous small nerves that run outward on each side from the celiac plexus to the adrenal glands. These nerves are joined by direct contributions from the terminal parts of the greater and lesser thoracic splanchnic nerves, and they communicate with the homolateral phrenic nerve and renal plexus. Small ganglia exist on the adrenal nerves and within the actual adrenal medulla; a proportion of sympathetic fibers may relay in these ganglia.

Parasympathetic fibers are conveyed to the celiac plexus in the celiac branch of the posterior vagal trunk, and some of these are involved with adrenal innervation and may relay in ganglia in or near the gland.

On each side, the adrenal nerves form an adrenal plexus along the medial border of the adrenal gland. Filaments associated with occasional ganglion cells spread out over the gland to form a delicate subcapsular plexus, from which fascicles or solitary fibers penetrate the cortex to reach the medulla, apparently without supplying cortical cells en route, although they do supply cortical vessels. Most of the branches of the adrenal plexus, however, enter the gland through or near its hilum as compact bundles, some of which accompany the adrenal arteries. These bundles run through the cortex to the medulla, where they ramify profusely and mostly terminate in synaptic-type endings around the medullary chromaffin cells; some fibers invaginate but do not penetrate the plasma membranes of these cells. The preganglionic sympathetic fibers end directly around the medullary cells because these cells are derived from the sympathetic anlage and are the homologues of sympathetic ganglion cells. Other fibers innervate the adrenal vessels, including the central vein.

Catecholamines are released from the adrenal medullary and sympathoneuronal systems—both are key components of the fight-or-flight reaction. The signs and symptoms of the fight-or-flight reaction include cutaneous and systemic vasoconstriction with cold and clammy skin, anxiety, agitation, piloerection, tachycardia, dilated pupils, hyperventilation, hyperglycemia, decreased gastrointestinal motility, and decreased urinary output. This reaction is triggered by neural signals from several sites in the brain (e.g., the hypothalamus, pons, and medulla), leading to synapses on cell bodies in the intermediolateral cell columns of the thoracolumbar spinal cord. The preganglionic sympathetic nerves leave the spinal cord and synapse in paravertebral and preaortic ganglia of the sympathetic chain. Preganglionic axons from the lower thoracic and lumbar ganglia innervate the adrenal medulla via the splanchnic nerve and ramify about cells of the medulla. Acetylcholine is the neurotransmitter in the ganglia, and the postganglionic fiber releases norepinephrine. The chromaffin cell of the adrenal medulla is a “postganglionic fiber equivalent,” and its chemical transmitters are epinephrine and norepinephrine.

HISTOLOGY OF THE ADRENAL GLANDS

The adrenal glands are composed of two separate and distinct endocrine tissues—the adrenal cortex and the adrenal medulla—and each is entirely different in embryologic origin, structure, and function. In adults, the cortex comprises about 90% of the adrenal gland and completely surrounds the thin layer of centrally located medulla. In histologic sections, the cortex is seen to be composed mainly of radially oriented cords of cells. During embryogenesis, cells destined to form the medulla migrate through the cortex. At birth, in addition to a thin outer layer of permanent cortex, there is a thick band of fetal cortex, which soon involutes.

The cells of the adrenal cortex are typically epithelioid in appearance, with centrally placed nuclei having two or more prominent nucleoli. The cytoplasm features a variable abundance of lipid-containing vacuoles in addition to mitochondria and the Golgi apparatus.

In the adrenal cortex, three concentrically arranged cell layers, or zones, can be identified on the basis of the grouping of cells and the disposition of cell cords. In the thin outermost layer, the zona glomerulosa, the cells occur in arched loops or round balls. The middle layer, the zona fasciculata, is the widest of the three zones and is composed of cells arranged in long straight cords, or fascicles. The innermost layer, the zona reticularis, is contiguous with the medulla, and the cell cords are entwined, forming a reticulum. The two inner zones are entirely dependent on pituitary corticotropin (adrenocorticotropic hormone [ACTH]) secretion for the maintenance of their structure and function. However, the zona glomerulosa remains structurally and functionally normal in the absence of ACTH. Under normal conditions, the cortical cells at the inner border of the cortex have few lipid vacuoles and are referred to as compact cells , in contrast to the lipid-laden light cells that occupy the midportion of the cortex. Under ACTH stimulation, the layer of compact cells increases in width at the expense of the layer of light cells.

The zona glomerulosa is primarily responsible for the secretion of aldosterone, a mineralocorticoid having the prime function of regulating sodium and potassium balance. The function of the zona glomerulosa is essentially independent of that of the remainder of the cortex. The control of aldosterone secretion involves the renal juxtaglomerular apparatus and the renin–angiotensin system. The zona fasciculata and reticularis can best be regarded as a functional unit, having as its primary purpose the secretion of the glucocorticoid cortisol and some adrenal androgens. Cortisol has a prominent role in regulating the catabolism of protein, facilitating gluconeogenesis, and suppressing inflammation.

The adrenal gland receives blood from 30 to 50 small arteries that penetrate the capsule at different points and form the capsular plexus of arterioles. These supply the capillaries that extend radially through the cortex and separate the cords of cells. The adrenal medulla has both a venous and an arterial blood supply. Capillaries from the cortex extend into the medulla as venous capillaries; a few medullary arterioles extend through the cortex to form arterial capillaries in the medulla. Both categories of vessels join to form veins that drain through the single large central adrenal vein. The venous tributaries enter the latter between thick bands of smooth muscle, longitudinally disposed in its wall.

The adrenal medulla is composed of columnar cells that secrete the catecholamines epinephrine, norepinephrine, and dopamine. Because the catecholamines are readily darkened by the oxidizing agent potassium dichromate, the medulla is often referred to as chromaffin tissue . Preganglionic sympathetic fibers enter the medulla and terminate directly on the parenchymal cells or scattered sympathetic ganglion cells.

BIOSYNTHESIS AND METABOLISM OF ADRENAL CORTICAL HORMONES

The steroids produced by the adrenal cortex include glucocorticoids, mineralocorticoids, adrenal androgens (17-ketosteroids), estrogens, and progestogens. Although some steroids are highly potent biologically, others are relatively inactive. Whereas the secretory activity and growth of the zona fasciculata and zona reticularis of the adrenal cortex are regulated by the pituitary secretion of corticotropin (adrenocorticotropic hormone [ACTH]), the secretion of aldosterone from the zona glomerulosa of the adrenal cortex is regulated by angiotensin II, potassium, and (to a lesser extent) ACTH. ACTH is released from pituitary corticotrophs on the basis of feedback regulation—if there is a decrease in the blood cortisol concentration, pulsatile corticotropin-releasing hormone (CRH) and ACTH secretion increase and raise the cortisol level again, which in turn inhibits further CRH and ACTH release. The hypothalamic–pituitary–adrenal axis feedback control is accompanied by a diurnal variation in ACTH secretion. The ACTH pulse frequency and amplitude are maximal between 2 and 8 am. After 8 am, there is a gradual daytime decrease in ACTH and cortisol secretion, reaching a nadir in the late evening hours. The circadian rhythm is dependent on both sleep–wake and day–night patterns. With overseas travel, it may take 10 to 14 days for the circadian rhythm to reset to the new time zone.

The diurnal rhythm in cortisol secretion is abolished in individuals with Cushing syndrome, whether the syndrome is caused by a primary adrenal tumor, eutopic ACTH, or ectopic ACTH hypersecretion. The feedback inhibition of ACTH by cortisol may be interrupted at any time by an overriding mechanism (e.g., stress). Stressful stimuli (e.g., fever, trauma, hypoglycemia, hypotension) reaching the cerebral cortex release the inhibition of the reticular formation or of the limbic system on hypothalamic centers in and around the tuberoinfundibular nucleus and the median eminence. Large neurons then secrete hypothalamic CRH. Vasopressin also has an ACTH-releasing effect. The proinflammatory cytokines (e.g., interleukins) increase ACTH secretion either directly or by augmenting CRH secretion. The greater the stress, the more ACTH is secreted. The upper secretory limit of endogenous cortisol is approximately 250 mg/d.

Cholesterol derived from acetate is stored in the adrenal cortex. Its cyclopentanophenanthrene 4-ring hydrocarbon nucleus (3 cyclohexane rings and a single cyclopentane ring) is modified by enzymes that induce hydroxyl groups into the ring (hydroxylases), but other enzymes (dehydrogenases) may remove hydrogen from a hydroxyl group, and others (oxidases) remove hydrogen from a CH group. Chemical structure determines function; for example, glucocorticoids are distinguished by an α-ketol group and an 11-hydroxyl group. Cleaving cholesterol into pregnenolone (the C21 precursor of all active steroid hormones) and isocaproaldehyde is the critical first step and occurs in a limited number of sites in the body (e.g., adrenal cortex, testicular Leydig cells, ovarian theca cells, trophoblast cells of the placenta, and certain glial and neuronal cells of the brain). The roles of different steroidogenic tissues are determined by how this process is regulated and in how pregnenolone is subsequently metabolized. Most of the steroidogenic enzymes are unidirectional, so the accumulation of product does not drive flux back to the substrate. In addition, whereas the P450-mediated hydroxylations and carbon–carbon bond cleavage reactions are irreversible, the hydroxysteroid dehydrogenase reactions are reversible. Glucocorticoids and progestogens have 21 carbon atoms (C21 steroids), androgens have 19 carbon atoms (C19 steroids), and estrogens have 18 carbon atoms (C18 steroids).

The steroidogenic acute regulatory protein (StAR) mobilizes cholesterol from the outer mitochondrial membrane to the inner mitochondrial membrane, where the rate-limiting steroid side-chain cleavage enzyme (P450scc) cleaves cholesterol to pregnenolone. StAR is induced by an increase in intracellular cyclic adenosine monophosphate (cAMP) after receptor activation by ACTH. P450scc and the CYP11B enzymes (11β-hydroxylase and aldosterone synthase) are mitochondrial enzymes and require an electron shuttle system (adrenodoxin/adrenodoxin reductase) to oxidize steroids, whereas 17α-hydroxylase and 21-hydroxylase are located in the endoplasmic reticulum, and electron transfer is accomplished from nicotinamide adenine dinucleotide phosphate by the enzyme P450 oxidoreductase (P450 OR). Finally, the 17,20-lyase activity of P450 CYP17 requires flavoprotein b5 that functions as an allosteric facilitator of the CYP17 and P450 OR interaction.

In the cytoplasm, pregnenolone is converted to progesterone by 3β-hydroxysteroid dehydrogenase (3β-HSD) by a reaction involving dehydrogenation of the 3-hydroxyl group and isomerization of the double bond at C5. Progesterone is hydroxylated to 17-hydroxyprogesterone through the activity of 17α-hydroxylase (P450c17). 17-Hydroxylation is a prerequisite for glucocorticoid synthesis (the zona glomerulosa does not express P450c17). P450c17 also possesses 17,20-lyase activity, which results in the production of the C19 adrenal androgens (dehydroepiandrosterone [DHEA] and androstenedione). Most of the adrenal androstenedione production is dependent on the conversion of dehydroepiandrosterone to androstenedione by 3β-HSD. 21-Hydroxylation of either progesterone in the zona glomerulosa or 17-hydroxyprogesterone (zona fasciculata) is performed by 21-hydroxylase (P450c21) to yield deoxycorticosterone or 11-deoxycortisol, respectively. The final step in cortisol biosynthesis—the conversion of 11-deoxycortisol to cortisol by 11β-hydroxylase (P450c11β)—takes place in the mitochondria. In the zona glomerulosa, P450c11β and aldosterone synthase (P450c11AS) convert deoxycorticosterone to corticosterone. P450c11AS is also required for the 18-hydroxylation and 18-methyloxidation steps to convert corticosterone to aldosterone via the intermediate 18-hydroxycorticosterone. Whereas aldosterone secretion is confined to the zona glomerulosa through the restricted expression of CYP11B2 , the zona glomerulosa cannot synthesize cortisol because it does not express CYP17 . In the zona reticularis, high levels of cytochrome b5 facilitate 17,20-lyase activity on P450c17, and the production of DHEA. DHEA is either converted to androstenedione by 3β-HSD or sulfated in the zona reticularis by the DHEA sulfotransferase ( SULT2A1 ) to form DHEA sulfate (DHEA-S). Androstenedione may be converted to testosterone by 17β-ketosteroid reductase (17β-HSD3) in the adrenal glands or gonads.

Under normal conditions, 10 to 20 mg of cortisol and 0.1 to 0.15 mg of aldosterone are secreted over 24 hours. The adult adrenal gland secretes approximately 4 mg of DHEA, 10 mg of DHEA-S, 1.5 mg of androstenedione, and 0.05 mg of testosterone over 24 hours. However, testosterone has 60 times the androgenic potency of even the most potent 17-ketosteroid (characterized by an oxygen atom in the 17 position). The adrenal androgens supply approximately 50% of circulating androgens in premenopausal women. The adrenal glands secrete small amounts of estradiol (derived from testosterone) and estrone (derived from androstenedione); both become important after menopause when the adrenal glands are the only source of estrogens in women.

Approximately 90% of cortisol in the plasma is bound, primarily by cortisol-binding globulin (CBG) and to a lesser extent by albumin. The hepatic production of CBG is increased in patients taking orally administered estrogen (e.g., oral contraceptive pill or postmenopausal estrogen replacement therapy), in pregnant women, and in patients with active hepatitis. Blood CBG concentrations are decreased in patients with cirrhosis, nephrotic syndrome, multiple myeloma, or hyperthyroidism. When cortisol is measured in the blood, it is the sum of the bound and free forms; thus, the CBG concentration has a substantial effect on the measured level of cortisol, appearing high in patients taking oral estrogen and low in patients with low CBG concentrations. In these settings, the clinician can measure the unbound or free cortisol concentration in the blood or the excretion of free cortisol through the kidneys, termed urinary free cortisol (which represents approximately 1% of the total cortisol secretion rate).

The circulating half-life of cortisol varies between 60 and 120 minutes. The interconversion of cortisol and cortisone via 11β-hydroxysteroid dehydrogenase (11β-HSD) regulates local corticosteroid hormone action. There are 2 distinct 11β-HSD isozymes: type 1 (11β-HSD1) is expressed primarily in the liver and converts cortisone to cortisol; type 2 (11β-HSD2) is found near the mineralocorticoid receptor in the kidney, colon, and salivary glands and inactivates cortisol to cortisone. Apparent mineralocorticoid excess is the result of impaired 11β-HSD2 activity. Cortisol can be a potent mineralocorticoid, and as a result of the enzyme deficiency, high levels of cortisol accumulate in the kidney. Thus, 11β-HSD2 normally excludes physiologic glucocorticoids from the nonselective mineralocorticoid receptor by converting them to the inactive 11-keto compound, cortisone. Decreased 11β-HSD2 activity may be hereditary or secondary to pharmacologic inhibition of enzyme activity by glycyrrhizic acid, the active principle of licorice root ( Glycyrrhiza glabra ). The clinical phenotype of patients with apparent mineralocorticoid excess includes hypertension, hypokalemia, metabolic alkalosis, low plasma renin activity, low plasma aldosterone concentration, and normal plasma cortisol levels. The diagnosis is confirmed by demonstrating an abnormal ratio of cortisol to cortisone (e.g., >10 : 1) in a 24-hour urine collection. The apparent mineralocorticoid excess state caused by ectopic ACTH secretion, commonly seen in patients with Cushing syndrome, is related to the high rates of cortisol production that overwhelm 11β-HSD2 activity.

The usual level of cortisone in the urine is approximately two- to threefold higher than the level of cortisol. The subsequent metabolism of cortisol and cortisone then follows similar pathways with reduction of the C4–5 double bond to form dihydrocortisol or dihydrocortisone followed by a hydroxylation step to form tetrahydrocortisol and tetrahydrocortisone, which are rapidly conjugated with glucuronic acid and excreted in the urine. Thus, primary sites of cortisol metabolism are the liver and kidney.

Aldosterone is also metabolized in the liver, where it undergoes tetrahydro reduction and is excreted by the kidneys as 3-glucuronide tetrahydroaldosterone; 20 to 30 μg of this conjugate is excreted daily in the urine. In addition, 5 to 15 μg per day of the aldosterone 3-oxoglucuronic acid conjugate is found in the urine as hydrolyzable aldosterone. A much smaller fraction of aldosterone (1–5 μg) appears in the urine in the free form.

THE BIOLOGIC ACTIONS OF CORTISOL

CARBOHYDRATE, PROTEIN, AND LIPID METABOLISM

Because of their actions on glycogen, protein, and lipid metabolism, glucocorticoids increase blood glucose concentrations. Glucocorticoids stimulate glycogen deposition in the liver by inhibiting the glycogen-mobilizing enzyme (glycogen phosphorylase) and by increasing glycogen synthase. They increase hepatic glucose output by activation of the gluconeogenic enzymes (glucose-6-phosphatase and phosphoenolpyruvate kinase). Lipolysis is activated in adipose tissue, increasing blood free fatty acid concentrations. Because of their enhancing and synergistic effects on the actions of other hormones (e.g., glucagon and catecholamines), increased glucocorticoid concentrations cause insulin resistance and an increased blood glucose concentration. Thus, over the short term, glucocorticoids support stress responses that require glucose for rapid and intense exertion. With long-term excess, glucocorticoids are diabetogenic. In addition, there is enhanced adipogenesis, especially in the visceral or central adipose tissue depots (centripetal distribution).

BLOOD PRESSURE CONTROL

Glucocorticoids increase glomerular filtration rate, proximal tubular epithelial sodium transport, and free water clearance. Excess glucocorticoids can overwhelm renal 11β-hydroxysteroid dehydrogenase isozyme type 2 (11β-HSD2), allowing access of cortisol to the mineralocorticoid receptor (see Plates 3-6 and 3-7 ) and resulting in renal sodium retention and potassium loss. Under normal physiologic conditions, glucocorticoids increase sensitivity to pressor agents such as catecholamines and angiotensin II in vascular smooth muscle. In addition, the synthesis of angiotensinogen is increased by glucocorticoids.

CUSHING SYNDROME—CLINICAL FINDINGS

Cushing syndrome is a symptom complex that results from prolonged exposure to supraphysiologic concentrations of glucocorticoids. The most common cause of Cushing syndrome is the use of synthetic glucocorticoids to treat an inflammatory condition, termed exogenous or iatrogenic Cushing syndrome . Endogenous or spontaneous Cushing syndrome is rare and is caused by hypersecretion of corticotropin (adrenocorticotropic hormone [ACTH]) (ACTH-dependent Cushing syndrome) or by primary adrenal hypersecretion of glucocorticoids (ACTH-independent Cushing syndrome).

Although Cushing syndrome is not common, the clinical features of hypercortisolism are common. The clinician's role is to (1) recognize Cushing syndrome, (2) confirm endogenous Cushing syndrome with biochemical tests, (3) determine the cause of Cushing syndrome, and (4) provide a definitive cure.

Typical signs and symptoms of Cushing syndrome include weight gain with central (centripetal) obesity; facial rounding with fat deposition in the temporal fossae and cheeks (“moon face”) and plethora; supraclavicular fat pads; dorsocervical fat pad (“buffalo hump”); easy (“spontaneous”) bruising (ecchymoses); fine “cigarette paper–thin skin” (subcutaneous blood vessels can be seen) that tears easily; poor wound healing; red-purple striae (usually >1 cm in diameter located over the abdomen, flanks, axilla, breasts, hips, and inner thighs); hyperpigmentation over the extensor surfaces and palmar creases (typically only apparent with markedly increased levels of ACTH); scalp hair thinning; proximal muscle weakness associated with muscle loss and resulting in thin extremities; emotional and cognitive changes (e.g., irritability, crying, depression, insomnia, restlessness); hirsutism and hyperandrogenism (e.g., acne); hypertension; osteopenia and osteoporosis with vertebral compression fractures; low back pain (associated with vertebral compression fractures, muscle wasting, and lordotic posture from abdominal weight gain); renal lithiasis; glucose intolerance and diabetes mellitus (caused by glucocorticoid-induced gluconeogenesis and peripheral insulin resistance from increased body fat); polyuria; hyperlipidemia; opportunistic and fungal infections (e.g., mucocutaneous candidiasis, tinea versicolor, pityriasis); menstrual dysfunction (oligomenorrhea or amenorrhea); and infertility. In addition to the preceding features, children with Cushing syndrome may present with generalized obesity and growth retardation.

The clinical features of Cushing syndrome may occur slowly over time; thus, comparison of the patient's current appearance with his or her appearance in old photographs is invaluable. Many of the signs and symptoms in the preceding text are common and are not distinguishing features (e.g., obesity, hypertension, abnormal glucose tolerance, menstrual dysfunction). Clinical suspicion for Cushing syndrome should increase with the simultaneous development of some of the more specific features (e.g., supraclavicular fat pads, wide purple striae, proximal muscle weakness). Because of the catabolic effect of glucocorticoids on skeletal muscle, most patients describe difficulty climbing stairs and an inability to rise from a seated position without using their arms. Cortisol has no androgenic activity, and the presence of hirsutism and acne depends on androgen excess, a finding more common in women with ACTH-dependent Cushing syndrome or adrenocortical carcinoma. The most common form of facial hair associated with Cushing syndrome in women is thin vellus hair over the sideburn area, cheeks, and upper lip. When Cushing syndrome is caused by an adrenal adenoma, it typically secretes only cortisol.

Standard laboratory studies may reveal fasting hyperglycemia, hyperlipidemia, hypokalemia (from glucocorticoid activity at the mineralocorticoid receptor), leukocytosis with relative lymphopenia, and albuminuria. Marked hypokalemia and severe hypertension are more common in persons with the more severe hypercortisolism of ectopic ACTH syndrome or adrenocortical carcinoma. When bone mineral density is measured, most patients with Cushing syndrome have osteoporosis. Causation is multifactorial and includes decreased intestinal calcium absorption, increased bone resorption, decreased bone formation, and decreased renal calcium reabsorption. These patients are also at increased risk for thrombophle-bitis and thromboembolic events. Untreated Cushing syndrome can be lethal.

TESTS USED IN THE DIAGNOSIS OF CUSHING SYNDROME

The evaluation of Cushing syndrome can be considered in three steps: (1) case-detection testing, (2) confirmatory testing, and (3) subtype testing.